By Yael Darr

This is a summary of the EDGE meeting in December 2021. In the first part of the meeting, Dr. Sabine Hannema interviewed the parents of a transgender child. According to the parents’ request, this part of the talk was not recorded.

In the second part, Professor Yael Darr talked about dwarfs and giants in the literature.

https://www.youtube.com/watch?v=ym5BwuL0zwI

Firstly, we need to think about dwarfs from a historical-cultural perspective. Prof Darr maps the 19th century as the time when stories about dwarfs rose. That was the time of the industrial revolution. Child labor was common during the early years of the Industrial Revolution. Trying to eliminate child labor, there was a debate about what is childhood? and what is adolescence? And what is the exact barrier between them? During the Victorian era in England the concept of childhood changed, lows were written about the age of consent for example. In 1875 the age of consent was 13 and it was changed to 16 years in 1885. This had an impact on the regulation of schools, working places, and very importantly the age of marriage and sex.

Dwarfs are little people but are not children. They do not have the traits that 19th-century romanticism gave children. Dwarfs are not necessarily cute they’re not necessarily nice. In a nutshell, I will discuss three classics that have small people as protagonists. The first one is Snow White and the Seven Dwarfs. Once it was published it became a canon It was first put on paper by the Brothers Grimm in 1812 although, of course, it was a folktale theme before.. Of note, the Brothers Grim collection was not written for children, rather they collected stories to write a history of old German poetry and to preserve history. Most of us are familiar with the Disney version of the story but the Brother Grimm’s version is dealing with the question of coming of age, and the dwarfs are not so important integral. In this version the dwarfs are men without sex, with no age, they are half old and half children, they do not have any romantic demands from snow white, they do not die, they are eternal/ essential children but they are not cute. In the Disney version, they have an important role, questioning the right way of a girl to become a woman. In 1937 snow white and the 7 dwarfs became the first full-length animated movie. In this version, the dwarfs are cute and childish, and snow-white is like a mother to them.

The second story is the Adventures of Alice in Wonderland. The story by Lewis Carroll, published in 1865, is a story about a child, who fluctuates with her height, and the attitude of all the surrounding creatures to these changes. Thus it is an example of how things change when you are a child or an adult, and what exactly makes the change; what is the threshold to maturity? Initially, Alice is cute and lovable and in the end, during her adventures, we change our feelings toward her. We do not know what to do with these phenomena of a growing child who becomes big or feels big and then being small. This is exactly what happens during adolescence. This is the way children and parents feel at the beginning of adolescence. Thus the fluctuation with height is not only with the protagonist but also with the readers. Lewis Carroll was the pen name of Charles Lutwidge Dodgson. The story was written to Alice Liddell, the daughter of his friend. The book is so complex that no child can read it, so it is again a game of “heights”.

The third book is Peter Pan by James Matthew Berry, published in 1911, but is considered part of the 19th century. Peter Pan is a child who refused to grow and in this respect is very different. While things happen to Alice and she could do nothing about it, Peter Pan simply refuses to grow and raises the question on eternal childhood but also at the same time on death. James Barrie was six years old when his elder brother died in an accident at age 14 years. His mother never recovered and was deeply depressed. It is suggested that J. M. Barrie may have based the character of Peter Pan on his older brother, as his mother and brother thought of him as forever a boy. Of note, Peter Pan is not a lovable child, he is resentful and obnoxious. Its character is very different from the way we see it in the 21st century as a metaphor of eternal youth. This is another example of a text for children that in fact, its first version was a play that was on stage in 1904 several years before the book was published. It is different from a Bildungsroman, which is about a young person who grows and eventually integrate into society. This is a story about an orphans who does not have a real place in society and lives out in Neverland somewhere. In that respect, it is a very disturbing story.

In summary, we had dwarfs as little men but without masculinity and no age, we have a girl who is not a girl because she changes all the time, and a boy who refused to grow and is partly dead, he is not part of time and space. These examples were both threatening but also very interesting to the 19th-century’s readers because they made them think and rethink about modern childhood and maybe modern adolescence, and because through them, one can reassure the new concepts of the modern child that was so important in the 19th century. We can think, why is it that in the 20th century, we needed to make all these three examples much more likable and all these small people resemble children and resemble and evoke the feelings we feel towards children. We took away the ambivalent feelings that the little people evoked in the 19th-century stories.

Orit Hamiel

Some points were highlighted during the conversation

• While in tales of the 15- 16th century society, most people were very short, and, most people didn’t live that long, the problem that we are facing as doctors in the 21st century did not exist in the past. This may explain why we have so many kinds of dwarfs or short people throughout the centuries. Currently, we are much more open to thinking about short stature as a handicap, and trying to correct it.
• Physically the timing of puberty was much later in the 19th century than it is today, (average age even up to 17-18 plus the standard deviation the variation was much larger than it is today, many people, did not mature till the early 20s), however, there were so many orphan children, with no family and no parents to take care of them, that emotionally and socially they became grown up in a very early age. The fact that the rules of childhood and adolescence were defined at that time, may explain, why so many stories were written at that period because these ideas were just crystallizing and were not so clear-cut as they are today.
• The 20th-century reinvention by Disney may portray the seven dwarfs as adults, they all have beards they’re clearly childish so they are like a combination. It is possible that in the 20th century we clearly portray them as grown-up vs children, whereas before maybe there it was less distinguished. Today, we know exactly what a child is but before it was much more amorphous.
• Our dichotomy between being a child and being an adult may also have changed, perhaps we are more open-minded enabling children to be grownups a little bit and definitely for grownups to be infantile sometimes. In our times this clear-cut notion of ages is changing.
• In many children’s books, they use a giant and dwarf to educate children to be kind to the small ones, and then. For example, the story about The Lion and the Mouse by Aesop shows that even the little ones can help the big ones, so the giants need to be kind to the small ones, and vice versa. Indeed children are small people as we say and they are the most important things in our life, but in fact, we control their lives from morning to night. Thus, the good stories about dwarfs or little animals enable them, to feel big and for at least five minutes or 10 minutes of the story, they feel empathy towards someone smaller than them. This is the role of all the pets that we find so many times in children’s stories
• Interestingly whereas transgender people are now accepted in society, small people still get an injection to grow bigger, whether you like it or not, it is terrible they have to be treated and we do not need to ask the consent of the child before.
• Environment and gender. It was emphasized that height is a cultural thing. A height that will be acceptable in Israel may be a problem in the Netherlands. Not only short stature is being perceived as a handicap, but people also ask to limit their height. So, it is not the actual height rather being like the others. There is also a matter of gender; for boys, it’s much more important to be taller than for girls, and vice versa, for girls it’s harder to be very tall.
• It was noted that in young adulthood these problems are generally over, studies show that short adults are happy people.
• Also it was noted that there is an impact of the formative years, ie. If one was always the shortest or just stopped growing early and thus has a notion of himself as a normal person despite being short.

 

Prof. Yael Darr is chair of the Master’s Program in the Research of Child and Youth Culture at Tel-Aviv University. Her research focuses on children’s culture in general and children’s literature in particular during the Jewish nation-building period in pre-state Palestine and the first decades of Israeli statehood. https://english.tau.ac.il/profile/yaelda

 

Dr Sabine Hannema is paediatric endocrinologist at the Centre for Atypical Sex and Gender Development at Amsterdam UMC since 2020. She is a board member of the Center of Expertise on Gender Dysphoria. Previously she was the endocrine lead of the gender clinic at Leiden University Medical Centre and worked in the DSD team at Erasmus University Medical Centre, Rotterdam. Her main areas of interest are DSD and transgender care.

Francis McGlone from Liverpool and Orit Pinhas-Hamiel from Tel Aviv
are conversing about

Touch; Appetite and Obesity

 

The conversation is available at the following link.

https://youtu.be/KiUHZSxVGkQ

 

A live conversation between

Paul Saenger New York, NY, USA

And, Cheri Deal, Montreal, Canada

With a comment by Ze’ev Hochberg

October 17, 2020

Cheri Deal: I’m going to introduce you, Paul Saenger. Although everyone knows you I’ll start by saying that you actually graduated from medical school in Munich and came to the US in 1969 where you worked at the Montefiore Medical Center. You did a fellowship with Maria new at Cornell and then for 30 years worked at the amount of your medical center and Albert Einstein College of Medicine. You cite having trained 50 fellows. And you mentioned also that you were president of LWPES (as PES was called once upon a time) in 2004 as well as President of the ninth joint meeting of LWPES, SLEP and ESPE welcoming 4000 delegates in 2009 in New York City. You were a visiting professor in both the Munich medical school and the Beijing Children’s Hospital. For the past 10 years you’ve been at the NYU Langone Health—Long Island in Mineola, New York.

Paul Saenger: Burden of treatment is defined as the impact of the work of being a patient   or the parent of a patient on functioning and wellbeing. It is most often associated with chronic conditions. 45 % of people have a chronic condition.  Burden of treatment is therefore very common.

In pediatric endocrinology burden of treatment is particularly common in:

• Type 1 and 2 Diabetes mellitus. Dexcom (Continuous Glucose Monitor) and closed loop systems diminish burden somewhat.
• Congenital adrenal hyperplasia: longer acting glucocorticoids may help
• Thyroid adherence to drug therapy is the major burden here and adherence diminishes in adolescence
• Novel drug therapy may help somewhat. Bypass surgery is helpful but carries an enormous burden of treatment after the procedure
• Hypogonadism, precocious Puberty: Longer acting GnRH inhibitors are helpful, new testosterone formulations allow self-injection.
• Growth disorders: Long acting growth hormone will be a new formulation touted to reduce treatment burden. Data to document that claim are not yet available. It will help to reduce treatment burden as growth hormone will only be injected once a week.

The   idea that illness sometimes involves hard and heavy work is not a new one. Patients with a chronic illness exhibit illness trajectories and help-seeking behaviors that health care providers   and policymakers perceive as costly and complex.

The emergence of the chronic patient has been seen in terms of symptom burdens, first conditions and then in the context of    multi-morbid conditions. The burdens of treatment itself as they engage with services, insurance companies, drug companies, clinicians, administrators, social workers aim at conditions that unfortunately cannot be cured but must instead be managed. This division over time, between  curative  effort applied to episodes of acute illness and injury (in hospital)  and the efforts  devoted to the management of life time illness trajectories (mainly  as  outpatients  has  profoundly  changed  the nature of patient hood   and  health care  providers). Endocrine care is not taking care of an appendicitis or an undescended testicle, it is chronic care. Parents and child have to do  treatment  work,  this  adding  the burden of  treatment to  the  burden of  symptoms   as  parents  and  patients confront  new  and  growing  demands to organize and coordinate their own care, to comply with complex treatment and self-monitoring regimens and to meet a whole range of expectations of  personal motivation, expertise and self -care.

As burdens accumulate and some groups of patients and parents are overwhelmed the consequences are likely to be poor healthcare outcomes increasing strain on care givers and rising demands and costs of health services. (Carl R May et al Rethinking the patient: using burden of treatment theory to understand the changing dynamics of illness BMC Health Services Research 2014 1428100).

Particularly important is treatment burden in adolescence where the treating physician will encounter major nonadherence to therapy and the keeping of appointments.

How can we address adherence to treatment a major aspect of treatment burden? (see Blaschke T and L Ostertag, NEJM  2005 353 :487-97).

Adherence is the preferred term because compliance suggests that the patient is passively following the doctors’ orders and that the treatment plan is not based on a therapeutic alliance or contract between   patient and physician. Achieving full adherence in pediatric patients requires not only the child’s cooperation but also a devoted, persistent, and adherent care giver. Adolescent patients create even more challenges, given the ubique developmental, psychosocial, and lifestyle issues implicit of adolescence. An added dimension of the situation is the involvement of the patient’s families. Rates of adherence to medication regimens among children with chronic conditions are similar to those among adults, averaging about 50 % with decrements occurring over time.

To improve adherence several strategies have been developed. One is use of medications with long half-lives (e.g. for precocious puberty, depot or extended release medications such as long acting growth hormone, transdermal preparations such as an estrogen patch for transexual or Turner patients).

Adherence is very variable over time with a steady decline with years of treatment, age.  Year 1 and 2 always report excellent adherence (see also M Brod et al Understanding treatment burden for children treated for GH deficiency   Patient 2017 10 653-666.)

Growth hormone deficiency

GH deficiency has a frequency of about 1: 3 500.  In 2003 the US FDA approved idiopathic short stature    defined as a height of below -2.25 SD ( Below 1^st percentile in height). The potential patient number jumped from 2100 suddenly to 1.2 % of US pediatric population that is 890000 potential patients who were meeting these criteria.

Idiopathic short stature was the first indication that emphasized height rather than underlying pathology as the qualifying criterion for treatment. This was blurring the boundary between disease and variation of normal- as an example of expansive biotechnology (Ada Grimberg et al, J of the Endocrine Society  2019;3(11):2023).

What is the burden of growth hormone deficiency?

Symptoms related:

Problems reaching things

Reduced performance in sports, physical aspects concerning also care givers

Reduced endurance

Reduced sleep

Poor appetite

Smallest among peers, concerning especially parents

Social /emotional wellbeing domain:

Worries about growing

Hurt feelings

Worries about being different

Bothered by size

Social unease, not fitting in

Teasing or being bullied

Mistaken for being younger

Parents worried about side effects

Administration burden of GH

Daily injections

Worrying when travelling

Worrying about storage and keeping supplies

According to F Haverkamp (Haverkamp F et al Clin Ther 2008 30 :307-16) the following factors might affect adherence:

Patient related actors:  Forgetfulness, other priorities, underestimating the disease

Treatment related factors: Frequent dosing, daily injections associated with pain

Health Care related factors (affecting especially parents): Shipping of GH, Insurance denials, Co Pay

Physician related factors:  Communication skills, medical competency, providing medical information.

Nonadherence with GH therapy is therefore common and is associated with reduced growth

Duration of GH therapy is negatively related to adherence. Other important factors are: age, convenience of an injection device, level of education, awareness of consequences of therapy.

Poor adherence has been studied and published for New Zealand, US and Spain showing that poor to moderate adherence leads to impaired growth velocity and lower IGF-1 levels. (De Pedro S et al Growth Hormone IGF Res. 2016 26:32-35, Cutfield WS et al, PLoS one 20;6e:16223   Bagnasco B et al, Endocrine Practice  2017;23:929-41)

US data show that only 20 % of pediatric patients initiated in 1997- 2001 remained on treatment after 4 years (Unpubl data, 2006. Genentech Rosenfeld R, Bakker B, Endocrine Practice 2008 vol 14,No  2).  Adherence of treatment is an extremely important variable that is difficult to assess reliably.

Recently a drug Vosoritide, a biological analogue of C-type natriuretic peptide (Savairayan R et  al, Lancet 396 Sep5, 2020), is being explored for this chronic, daily treatment a achondroplasia. In this disease entity, lack of interest in parents for using this chronic treatment in their children has been recognized. Particularly  parents  who  are  themselves achondroplastic ( about  20  % of  all  achondroplastic  patients have parents with achondroplasia) are much less interested in treating their  affected child because they feel the height improvement is minimal and the treatment lasts from infancy  to adolescence with small improvements in final height  (less than 1SD). Parents have “dwarf pride” and don’t want to subject their children to this treatment (NYT   Sept 7, 2020 page A11).

A more forgiving treatment using long acting Vosoritide may be more acceptable to parents and patients   in this condition as well.

In summary since most endocrine diseases are chronic treatment burden is high and it is measurable.  One of the approaches utilized in Pediatric Endocrinology is less frequent dosing which reduces treatment burden. Whether it will improve adherence and/or outcomes such as height has not been shown to date. This will hopefully lead to clinical studies after approval of the novel therapy with long acting growth hormone.

Recognized parent treatment burdens are   emotional wellbeing and interference. Treatment interfered with overnight sleepovers or other travel activities. We must recognize that daily injections are disruptive Long acting growth hormone may diminish these disruptions. Treatment burden severity may be modified by the duration of treatment and treatment effectiveness.

Ze’ev Hochberg: In various parts of the world, the main burden of pediatric endocrine diseases is financial. When you sit it in a clinic in Africa or India or in many other countries, you have to think of the costs of a blood test or a prescription. Do you need to test both LH and FSH or one is enough? In developed country there is also the issue of cost, but the cost is covered by the society.

Deal: Yeah, I think that’s very true. So, what do you think, Paul?

Saenger: We can see it in countries where heightism is more prevalent – Asian countries. This economic gap is even more magnified and just because you said about FSH and LH. I know lots of colleagues in New York who insist on measuring free T3 and the reverse T3 because they didn’t know look at their lab manuals. I mean, talking about throwing money out the window. That’s what it is for the growth problems, I think, unless you want to re-educate the population.

 

 

 

 

A live conversation between

Cheri Deal, Montreal, Canada

And Paul Saenger, New York, NY, USA

October 17, 2020.

Comments by Lars Sävendahl, Ze’ev Hochberg. Harvey Guyda and Michael Ranke

Cheri Deal: According to the WHO European Health Information Gateway, the number of women of all ages in medicine has increased steadily in European countries since 1980 when the statistics became available.  Looking at the most recent mean data in 2014 for 27 countries of the EU, 52% of physicians are women (1).  This month in Academic Medicine, Pelley and Carnes published the data for the US physician workforce, which has gradually reached a steady state of near 50% (2).  In Canada, according to the CIHI (3), the number of female specialists has increased steadily from 9% in 1978; currently 54% of physicians under the age of 40 are women.  My graduating class in 1985 was the first class in Canadian medical schools to have an equal ratio of male and female students. While these data demonstrates an overall improvement for diversity with respect to gender, the statistics in the US and Canada for other minority groups are far less reassuring.

I will focus the talk today primarily on what this changing gender demographic means at several  levels, including gender segregation across specialties, evolution of pay scales as a function of gender, implications for the future endocrinology workforce, career trajectories particularly in academic medicine, and finally, what we know about  patient preferences and satisfaction.  I have based the observations that I will share with you today on a literature review and include pertinent articles in a reference list to the transcript of this discussion.  Most of the data comes from a North American context, some from the European context, and a bit from Asian countries.

Women and our Societies

Let’s start with a quick recap of the history of ESPE and LWPES/PES to see how women have contributed to these medical societies from the beginning.  I apologise in advance for not commenting on data from sister societies in other parts of the globe!  I invite readers from these societies to send in their comments to EDGE.

As I learned from reading Wolfgang Sippell’s excellent history of 50 years of ESPE (4), this society began as a club of 26 members, invited by Andrea Prader to a meeting in Zurich – at the time only 2 women were invited, and these happened to be Swiss colleagues of Dr. Prader.  The official birth of ESPE was in 1965, with the founding members now expanded to 30 but with only Ruth Illig from Switzerland representing the fair sex… As of 2020 there were 1332 members with roughly equal numbers of Males, Females and ‘undisclosed  gender’ (data obtained from ESPE office, courtesy of Anita Hokken-Koelega and Joanne Fox-Evens).   This makes it difficult to track gender-specific data, although I suppose it is being done in a conscious effort to show that we no longer think of the world in a binary fashion.  I was unable to find the gender distribution for past ESPE Secretary Generals on the ESPE website, but looking at the ESPE Annual Meetings since 1990, it is only more recently that there are two Presidents of each meeting, one male and one female, and I do not have the statistics.  This said, 4 of the current 10 ESPE Council members are women, including Anita Hoeken-Koelega, the Secretary General.

LWPES, later the PES, was founded in the early 70s by Robert Blizzard and Claude Migeon, but I could not find a list of the names of the founding members.  Del Fisher’s 2004 ‘Short History of Ped Endo in North America’ (5) does name the early presidents: from 1972 to 1988, there were 4 women (13%), but in the last 18 years, 50% of PES Presidents have been women. Membership now tops 1300 and is probably close to 45% female – I was unable to obtain the current gender breakdown from PES.

How are Academic Female Pediatric Endocrinologists doing in ESPE and PES?

One of the ways we can follow the impact of the feminisation on career progression of women pediatric endocrinologists is to look at the proportion of women receiving awards.  An indicator of the health of our specialty will be to see the number of female awardees rise with the numbers of women members. I looked at the previous winners of the ESPE Andrea Prader Prize for career contributions over the period of 1988-2019 and noted 4 women (8% of the awards), but in last 8 years this has climbed to 25% .  Turning to the ESPE Young Investigator Award Winners from 1993-2019 – there were 18 women/38 total awards with equal distributions in first and second half of this time period (47%).  Interestingly, in the 10 years where two awards were given, only once was it not to both a man and a woman (most recently, in 2018, it was given to 2 women).

PES has awarded 14 Jud Van Wyk Prizes for career achievements between 2006-2019, with only 1 woman, Maria New, granted this prestigious award.  Of the 67 LWPES/PES Clinical Scholar Awards for Junior investigators (from 1987-2019), 44% of the first 32 awards went to women.  Considering only the more recent 37 awards, 65% of these awards went to women.

From the ESPE and the PES data, it is clear that young female endocrinologists are being recognised for their career potential but it remains to be seen if they will persist in their career aspirations and be judged as worthy of our Societies highest honours in the near future.

How does Pediatric Endocrinology compare to other specialty and subspecialty training with respect to gender ratios?

Over the last 2 decades, specialty choices have remained consistent according to the AMA data of 2019, with the highest numbers of FEMALE trainees going into ObGyn (83%), Allergy and immunology (73.5%), Pediatrics (72%), Medical genetics and genomics (67%), Hospice and palliative medicine (66%), and Dermatology (60%).  As we have seen in the past as well, MALE physicians heavily dominate the surgical specialties and radiology.  When the salary is plotted against the female share of the specialty, two things need mentioning: first, there is a strong negative correlation between earnings and the % of females in the workforce, explaining 64% of the variation in salaries and, secondly, Pediatrics and Endocrinology (along with Psychiatry and Family Medicine) received the lowest salaries of the 35 medical specialties shown (2).

Data from an Endocrine Society White Paper in 2014 (6) showed that the adult US physician workforce in 2011 consisted of about 38% women board-certified in Adult Endocrinology. Board certified Pediatric Endocrinologists were comprised of 51% women.   US training programs, however, between 2010 – 2014 showed that between 65% and 75% of Endocrine trainees were female (7).  Our Canadian workforce data (CAPER)  for Pediatric Endocrine trainees (excluding visa trainees) between 2015 and 2019 gives a consistent female predominance reaching over 80% with only slightly less female trainees (but over 70%) in Adult Endocrinology (8).

Katai et al and The Japan Endocrine Society Women Endocrinologists Associations noted in their 2019 report in the Endocrine Journal that Japan has the lowest number of women medical doctors (21%) of all OECD countries. However, among the youngest physician population of Japanese Endocrinologists (under age 40), this has now reached almost 50% (9). This is an example of an international gender trend that is touching even the more conservative countries with regards to supporting women in the medical workforce, specifically in Endocrinology.

Elaine Pelley, a U.S. Endocrinologist, had previously warned about the impact of the gender shift on the future of Endocrinology in a special feature article in JCEM, 2016, based on a non-systematic literature review and access to workforce statistics from various sources (10).  The main message of Pelley and colleagues to the community of adult endocrinologists was that, at least for the period from 2010 to 2014, the total number of applicants to endocrine fellowships fell , but principally because of a drop in the number of MALE applicants, contributing to the projected adult endocrinologist shortage also documented by an Endocrine Society workforce report in the same year.  This occupational segregation,  where there was also a documented  gender annual pay gap of between 38,000 and 66,000$ per year, would be expected to lead to further declines in male applicants since male physicians prefer higher-paying specialties, even upon entrance to medical school according to data in the literature.  If you would like to hear Dr. Pelley interviewed by Toni Gallo, listen to this recent Podcast (Gender segregation by specialty in medicine. Academic Medicine Podcast. https://podcasts.apple.com/us/podcast/gender-segregation-by-specialty-in-medicine/id1112697692?i=1000488347677 )

The Cost of Caring – Why do salaries drop when women enter a profession?

The observation that there is a gender-based salary inequity is not new; it has been demonstrated not only across occupations, but also throughout history.  Consider, for instance that secretaries were traditionally male and as a profession, it carried a very high status and an excellent remuneration.  This was true throughout history until the 1880’s, and coincided with the advent of the typewriter where women’s skills were found more valuable – particularly their manual dexterity.  Teaching became another preferred female profession only in the late 19^th century, in part because they could be paid less than males and in part because with the advent of male-populated school boards who deemed women would be more compliant with authority and with rules.

‘Caring work’, such as child care, teaching, physical and psychological therapy and nursing, has drawn more women than men since women entered the labor force. Caring work, according to England and Folbre (11) involves providing face to face work, a relationship with the person receiving the service, a certain degree of altruism on behalf of the caregiver, and a belief that the personal rewards in terms of job satisfaction cannot be ‘priced’.  Caring labor has been culturally devalued, since the implicit bias in our western culture is that the skills required are 1) those of a woman and mother, 2) are biologically based and come naturally and 3) occur regardless of the degree of education required for the job.  Caring professions have been termed the ‘sacred cow’ because to ‘commodify’ love and care seems offensive.  As England and Flobre conclude – the principle that money cannot buy love and caring may have the unintended and perverse consequence of perpetuating low pay for caring work.

This seems to be the case for physicians in the most ‘caring’ specialties, classically, Pediatrics and ObGyn.  And, as I previously stated, these are two of the most feminised specialties, with Pediatrics being the least well remunerated and ObGyn also at the lower end of the pay scale despite being a technique and surgery-oriented specialty. Will this feminisation see the salaries of Pediatric Endocrinologists fall as well, as governments seek to curb health-care costs?  If so, this will potentially have implications for continuing to attract male candidates to our specialty.

Let’s get back to the GENDER PAY GAP:  What factors contribute to the gender pay gap in Academia (which continues to be worse than in other clinical settings)?

Several studies mostly from the UK and the US, and this summer from Canada (12) have shown a clear gender pay gap whether in clinical, research or teaching environments. Interestingly it persists after adjustment for factors like physician age, specialty, number of hours worked and type of practice.  Even in the UK, where there is not a fee-for-service model, NHS salaried female MD employees have consistently earned less per hour than their male colleagues (13).  Women are more likely to work part time, particularly during the time they are raising young children, and there is increasing acceptance of longer maternity leaves which in the past, were frowned upon.

According to some studies, the difference in income is most likely due to the type of work performed and the amount of time providing counselling and addressing psychosocial issues.  Visits may be longer, with less patients seen per hour. The completeness of history taking and clinical note taking has also been suggested to differ by gender although data is less available.  In one audit of clinical care in China published in the Lancet in 2018 (14), 309 primary care providers were audited for their adherence to check-lists based on international guidelines for 3 common clinical problems, in a standardised setting.  Female MDs completed 15% more of checklist items than male MDs, and were also 15% more likely to prescribe the correct treatment, however no comment was made concerning the length of the visits by gender.

In academic settings, data has also shown that women spend more time teaching and providing clinical care, and have less protected research time.  It is beyond the scope of our discussion to summarise all the data on Gender-Equity and progression in an academic careers, but it is clear that there are multiple factors contributing to gender bias and to the long-standing underrepresentation of women in major leadership positions and in tenured faculty positions. For those who wish to read further, there was a review of empirical data by Edmonds et al in the Lancet (15) looking at the question of why fewer women choose research careers, and 4 major and 4 minor themes were recurrent.  Many of these themes have continued to be researched.  For example, insufficient advocacy of women by their sponsors (16) and differential scoring of NIH or CIHR grant applications (17) have been shown to be contributing factors.  Lastly – Starmer and colleagues (18) used data from the American Academy of Pediatrics Pediatrician Life and Career Experience study, based on questionnaires answered by 1300 participants.  A significantly greater number of male pediatricians still had stay-at-home partners and married women pediatricians do proportionately more of household and childcare related chores (and also have a higher divorce rate, in passing).  Even if they are able to maintain a high-powered career, concerns about female physician burn-out are discussed in most academic centers, and it is a growing concern as the physician work-force becomes feminised.

In particular, the current COVID-19 Pandemic has already proven to weigh more heavily on female healthcare providers as discussed by Jones and colleagues this summer (19).  They noted that women are more likely to be in the ‘frontline’ clinical positions AND less well represented in leadership positions where they can impact on decision-making, thus they are more exposed to feelings of powerlessness.  Increasing demands at home because of school closures and care of elderly parents who may also be sick can add to the workload of female physicians.  Competition between spouses for ‘work-time’ can add stress to the couple, and guilt that physicians may be exposing their own families to risk is also frequently voiced.  Jones et al offer recommendations to monitor and help offset this collateral damage to colleagues, including understanding the potential decline in research productivity while recognising institutional contributions and seeking to fairly compensate physicians, male and female, for increased work demands during the pandemic.

My concerns from reading much of this data is whether or not we can encourage and nurture an increasingly feminised workforce to pursue a life-long career in Pediatric Endocrinology.  If we fail to do this, will we see a decline in the historic trend of significant academic and research contributions to the field of Pediatric Endocrinology in the future?

Endocrinology and Projected Workforce Needs

You may have seen the special commentary published by Robert Vigersky in JCEM in 2014 (20), giving the projections of supply and demand considerations of the adult and pediatric endocrinology workforce compiled by the LEWIS GROUP for the Endocrine Society.  The data came from the American Medical Association, the American Board of Pediatrics and the American Board of Internal medicine, the American Association of Medical Colleges and US Mortality census.  In addition, data was collected by a survey sent to 1689 randomly sampled board-certified endocrinologists; response rate was 21%.

In reviewing the factors affecting the supply and demand of Pediatric Endocrinologists, there was an increase of 6.6% per year in first year fellows between 1998 and 2011, resulting in over twice as many first-year trainees during this time period. The number of third year fellows had approximately tripled over a similar time period.  Taking into account 1) projected attrition (deemed small since pediatric endocrinologists are in generally very satisfied with their profession), 2) retirement ages based on their questionnaires, 3) a slightly contracting proportion of patients in the pediatric age group, and 4) smaller increases in the number of patients requiring endocrine care (certainly relative to the projected increase adult endocrinologists will see because of obesity) – they felt that the US would rapidly enter into a situation of excess Pediatric Endocrinologists, citing 2015 as the break even point.  There were, of course, many factors that could not be factored in, notably user rates in a non-universal healthcare system, insurance payouts, lifestyle trends, reliance on educators and nurse practitioners, patient demands for new medications and new technologies, guidelines for optimal care and regulatory requirements.  Most notably, in contrast to their consideration of the obesity epidemic’s repercussion on demand for adult endocrinologists,  other than small increases in T1D, little thought was given to the increased endocrine demands  of pediatric cancer survivors, pediatric obesity, SGA children and intersex patients, not to mention the increasing numbers of patients being treated with GH, pubertal blockers,  whether justifiably or not.  It is therefore not clear if this scenario is becoming a reality in the US as of yet.

This projected excess supply after 2016 was not the case for Adult Endocrinologists.  Vigersly et al suggest that it would take until  2025 for supply to match demand if fellowship positions were increased by 5.5% per year.

The Gender Gap and the Adult Endocrinology Workforce

Since the Endocrine Society’s LEWIS report and Vigersly’s article 6 years ago, Romeo et al (21) explore the situation in another JCEM commentary this summer.  It does not focus on gender, but more on the implications for the decline in the ratio of application-to-available-positions, now at 1.1.  What this means for gender diversity and for the quality of the trainees given the smaller pool of applicants is difficult to assess at this point.  Also noted was that the numbers of first year fellows in Adult Endocrinology graduating from US medical faculties has declined from 56 % to 40%, with now the majority of fellowships going to foreign medical graduates, often representing minority groups.  This is definitely a positive trend towards cultural diversity, and presumably will occur in Pediatric Endocrinology as well but as noted above, it is mostly male applications that are on the decline in adult endocrinology.

Canada has handled both the Adult and the Pediatric Endocrine workforce supply differently, owing to the fact that positions are strongly limited by the provinces and the fact that we have fewer training programs than the US – only  7 Pediatric Endocrine training programs, and 12 Adult Endocrinology training programs.  The most recent CAPER data (8) shows a small increase in the numbers of Ped Endo fellows in training, in 2005 there were 25 and in 2019, 29; this is in contrast to the Adult Endocrinology trainees where numbers have steadily increased  since 2005 from 48 to 78.  Canadian programs still have more applications than positions (or funds in the case of non-Canadian applicants), and we are also seeing a small rise in the number of foreign trained Pediatricians seeking to train in Pediatric Endocrinology.  The financial impact of medical training is far less in Canada than in the US, and this may be one reason that the specialty remains attractive for both Adult and Pediatric Endocrinology hopefuls.

Canada is also seeing a small increase in the numbers of Pediatric Endocrinologists going into community hospital practice. Prior to the beginning of the 21^st century, 95 of Pediatric Endocrinologists in Canada practiced in Academic centers; those who continue to be employed by University Centers are now on salary or on mixed models of payment.  What this means for remuneration of community Pediatric Endocrinologists is hard to guess, although community pediatric endocrinologists may see proportionately more patients with ISS, early puberty and obesity. Will increasing numbers of community Pediatric Endocrinologists mean that they may become more proactive with treatments because of a need for income generation, thus moving away from a more conservative approach to treatment?

What is the data on the Impact of Physician Gender on Practice of Ped Endo?

Dr Smuel (22) did a survey of 155 pediatric endocrinologists to determine whether hormonal treatments for frequent clinical cases – in particular ISS, early and delayed puberty – were delivered with different frequencies based on gender (M 37% F 63%), age and place of practice (28% Israeli, 72% international). There were striking gender differences in willingness to treat among the Israeli Pediatric Endocrinologists with female physicians being more proactive, and overall, Israeli physicians were more likely to offer treatment than those from other countries despite guidelines that tend to be more conservative.  Factors driving the treatment were hypothesized to include differences in cultural norms and gender-influenced personal belief systems, but I do not know the proportion of independently practicing physicians sampled versus those practicing in academic centers, and how the types of remuneration may have influenced the results of this study.

Impact of Physician Gender on Patient Satisfaction

I will end this talk with a brief review of some of the data examining whether gender impacts on patient satisfaction, although little has been researched in the context of the pediatric endocrine patient.

As an anecdote, let me mention an article in a February issue of the New York Times in 2001, describing the case of a male obstetrician that was fired from his group practice because of his inability to attract patients.  He was suing his colleagues for gender bias and the practice of honoring patients’ requests to have female physicians over equally-qualified male physicians.

This article was mentioned in a nice review by Debra Roter in the same year (23), which looked at how physician gender can shape communication dynamics.  She pointed out that previous studies reveal only a weak preference for gender-same physicians, particularly when the health complaint is not gender-specific.  However, data does show that there is a preference for same sex when gynecologic or obstetrical care is considered.  This was also examined in the context of pediatric consultations (24), using questionnaires of 125 parent-child pairs after an outpatient visit at a University Teaching Hospital.  While 54% cited no preference, 38% wanted female doctors and 8% wanted male doctors.  When female patients age 9 and older were polled, thus within pubertal age groups, 98% wanted female doctors, and when they were able to have a consultation with a woman, they reported greater satisfaction with the visit and feeling more comfortable.

One of the first papers to discuss physician gender effects on the doctor-patient relationship was written by Judith Gray, a specialist in Community Medicine with the Manchester Area Health Authority in the early 80s (25).  She pointed out that classic medical training prior to the 1980s emphasized a mechanistic, analytical and rational approach which counseled keeping an emotional distance.  This contrasts with female socialization emphasizing caring, emotional involvement and nurturing.  At the same time that the paternalistic and more distant medical model was being taught, studies found that patients preferred that their doctors to be understanding, take more time, explain more completely and take a personal interest. Grey also highlighted studies that showed that patients speak up more to female physicians, and felt that their female doctors were ‘friendly’.  Hers was one of the wake-up calls that stimulated another 3 decades of research into gender-based differences in verbal and  non-verbal communication styles and the impact this has on patient satisfaction, resulting now in almost all Universities incorporating reflective and observational teaching methods  of effective and non-effective communication.

Medical visits are actually very complex social interactions which are both dynamic and reciprocal, and different physician qualities may be valued or be beneficial depending on the gender of both the physician and the patient.  In the context of the pediatric visit, communication is tripartite with the gender of the caregiver accompanying the patient also to be taken into consideration.  Empirical data exists showing a link between patient satisfaction and outcome measures including compliance, so it behooves us to be cognisant of how we can contribute to increased patient satisfaction. 

Communication styles thus can influence the therapeutic relationship in several ways, including the degree of partnership in the relationship, the extent to which psychosocial issues are openly discussed, and the patient expectations and judgement (26). Gender-based communication stereotypes do have support in the literature, with women being found to be more accurate in understanding nonverbal communication and in physically expressing more positive behavior with smiles, nods and gazes. Data suggests that they are also more comfortable with emotional closeness and less hierarchical in social relations. Hall and Roter pointed out (27) that the differences are not large, but it is not clear whether medical education can level the communication field.

Concerning patient expectations, a Swiss study by Mast and colleagues (28) had 163 volunteer patients look at a series of pre-set physician-patient interaction videos, and grade what they perceived to be the degree of patient satisfaction based on seeing the physician but only hearing the patient speak.   The viewers were most satisfied with the female physicians who behaved in line with a female gender role, whereas for male physicians satisfaction was high for a broader range of behaviors only some of which were more in line with a male gender role suggesting that inherent biases are may have been at play.  The Implicit Association Test (IAT) is being increasingly used to examine implicit gender biases in medicine, both in health care professionals and in patients. If you have not yet taken it, it is worth a look (https://implicit.harvard.edu/implicit/canada/takeatest.html).

Furthermore, inherent physician attributes may also affect patient satisfaction, as shown by an enormous analysis of almost 52,000 in-patient surveys on 914 physicians, 76% of whom were male so female physicians were inadequately represented in all the specialties (29).  No significant associations were found between patients and physician gender, ethnicity and race but were associated with physician specialty (ObGyn’s scored the highest) and age (older physicians fared better) –  with no pediatricians or pediatric endocrinologists represented in their sample.

Evidence also supports the importance of providing diversity within the pool of physicians when possible, in order to increase patient-physician partnerships.  This in turn has been shown to increase patient satisfaction.  Based on a large dataset of white, African American and other minority adult patients and an equally diverse group of primary care physicians, they showed by telephone questionnaires that participatory decision making was highest in relationships that were race and gender concordant – again emphasizing the complexity of the interactions at play (30).

I will stop here and simply conclude by saying that I hope that the future of Pediatric Endocrinology sees increasing diversity among our trainees but a more equal balance between genders.  I do not want to see Pediatrics and Pediatric Endocrinology becoming uniquely the domain of women. The literature shows that male and females bring different strengths to the table, and a gender-diverse physician team offers better chances of successfully serving their patients with regards to satisfaction and ultimately with better clinical outcomes.

Paul Saenger: Thank you Cheri.  I had a paper to review, which was forecasting the death of  Pediatric Endocrinology and showed  that the number of applicants is declining. And this is just for the last five years. And it’s a self-fulfilling prophecy  although they didn’t say that our sub-specialty will abolish itself. Some things that these authors quoted that need to be fixed include 1) The pay scale. We are, as you remarked correctly, down at the bottom of the pay scale with psychiatrists and that needs to be fixed. Certainly, we don’t have any procedures, you know. And 2) The training has to be shortened and they have to do away with this academic paper that you have to submit in order to complete the requirements for the fellowship in the US. I do not know how it is in other countries. We have these highest quality structured Fellowship programs in Canada and in the US. I think in the rest of the world it’s more loosely defined and it’s not as rigid as what we have here.  This was a paper painted a very bleak picture. And I’m not sure from listening to you that that is truly the case.

Deal: I don’t think it’s the case in Canada. I know that the US is extremely concerned. And again, I think there are both cultural and workforce factors at play here; the three year

requirement to training is not the case in Canada, although anyone wanting to be an academic physician will not be recruited in general  unless they’ve done at least three years of pediatric training and have had some exposure  to medical or pedagogical research or another advanced degree say in Ethics or Law .  I don’t have that same sense that factors at play in the US are the same in Canada.  Remuneration has changed for all us, however. We used to be able to bill for radioimmunoassays that we supervised but hormone assays are now taken over by the Clinical Biochemists and high throughput analytics. In Canada, we have highly subsidized medical education, so that we do not graduate with crushing debt as in the US.  Most academic centers in Canada have some sort of practice plans or practice pools and do not work strictly on fee-for-service; this has certainly helped us in my center.  In Quebec, we have mixed funding (hourly salary and modest additional fee for services); we can also bill for telephone consultations.  We are working hard to get bone age reading being a billable expense in Canada, although more and more centers are using relatively high cost computer-based assessments of bone age films.  Currently diabetes care is very well remunerated now that we are using pumps – but granted, the care of these patients is more intense.  I don’t know about Europe, and I don’t know how things will evolve.

But to me, what wasn’t mentioned in that article and I think is one of the most threatening aspects for pediatric endocrinology in Canada is not that we’re going to phase ourselves out but that we’re going to move from an academic to a community type of practice as is seen in many, many countries around the world, particularly if the government restricts the number of academic positions but Universities continue to train more fellows.  Academic medicine might also be seen as undesirable if you are carrying a very large debt and you need a revenue-generating type of practice, not as easy to have when you are seeing complex cases in tertiary/quaternary care academic hospitals. Community practice often involves solo clinics, and I have always felt that this is a fast track to loosing skill sets and does not serve patients well.  More heads are always better than one.  I think in the past century that if you look at the Chiefs of Internal Medicine, Chiefs of Pediatrics and even Deans, these were very often held by endocrinologists or pediatric endocrinologists. We have a very challenging specialty, which requires interactions with many other specialties for our complex cases, and this means that we are good at seeing the perspective of other non-endocrine colleagues.  But where are the pediatric endocrinologist chairs – particularly women but also men –  now? I think their numbers are declining. Personally, I know they are in Canada. So there are threats, but I don’t think that ours in Canada are necessarily those in the medical system in the US.

Lars Sävendahl: Thank you very much Cheri for an excellent lecture. If you agree, I will make a few points. First, regarding the association between salaries and gender distribution in Peds Endo. Supporting such an association is my personal experience from running many international courses in Peds Endo over the last 2 decades including the Advanced Postgraduate Course on Growth and Growth Disorders which was started by Martin Ritzén. We have seen a continuous increase in female to male ratio where this year almost 90% of the applicant fellows were female. It is also clear that the female predominance is less pronounced in the Nordic countries where salaries are quite even between specialities/sub-specialities. This observation further supports your point that salary, at least partly, determines what speciality young doctors choose. Second, regarding female representation in our professional societies. I believe a huge change has taken place over the last decade. For example, ESPE in 2014 introduced mandatory dual presidency where the President and vice President must be of opposite sex.

Deal: I looked really hard to try to find the names of the female presidents and they’re not traceable on the website.  It  would be very helpful to put those up. I personally was interested in looking at them.

Ze’ev Hochberg: A question for you, Cheri. Do you feel that it makes a difference whether a child is being seen by a male or female doctor? Particularly in the cases of precious puberty in a girl or a boy with delayed puberty? I hear from a colleague that she finds it difficult to sympathize with a boy with delayed puberty. What do you think?

Deal: This is an interesting question, and we did a little informal internal audit to look at how frequently female colleagues prescribe testosterone for delayed puberty in males versus how frequently it is given it is given by male colleagues.  My impression is that we actually, as women, prescribe testosterone a little bit more frequently. How do female physicians relate to precocious puberty in little girls? All I can say is that from my own personal experience, the parents always tell me, either as they walk into the room and see me or when they walk out: ‘Oh, our daughter is/was so happy that she could see a woman.’ So there’s something about little girls going through puberty being conscious of their bodies that I think makes them extremely anxious about being examined by a male physician.  On the contrary, I think boys with delayed puberty look upon the female physician as a little bit of a mother. They actually like being reassured that there are normal by a mother figure  and I think their own mothers (thankfully) are not comfortable pulling down their adolescent’s pants!  So I wasn’t surprised to see this.  Data does show that older physicians tend to be less interventionist particularly within the range of normal constitutionally delayed or early puberty.

Harvey Guyda: I wondered at the gestation of your EDGE topic, as I have always been surrounded by highly successful women in Ped Endo, most of whom raised a family as well. Here are some examples (from the second half of the 20^th century, now retired or deceased):

• Eleanor McGarry – one of earliest to study use of GH in Canada (therefore linked to Ped Endo), with John Beck at RVH and preceded Henry Friesen. Received CSEM DSA.
• Beverly Murphy – a pioneer in steroids and pregnancy, origins of Fetal Endocrinology. CSEM Distinguished Service Award (DSA) 1993.
• Sonia Salisbury – adult endocrinologist by training who succeeded in Ped Endo. CSEM DSA 1994. (two females in a row!)
• Cindy Goodyer, PhD, who provided leadership with CSEM DSA 2000, an adult organization that accepted her PhD and Ped Endo affiliation.
• Heather Dean, you know her accomplishments. CSEM DSA 2001 (another two females in a row!)
• Eleanor Colle – one of earliest to study Ped Endo in USA. One of my main mentors. Raised 5 kids and knitted thousands of items without blinking an eye. Broke the women’s barrier to leadership at McGill. First office at MCH was in a centrifuge room, that I also shared!
• Ruth Illig – German pioneer in Ped Endo, one of founders of ESPE. I note that the Joint meeting has become ICPE, but that CPEG is not a member. Strange, given that we hosted it in 2001!
• Selna Kaplan, sidekick to Mel Grumbach, but strong in her own right. One of earliest to treat with GH in USA, principal author in earliest GH reports. Endocrine Society DSA and Koch Award with Grumbach.
• Jo Anne Brasel (unmarried)- despite her severe medical disability that ultimately claimed her life. She excelled as a teacher and mentor, including to me. President of SPR in1978 and of LWPES in 1992.
• Ann Johanson (unmarried)- my colleague at Hopkins, died earlier this year. Over 15 years, she developed Ped Endo at University of Virginia and was first female full professor there. Bob Blizzard, her and my mentor, followed her there as Chaiman of Peds. Ann then joined Genentech as first female Director of Endocrinology and was in senior management when they launched their first synthetic GH in 1995.

Deal: Thanks for compiling this list, and as you know, many of them were mentors for me during my training and early career.  I am always happy to honor excellence, and these women deserve cudos.  But we are speaking of statistics, not of stars, when we examine how women are doing globally in medicine.  As you see from the transcript from our EDGE discussion, the data is there, and it is concerning.

The topic of the feminisation of medicine was actually suggested to me by Ze’ev Hochberg (I presumed that not many male colleagues would have accepted to tackle it so I agreed), and as I read more and more, it actually made me sad to see how we are evolving.  This in no way means that I am not proud and often in awe of smart and successful women that I have had the pleasure of working with, just that I believe that everything should be in balance.  And if I am honest – I have always had the most fun on committees and executive boards where there were almost equal gender ratios.  I felt that the thinking was more out of the box, the discussions were more civil (less testosterone-driven??) and there was usually an evolution of the group dynamics in a very positive manner.  So my concerns now are how to keep the guys in Pediatrics…  The point made my Lars Sävendahl is interesting, and suggests that the Nordic countries are on the right track…we need to learn from them.  You may find the references below of interest.

Michael Ranke: Congratulations! This is a wonderful article dealing with numerous aspects of this complex issue. And having not known the content of your presentation in advance my loose comments appear to be not completely appropriate within the context. We need to investigate the gender difference from the disease perspective in children (not only during adolescence). I still think this is somewhat neglected. However, more importantly, about the points you have addressed, it is clear that the gender issue within medicine -specifically ped. endo – is of basic relevance for the development of the specialty in terms of   providing care as well as research and teaching. It is therefore that I think that the societies should embark on joint structured project evaluating the development of the structures – including the gender of health providers – in a selected number of countries with diverse medical systems. A specific aspect within such a project in ped-endo is the academic research settings since these are driving the progress in the field and the structures of education. The discussion of academic developments in males/females certainly plays on the background of the changing qualifications/ techniques which are required to have a successful academic career. The changing demands may also have a different impact on males/female who experience a changing role in private and professional settings.  The information collected will serve the ped-endo societies in their strategic outlook and would greatly help our medical systems in their planning. I can only encourage you to lead such an initiative. Due to the relevance, I assume that there will be funding (if fighting Covid-19 has not used -up all resources).

Deal: Thanks Michael.  As I mentioned in the talk, one of the interesting changes in the data collection of public and private bodies, including medical societies, is the trend not to declare gender, or to drop the question entirely.  Our governments have wrestled with the impact of dropping gender statistics and ethnicity data in an effort to move away from a binary and racist society.  In France, for example, the government does not collect labour force data based on ethnicity. I liken this to trying to treat a patient without a diagnosis: how do you decide if there is a problem to address?  It is suspected that youth unemployment among the Maghrébin (North Africans) in the Paris suburbs is  50%…but where are the solutions if we can’t measure either the scope of the problem or the effectiveness of our interventions?

Returning to your call for the need to collect data within our Pediatric Endocrine societies – I agree of course. The addition of additional boxes to check such as ‘other’ or ‘prefer not to state’ is laudable in that it respects those individuals in the LGBTQ community whose numbers are growing.  However, I really think that it is important that people do have a chance to mark ‘male’, ‘female’ or ‘other’ and that they should not choose a third answer purely for political reasons as I suspect is being done by many ESPE members.  Data on ethnicity is equally important.  How to reassure prospective members that this information is precisely to avoid discrimination and how to explain the importance of these data to them is not easy, but we cannot plan our workforce needs or determine if discrimination exists without the data – for any group – including males!

REFERENCES

1. WHO European Health Information Gateway. https://gateway.euro.who.int/en/indicators/hlthres_137-of-physicians-by-sex-all-ages/
2. Pelley E and Carnes M. When a Specialty Becomes ‘Women’s Work’: Trends in and Implications of Specialty Gender Segregation in Medicine.  Academic Med 95:1499-15-6, 2020.
3. Canadian Institute for Health Information (CIHI). Physicians in Canada, 2018. Ottawa, ON. https://www.cihi.ca/sites/default/files/document/physicians-in-canada-2018.pdf
4. Sippell, Wolfgang G, Ed. ESPE – The First 50 Years.  A History of the European Society for Paediatric Endocrinology.  Karger AG, Basel Switzerland, 2011.
5. Fisher DA. A Short History of Pediatric Endocrinology in North America. Ped Res 55:716-726, 2004.
6. Endocrine Society White Paper, submitted by The Lewin Group. Endocrine Clinical Workforce: Supply and Demand Projections.  June 2014. https://www.endocrine.org/-/media/endosociety/files/advocacy-and-outreach/other-documents/2014-06-white-paper–endocrinology-workforce.pdf?la=en
7. American Association of Medical Colleges (AAMC). 2019 Report on Residents. https://www.aamc.org/data-reports/students-residents/interactive-data/report-residents/2019/table-b3-number-active-residents-type-medical-school-gme-specialty-and-sex
8. Canadian Post-MD Education Registry (CAPER). 2019-2020 Census Data. https://caper.ca/sites/default/files/pdf/annual-census/2019-20-CAPER_Census_en.pdf
9. Katai M et al, Reducing the Gender Gap in Academic Activities: A 10-year progress report by the Japan Endocrine Society Women Endocrinologists Association (JES-We-Can). Endocrine J 66:359-68, 2019.
10. Pelley E et al. Female Physicians and the Future of Endocrinology.  J Clin Endocrinol Metab 101:16-22, 2016.
11. England P and Folbre N. Annals Am Acad Pol and Soc Sci. The Cost of Caring. 561:39-51, 1999.
12. Cohen M and Kiran T. Closing the Gender Pay Gap in Canadian medicine. CMAJ 192:e1011-7, 2020.
13. British Medical Association. DHSC-commissioned Review of the Gender Pay Gap in Medicine. https://www.bma.org.uk/pay-and-contracts/pay/how-doctors-pay-is-decided/review-of-the-gender-pay-gap-in-medicine. Last reviewed  September 7, 2020.
14. Xue H et al. How Does Physician Gender Influence Primary Care Quality? Evidence from a standardised patient audit study in China. Lancet 392 (S66 – poster abstracts), 2018. DOI: 1016/S0140-6736(18)32695-3
15. Edmonds LD. Why Do Women Choose or Reject Careers in Academic Medicine? A narrative review of empirical evidence. Lancet 388:2948-58, 2016.
16. Patton et al. Differences in Mentor-Mentee Sponsorship in Male vs Female Recipients of National Institutes of Health Grants. Jama Intern Med 177:580-2, 2017.
17. Spector ND et al. Women in Pediatrics: Progress, barriers and opportunities for equity, diversity and inclusion. Pediatrics 144:e20192149, 2019.
18. Starmer AJ et al. Gender Discrepancies Related to Pediatrician Work-Life Balance and Household Responsibilities. Pediatrics 144:1-10, 2019. DOI 10.1542/peds.2018-2926.
19. Jones Y et al. Collateral Damage: How COVID-19 is Adversely Impacting Women Physicians.  J Hosp Med. 15:507-9, 2020.
20. Vigoursky RA et al. The Clinical Endocrinology Workforce: Current status and future projections of supply and demand.
21. Romeo GR et al. Trends in the Endocrinology Fellowship Recruitment: Reasons for concern and possible interventions. J Clin Endocrinol Metab 105:1701-06, 2020.
22. Smuel K and Yeshayahu Y. ‘Real-world’ Pediatric Endocrine Practice: How much is it influenced by physician’s gender and region of practice.  Results of an international survey.  J Eval Clin Pract. 23:866-9, 2017.
23. Roter DL and Hall JA. How Physician Gender Shapes the Communication and Evaluation of Medical Care.  Mayo Clin Proc. 76:673-6, 2001.
24. Turow JA and Sterling RC. The Role and Impact of Gender and Age on Children’s Preferences for Pediatricians. Ambulatory Pediatrics 4:340-3, 
25. Gray J. The Effect of the Doctor’s Sex on the Doctor-Patient Relationship. J Royal Coll Gen Practit 32:167-9, 1982.
26. Hall JA et al. Patients’ Satisfaction with Male Versus Female Physicians. A Meta-analysis. Medical Care 49:611-7, 2011.
27. Hall JA and Roter DL. Medical Communication and Gender: A summary of research. J Gender-Specific Medicine 1:39-42, 1998.
28. Mast MS et al. Physician Gender Affects How Physician Nonverbal Behavior is Related to Patient Satisfaction. J Med Care 46:/1212-8, 2008.
29. Chen JG et al. Relationship Between Patient Satisfaction and Physician Characteristics. J Patient Exper 4:177-184, 2017.
30. Cooper-Patrick LC et al. Race, Gender and Partnership in the Patient-Physician Relationship. JAMA 282:583-9, 1999.

A live conversation between

Margaret Zacharin, Melbourne, Australia

Abiola Oduwole, Lagos,Nigeria

and

Ze’ev Hochberg, Haifa, Israel

Transcribed by Despoina Manousaki

Comments by Herwig Frisch, Paul Saenger, Gabriele Hausler, Ken Ong, Michael Ranke

Ze’ev Hochberg: I will start with a short introduction to the concept of Disease Burden. It is mostly defined as the impact of a health problem on society as measured by financial cost, work productivity, mortality and morbidity, and utilization of healthcare resources at the national or world level. It is often quantified in terms of quality-adjusted life years or disability-adjusted life years, both of which quantify the number of years lost due to disease (YLD). In 2004, the health issue leading to the highest YLD for both men and women was depression; in 2010, it was lower back pain.

Our conversation today deals rather with the personal and family burden associated with a disease and the personal costs that include mostly disability, discrimination, and financial burden. As pediatricians, we are aware of many more subtle aspects of a disease burden, and certainly when dealing with CAH. Important types of burden cannot be counted in measures of mortality, or in economic costing.

Because the traditional medical approach focuses on the individual who is ill, it often ignores the burden of disease for families, households, and the community.

Disease burden is, by definition, a negative term—it is not surprising, then, that measures of disease burden concentrate on the factors that cause illness or make it worse. But a few researchers have argued that a full understanding of burden of disease involves an appreciation of factors that protect and promote health, such as social cohesion, healthy peer relationships, and supportive school or work environments.

Some measures of burden of disease are based on the view that interventions should do the greatest good for the largest number of people. This is certainly true for developing countries. But achieving greater justice in health may involve sometimes doing the most good for a small number of people, who carry the heaviest burden of disease. Often, non-infectious non-oncological diseases like CAH, but also other endocrine diseases, are ignored.  Our conversation today is about an additional complexity of CAH – having it in developing countries. As if the burden of CAH was not heavy enough also in developed countries.

We will hear the views of Margaret and Abiola.

Professor Margaret Zacharin is a child and adult clinical endocrinologist working at The Royal Children’s Hospital. To us, she is best known as a teacher and an experienced endocrinologist due to her work in India, other Asian countries, Africa and ESPE.

Professor Abiola Oduwole is a Pediatric Endocrinologist from Lagos University Teaching Hospital. For us she is mostly the founder and chief coordinator of the Pediatric Endocrinology Training Centre for West Africa (PETCWA) and the founder and the mother of pediatric endocrinology in Africa. Unfortunately, she was denied a visa to Austria, but she has submitted her views in writing.

Margaret Zacharin: Thank you Ze’ev and I hope everybody can understand my accent. Thank you for the opportunity to participate today. This morning, when I got up, I thought this was a difficult topic, I looked in the mirror and told myself: the stage is yours; on the other hand, perhaps, as endocrinologists, we do have a little bit more experience….So I hope to challenge you today. I will read some of this because it is quite complicated.

If you were to stop any random person in the street and ask what he or she thought the single most important element that defines a male or female, how many would say X and Y?

No matter how modern we are, flexible, relaxed, at ease with gender fluidity, comfortable with differences, variations or alterations in sex development we might tell ourselves we feel, it remains a cold fact that most of the world think differently and those small chromosomes create much angst for individuals, families and communities.

To be confronted by confusion or uncertainty in any sphere of life is traumatic, unsettling and demands early positive resolution, or the outcome is likely to have long-term adverse ramifications.  The human condition demands clarity and purpose and relatively few individuals can cope with prolonged uncertainty in any field.  Furthermore, from earliest experience most of us tend to crave a degree of similarity, both in form and thought.  Those who are or who feel different often struggle for very long periods to find a niche where self-expression is accepted, tolerated, and provides satisfaction, pride and importantly self-worth.

So let us now consider how fortunate birth and educational opportunities might have informed successful transition to the cultured, broad minded, tolerant and self-tolerant individuals we like to think of as ourselves, as highly trained personnel from every continent and country, and how we might have coped had we not been given these advantages.  Think then, of how a family from an isolated community in a village in Kenya, Sudan, Nigeria, North Pakistan, or India, Vietnam or indeed anywhere, might cope, those financial and educational advantages not having been conferred; confronted with a set of circumstances so radically different from anything they could have imagined. For them, as for us, X and Y have an identical meaning, whether they may be nameable.

Today we are talking of only a tiny microcosm of the psychological and financial upheaval incurred when an infant is born with a disorder of sex development, in this case, with congenital adrenal hyperplasia.  For this audience we do not need to dwell on the terrible toll for a family where a baby or child dies, but the reality is that, in many of those countries mentioned, the sole clue to a baby with CAH may be a history of one or many, infant or childhood deaths in a family, frequently a sad procession of ghostly boys.

 

The first and foremost confrontation for a family when a diagnosis of CAH is made is the spectre of what might have been, had someone only known.  Death stalks life in many places, in a way no longer known or even considered in wealthy or educated societies.  Families accept a huge toll to infection, starvation, and a great unknown. Grieving is perhaps different in situations when the grasp on life itself is tenuous.  We cannot not enter the lives of others to know how deep or pervasive that pain remains.

But for now, we imagine that a diagnosis of CAH IS considered in the neonate, in some more distant clime than that in which we feel at home, where a baby with genital ambiguity is born who would possibly be a female with CAH. Reported incidence of mixed gonadal dysgenesis or 5ARD in many countries is significantly higher than that of CAH, presumably because many cases are missed.  A vomiting boy with increasing pigmentation remains much less likely to be detected and in most of these places boys with severe salt wasting CAH do not exist.

Since the very first question asked by the parents is, “is it a boy or a girl?” take a moment to imagine the darkness and confusion descending on a village parent with minimal primary education, given this circumstance. This shock, incomprehensible although it is, has to be assimilated, considered, transmitted to as few as possible and concealed from inquisitive and uncomprehending eyes, in a matter of minutes to hours.  How then to cope with the consequences?

Assuming a more or less correct diagnosis can be made, often with minimal available tools, such as electrolytes and an ultrasound, and that a proper, informed discussion has been made –which is often not available- the cascade may be different in differing circumstances.  The essential question, however, remains:  What is it, to be a boy or a girl in the context of a family’s circumstances and conditions? Intrinsic features of identity as a boy or girl cover all aspects of physical and medical needs, emotional, social, sexual health, community acceptance and future fertility. ‘Best’ choice in our terms may be very different from best in a village setting, in circumstances where children often do not have access to surgery. While physical differences and deformities are rife and accepted in communities, is it the same for genital differences?

We may now focus on some areas of the world where resources are constrained and circumstances may differ wildly from those within our own bounds of education, cultural, social, and sexual acceptance. We speak here solely of those who have not had these opportunities.

In India, considerations are complex, fertility looms large in the public consciousness and it is often the overwhelming consideration when a family is confronted with a baby with CAH. Fear of abduction or assimilation by the hijra may be overriding, resulting in secrecy, deception, and chronic anxiety.  Being male has advantages we no longer dream about: to be the bread winner, to be marriageable, to inherit and to be the primary carer of parents as they grow older, particularly in the case of the oldest boy.  If an infant is severely virilised, no amount of discussion of a potentially fertile female with CAH may weigh in the scales. Financial constraint, surgical outcome and uncertainty regarding gender identity complicate decision making.  For those diagnosed late, where increasing virilisation or a male sex of rearing has been chosen, there comes an increasing burden of decision making.

Amongst those who have all the advantages of high quality specialized medical management  at their fingertips, some self-righteous decisions may be made that are simply irrelevant when put in the context of such a family, living in circumstances that demand constraints and with limits that do not affect those who have choice. To suggest a change of sex for an 8 or 10 year old, XX female with CAH, reared as a male, requires the child to have a flexible or unformed gender identify, to entertain massive social upheaval, such that the family must move themselves from home and community to an entirely new environment where they can make a new life in the opposite gender.  Essentially, they are being asked to be a shadow on a landscape of fear of the unknown. Add to these burdens the trauma of suggested genital reconstructive surgery and the pressure of decisions being taken by others on the behalf of the child.  Many studies have shown that, once established, such a male gender identify cannot be changed and that adult outcomes are dismal when efforts to do so are employed. In India, Ammini et al have reported 26 children presenting late with virilising CAH, three of whom were raised as boys, where gender identity was concordant with sex of rearing.

In India, for the majority of the population there remains a vast social divide, where conventions are paramount. Lack of disclosure regarding physical differences and childbearing capacity at the time of arranging a marriage, for a significant proportion of the community, may result in social disgrace and return of the girl. By contrast, Malay Islamic law favours a female sex of rearing, in terms of inheritance laws, with retention of a woman’s control over her finances under all circumstances. So, community traditions have differing bearing on family perceptions.

Yet another angle may arise, where there may be decisions to be made in circumstances of increasing  virilization in early steroidogenic disorders such as 17 hydroxylase deficiency. Take, for instance, an example of a girl who has lived a life amongst women, who has no experience of living with or amongst boys but who is attracted to a male role, due to progressive virilization.  Her decision to live as a male would theoretically result in all the advantages discussed previously but might be outweighed by the isolation and social shock of suddenly living in a male environment. To test this proposal, she would have to undertake the upheaval of transition to a totally new city, town or village, with no support, with all the oppressive features of being entirely alone and unguided in a new world- daunting indeed! Finding a compromise with social, emotional and family support may be a totally overwhelming proposition.

Reliable information as to the impact of any or all of these factors remains extremely limited.  Prof Bhatia et al, again from India, have studied families with DSD in North India, where appearance of genitalia, medical advice, ability to bear children, economic independence, religious beliefs were listed as the most important features in decision making. A small cohort of ten young people there, aged 12 to adulthood were asked about timing of genital surgery. All but one of them indicated a preference for early surgery to reduce differences from peers, to improve self-confidence and to reduce the mental trauma of to being compared with other children.

In Vietnam the choice of sex rearing is perhaps easier for a child with CAH, as there is less emphasis on fertility than on the health of the child.  Medicines availability, continuity and cost are overriding features and the quality of surgery and long-term outcome are variable and can cause enormous difficulties. Financial considerations may be so overriding that traditional medicines can be preferred. Medicines as glucocorticoid are still purchased outside of the country and mineralocorticoid is unavailable except where access to external purchase is possible. One bottle of fludrocortisone was reported to cost half the annual income for a family in a survey by Warne et al. Stigma and ostracization within a village community have been demonstrated there, as in India. The support group Care and Living with Neighbours (CLAN)

has been well established in Vietnam for over 10 years, allowing some access to family and community support for CAH. In a study by Warne et al, religion was not reported to play a big role in decision making, as to sex of rearing, but early decision making and hopefully adequate surgery was considered paramount to reduce the social impact of physical difference, with great anguish in families where differences persisted.

In Africa diagnosis is more often late, due to home deliveries, lack of identification of genital ambiguity, with less rigorous midwife training to recognise variations in genital appearance and with the problem of ‘identification’ of a sick neonate as being due to an infectious cause rather than with a possible consideration of CAH.  Death due to gastroenteritis or HIV is still prominent and, sadly, male infants and boys with severe salt wasting CAH simply do not exist in many of these environments.  Secrecy, fear of tribal indiscretions and beliefs that ambiguity may have been brought about by an evil eye or a curse is still prevalent in some societies.  Availability, cost and continuity of medications and the tyranny of distance are all considerations. Together, these issues may be overridden by a powerful need to conceal genital changes from family and community.

Even assuming a correct diagnosis is made and medications are able to be administered, a child may die in ensuing months, related to lack of understanding of a family for the need to increase medications during illness and also compounded for some families, by lack of confident belief in western medicine, rather than a lack of understanding.  Going home via the witch doctor is still a common cause of action by some.

Recognition of religious aspects of community life is essential to diagnostic decision making, where applicable and should be an integral part of providing optimal outcomes and reducing potential harms in the cultural environment of a family .This has been well-reported by Meyer-Bahlburg,  by Warne and Raza, in various publications. Lack of recognition of these aspects of gender-related issues, where a family is living in a community outside of their cultural norm, can compound difficulties throughout a lifetime. A suggestion has been made by Zainuddin to include a religious authority in the multidisciplinary team under these circumstances. Not a typical path for our communications with families at this time, I think.

We may rail against the continued morbidity and mortality incurred by these problems but do we ever really consider having to walk 300 – 400 km to seek help or to take the local bus over several days to see a doctor who provides unaffordable medications in quantities that will last only weeks and where the purchase of such medications causes the whole family’s nutritional intake to suffer severely.  Is it any wonder that, for some, the death of an infant so affected may be preferable to imposing even more adverse circumstances upon healthy members of a family. This is not confined to the African continent.  I have personal experience in India of parents bringing their sick child to hospital, asking for good advice and management, but where they cannot afford the fare home.

Where then lies the ethical dilemma of benefit versus harm?  Do we invoke the Hippocratic oath as most of us were taught or do we understand that sometimes survival hangs in the balance of the scales.  Is the benefit paramount, of correct diagnosis of an infant with salt losing CAH being managed with steroid and surgery and made permanently steroid dependent, with risks for hospitalisation and death stalking her childhood and adolescence or is there a benefit to a healthy 46XX male with no apparent steroid requirement except in times of stress, who can obtain employment, be a breadwinner for the family and who can marry in his community?

Are  ethics immutable, created and determined by discussions, determined by erudite discussion and drawing upon learned philosophies from  Aristoteles to Kant, to John Stuart Mill; or there is space or a place where reality is so far from the circumstances where these rules have been formulated and elected, that all educated and knowledgeable physicians of every country, ought consider a part of our universe where potential pain or irretrievable sorrow may follow  if we fail to take these considerations into account when delivering our judgement and the “rightness” of our views.

Hochberg: CAH is certainly not the only disease that is polarizing us in Africa. In Africa and many developing countries, it was the standard that a woman delivers seven children, and five of them survive to the tribe. What I am saying is that, while it is acceptable to those of us coming from industrial societies that you try to do all you can by introducing modern medicine and teach the complexity of CAH and its treatment, the environment in Africa is so different and the ethics may be too. So that often it is not possible and not advisable to insist on using modern day Western medicine and ethics.

Zacharin:  I think the message is the same. From a European point of view, perhaps it is directed more towards the African continent, but the Indian subcontinent and many other places are exactly the same. The cost and availability of medicines, to undertake transformation of a child who is dying to a child who is healthy, poses enormous social, nutritional, financial discomfort on the family, may be worth the risk; but maybe not. What if none in the family can eat because one very young girl member needs daily medications. I think the trouble is that we sit in judgement on people when we have no notion who they are; and yes we can’t live and deliver a standard of care in a state of ignorance, but we are in a position where we must understand that the cost of delivery of this standard is very high.

Hochberg: We started PETCA in Nairobi, and I recall the second tutor, Violetta Iotova who returned quite shocked from her experience. She wrote an article about a father of a child with newly diagnosed diabetes. She explained to him what it involves managing the child. That father responded to her: “I have five children to feed and look after other than the one with childhood diabetes, I won’t let you treat him”. She wrote of this experience, and it was rejected by Hormone Research in Pediatrics, because it contradicted the ethics of the editor.

Zacharin: Which is the question that I am asking all of us. And there is no answer to it, clearly. I think the answer will shift, as there is more capacity for education, better nutrition, and better access to medicines in many places. So it becomes realistic to have changes. I was very impressed in India, when I was visiting a small outlying hospital in country in Northern India run by Catholic nuns, who treated a host of children daily. On one day, there was a child being carried by his parents, who clearly had tetanus. They offered the mother vaccination with possible palliative care to this child, but the parents were unable to accept that and went home. I asked the nun, who did not make any attempt to impose her ethics on the family, what would happen? She said, they will go home by the river, because that’s the only possibility for them. She understood, as a woman with high ethical principles that it was totally acceptable, because she was aware that there were variations in life that simply cannot change.

Hochberg: Unfortunately, Abiola is not here. Prof. Abiola Oduwole is a pediatric endocrinologist from Lagos University teaching hospital. For us she is the founder and chief coordinator of the paediatric endocrine training centre in Western Africa, and the founder and mother of all pediatric endocrinology in Africa. As she is not here, she sent us some words.

Abiola Oduwole: How can the burden of disease be fully appreciated? A disease or anything that no one accepts that it exists or where the few who knows of its existence refuses to acknowledge it for different reasons. It is a hard task to quantify or qualify that disease burden accurately. It can only be partial.

Why the lack of or ignoring or shying away from the diagnosis of CAH?  Informal research on KPA among the population showed that, most diseases, even when rare is known by the natives but by a vernacular name. However, indeterminate sex gender has no known traditional name. It is like such a thing does not exist on the face of the earth. Why the dead like silence? Usually, the fear of the unknown charted future of what they have observed in the baby creates the silence. Also, lack of knowledge of its origin, why it happened, what to do, custom, religious and belief of the observing individual modulate the response.

The observing individuals are/are most likely one or a combination of the following. The traditional birth attendant or the newly delivered mother or the elderly member/s of the family member who assisted in delivery such as the grandmother or the poorly trained nurse assistant who perhaps is the only medically trained personnel in the community or even a complacent physician. Managing this child with an undetermined gender starts from when the child was delivered. What was the response of those that were there as at that moment?  Which gender to allocate the newborn is the initial question?  Other questions are simultaneously running through the mind. Such as what to tell the mother and relatives. The background of the parents’ fertility, pregnant history, inheritance issue, where, all had been waiting for a male-gendered baby, acceptance of the child if the observed announcing the truth. The birth attendant in a split second will take the easiest and profitable path by announcing the expected and acceptable gender.

Let us take a step back into the Africa of old using Nigeria as an example. Any child born with an abnormality the relatives either kill immediately or left in the forest without any qualm. An ominous silence is a word. Who wants to invite the wrath of the deity? Until the 1800s in the Eastern part of Nigeria and some other parts too.  Mary Slessor a missionary came to that area twins were killed or the stronger of the two preserved and the weaker killed. Whom to blame, such children were thought to bring misfortune. Therefore, killing a child with no gender or conniving with parents and giving the most desired gender by the parents was the norm.

When the modern health delivery system became available, trained midwives became available in the southern part of Nigeria, taking deliveries, recognizing and occasionally archiving births in a record. Despite this advance, gender determination when indeterminate was according to the midwife’s beliefs, religion and culture.  The introduction of paediatricians into the health system followed the era, as mentioned above.  When parents appreciated that the condition of the child remains peculiar, bring them forward to see the paediatricians. Unfortunately, although seen by the general paediatrician lack of laboratory support and poor knowledge of the problem led to nothing done per se. When the paediatric endocrinologist became available through regular and persistent information on different media platform about DSD, the populace became more knowledgeable and brought their children to see the specialist. After making the diagnosis, the next phase of burden commenced. A necessity to develop a CAH team, make drugs available and regular with affordable, easily accessed laboratory for investigations became the burden.

Through this narration, we can highlight the burden in the African or other low socioeconomic setting countries to the below mentioned. Late hospital presentation at age the child already has a known gender classification by a gender-specific name. Raring which is gender-sensitive for the culture of raring. It prevents proper classification as either a mild non -classical CAH missed at birth or a late-onset CAH. An apparent low prevalence rate gives a picture of a rarity. In the paper by Oyenusi, Oduwole et al. onset was more common in the age group 4-8 years, and some presented very late like 16 years. The children were more of non-classical non-salt-wasting 21 hydroxylase types of CAH. If we take this observation in the contest of previous narration, assuming the severe types died without recognition of diagnosis is appropriate. Alternatively, if delivered death from infection or purposed infanticide ensured non-diagnosis. Usually missed is the male child with CAH because the pride of having a well- endowed male infant prevents special attention paid to the absurd or incongruence with age and size.

Non-acceptance and denial of diagnosis when the obvious that it is a lifelong disease that may need surgery causes a conflict with their beliefs, religion, and culture.  Therefore, rejection of diagnosis, noncompliance with drugs, secrecy and non – disclosure to relatives to aid detection of other members or newborn in the family becomes the norm.

Due to poor data collection, the government has no policy in place to help or ameliorate or mitigate sufferings by patient and caretakers.

Laboratory support is abysmal and expensive. In most countries only cortisol, testosterone is available. Paediatric Endocrinologist has learnt to use these parameters for diagnosis and monitoring.

Hydrocortisone is available in only some countries but is expensive, not readily accessible. Most children are on Prednisolone whose strength of either 5 mg or higher makes proper dosing tricky. The result is very erratic.

The high burden for parents and later the young adults as care is out of pocket. Very few countries have a health insurance scheme. When available endocrine disorder not inclusive.

Very few informed medical personnel to cater to millions of people misdiagnosis, non- diagnosis and underdiagnosed is the norm.

In Africa, the era of a child expressing a preference for gender is still rare. Parents pick.  The court case of the famous Kenyan athlete who wants to remain untreated and retain the effect of the high testosterone is well known.

It is a high burden disease in Africa for various reasons.  Quantifying the burden is at present difficult due to lack of data. No country in Africa knows the true prevalence of all minimally available data is hospital-based.

Ken Ong: I have to propose the line that unavoidable death of any child or infant is unethical. Of course, there are financial considerations, situations where families and communities cannot afford healthcare. Still, it is unethical. The blame is the global distribution or access to healthcare, that is unethical. I am not blaming the parents in that situation, it is not illegal, but it is certainly an unethical situation. In the context where there is lot of financial issues, let alone concerns about identity, illness of the child, conception of the family of course, that’s still unethical, but the blame then shifts more towards the wider family, the community, the society. The third choice, I think Margaret raised, was is it ethical to raise a 46XX child with CAH as male? I think this is a different type of ethical question. I think now in our community, and for many decades, we have challenged the idea of gender, with fluidity and more flexibility in the legal determination, and understanding of gender. And in the last decade, we are overtaken by the sex-less society and a fluidity that was not expected or necessarily wanted. So, I would ask what are the ethical arguments against raising a 46XX individual as male?

Zacharin: Not to pinpoint what your definition of ethics is…..is ethics not related to benefit versus risk?

Ong: Is ethics related to benefit versus risk? I think that ethics is a bit higher than that…

Zacharin: We must accept a certain range of gender issues in the community. Our binary view of gender is now challenged, but when it comes to an infant, where circumstances are so different to our own, we are not so conscious. Is it better to compromise the survival of a family by saving a baby or is it possible that death of an affected individual may sometimes be a better option? I am not saying that it is right or wrong, I am just asking you to think about it.

Herwig Frisch: You mentioned that often the families cannot afford the price of the treatment. So, I am asking, if hydrocortisone is still expensive, especially in India, which produces so many generics. So according to the pharmaceutical companies, would they be motivated to produce this free of charge?   

Zacharin: In places like India, the provision of medication is not so much of a problem, it is the timing of presentation for care. The vast majority of these described problems occur in families who reside in insecure environments, where they have little or no access to high quality medical care. Most births are at home, without trained personnel, families lack education and they cannot bring the child to care, or it may take two days on the bus to get there. In Africa, it is even more complicated by views suspicious of western medicine for some-I don’t think that’s an issue in India-. There, largely, if a child gets to a doctor, provision of medication is not a problem.

Frisch: What about vaccinations, which is a much more frequent problem for instance? Is this available in these countries?

Zacharin: Yes, in most places outside Africa, I don’t know about Africa, but in India, again, I think there is more access and belief in benefits of vaccination by families.  I don’t think this is something that we can change in one generation, we are trying…

Paul Saenger: I think you mentioned the interest. This is embedded in Indian culture, and while among Indian physicians nobody is taking this on, it still happens. When you look at legal implications, it is not even specified according to the inheritance rules, how much goes to males how much goes to the female, and the intersex child is settled in between. So this is going on for a long-time. Even the Indian physicians they are descriptive, but they are not providing any solution. Price is not the issue, it is the stigma of the condition. And it is very difficult to grab this.

Michael Ranke: There are two issues. One is of course the complicated issue of the gender assignment that it’s going on, and the other, simpler issue is provision of medications and medicine itself. And I think that as we talk about the ethics, ethics of course always depend on the social and environmental circumstance, and we know this. But I think the issue whether medication is available to mankind at a reasonable price, is an issue of ethics beyond the issue of the locals. It is our issue and most probably the cost of this meeting here would be enough to provide everybody the fludrocortisone and all of the rest of rare endocrine disease with drugs. That’s something we never really discussed in our endocrine society, and we are going with new, less important development such as long-acting GH.

Zacharin: I think this is an enormously important topic for institutions such as ESPE to address, because it is something that we can address, and we can put pressure upon WHO to do more than tick boxes. These are essential medications, and we do nothing for that, other than give lip service to it. As individuals we can clearly make an impact, which will allow improved care for a few, but as a group we can make demands that have the capacity to benefit many.

It does not alter the fact that there are thousands of other issues. If a family goes to the witch doctor, no one has medication that will cure that problem. Access to anything, for example insulin, in many of these communities is intermittent, brands and durations of action are different, distribution and cost may be overriding factors. As a group, we should attempt to try to make an impact. The pediatric endocrine group (GPED), with JP Chanoine as secretary general at the moment, is making efforts, but it is a very small group. Ff we can engage the larger community of endocrinologists that would be great.

Hochberg: The word ethics was used today more than usual for in pediatric endocrinologists, and of course ethics changes with the environment. The question is if we as a group of doctors caring for other people, and as scientists from well-off countries, if we should discuss ethics for families who do not have the means, the knowledge, the education. And if what we do, writing books about pediatric endocrinology, organizing pediatric endocrine training centre in Africa, if this is something we need, or if we should change the content of them. From the very beginning of PETCA, some of our colleagues were sceptical: “I am against it, because once you go and teach all this sophisticated endocrinology, genetics etc for people who cannot afford to do any of it, this is unethical to me”. From the very beginning these colleagues refused to take part in our Africa activity. And this is what we must discuss in the future.

 

 

The definition of gender in competitive athletes

A live conversation between

Martin Ritzén, Stockholm, Sweden

and

Ivo  JP Arnhold, São Paulo, Brazil

With comments by Paul Saenger, Jan Lebl, Jan-Maarten Wit, Ken Ong, Ze’ev Hochberg, Lyne Chiniara and Michael Ranke

Transcribed by Lyne Chiniara

Ivo Arnhold: As pediatric endocrinologists, we help individuals with differences (or disorders) of sex development (DSD). The DSDs deal with several challenges, among others their classification to participate in competitive sports. To discuss this issue, we are fortunate to have Dr. Martin Ritzén, Professor Emeritus at the Karolinska Institutet, Stockholm, Sweden, a well-known expert on the area of DSDs and an adviser to international sports authorities such as IAAF and IOC.

In almost all sports, athletes are divided into male and female categories. Subjects with DSDs must also compete accordingly. How can one preserve the right to compete and privacy of these individuals and maintain a fair level towards other competitors?

These are some main points we would like you to address: Why are men stronger and faster than women? Are individuals with DSDs overrepresented in some sports? Which DSDs and other causes of hyperandrogenism confer an advantage in sports and why? Doping vs. penalizing natural attributes. What are the present regulations for individuals with DSDs (and transsexuals) to participate as women? Different points of view and future trends.

Martin Ritzén: Basically all competitive sports have two different categories of participants: Female and Male. The only exception that I know about is for equestrian competitions.  You can ride a horse as female or as male, in the same category. Five years ago, for the first time in history, one of the very famous horse races in Australia was won by a female, and that made headlines all around Australia. But otherwise the first thing to decide is whether the competitor is female or male.

The reason for this division is that in events that require speed and strength, males are generally superior to women. Without this categorization, women would stand no chance of winning World or Olympic championships. This is evident from comparing the results at world championships in running events; elite female competitors would end up far behind the males. The female gold medallist generally ends up at around 50th place if competing in the male category. The time difference is about 10-12%, in running time or other sports events. This is true for most sports event.

There has been a longstanding debate in how to define a person that is eligible to compete in the female category. In the 1930s, there were some publicized cases of women who won Olympic medals. For instance, Stella Walsh, of Polish origin, was named “the fastest woman in the world”. Her nickname was «Stella the fella», which indicates she was thought to be quite masculine. Unfortunately, she was killed in a traffic accident, and the autopsy revealed she had an intersex condition, but was raised and lived as a female.

Dora Ratjen was a German high jump competitor in the 1936 Olympics who was quite masculine. She ended up 4th in the Olympic Games in Berlin. Afterwards a rumour was spread that she was a masquerading male, who was competing to show the superiority of the Nazi regime. She later changed from female to male sex, and again this was used to say she was masquerading as a female. This was probably not true; rather, she probably had a DSD condition.

The separation of athletes into female and male categories requires a clear definition of the two. Since males are superior to women, most of the discussions aim at defining who is eligible to compete in the female category – how masculine can a woman be and still compete as a woman? The initial concerns were that some men might masquerade as females in elite competitions. This proved to be very rare. But suspicions that some successful female athletes were male persisted.

The risk of masquerading males as a female was brought up in 1948. The first athletic body to request documentation of somatic sex was the British Women´s Athletes Association. The sports authorities then decided to use “objective” proofs of femaleness. The first method was the “nude parade”; the women were requested to show themselves to a panel of gynaecologists. This was soon abandoned in favour of sex chromatin testing; a negative result, suggesting XY rather than XX karyotype, would disqualify the athlete. This was used for a number of years until this also proved inadequate. For example, women with androgen insensitivity were prohibited from competing as females, in spite of the fact that their androgen insensitivity made them even less masculine than healthy women. A famous case was the one of the Spanish athlete Maria Patino; she wrote a book about her situation as having CAIS. She underwent the sex chromatin test and first passed, because it is an unreliable test, but at a different competition, she had forgotten her certificate and went through the test again; this time she was disqualified because she did not have two X chromosomes. She was completely female because of CAIS, and you all know that having higher levels of testosterone does not make her more competitive because her body does not respond to the androgens. Her fiancé left her, she was stripped of all her previous medals. Later, when her diagnosis was revealed, she got them back.

Then, SRY testing had appeared; you could then prove that this person had a Y chromosome, and that worked for a while. However, in the Atlanta Olympic in 1996, a study showed that when all female athletes were tested for SRY, eight were SRY positive, but none of them was virilised. Some of them were gonadectomised years before, and still were very good at sports. One of them was a patient of mine; she had PAIS, with gonads removed in the neonatal period. Did she still benefit from having a Y chromosome 20 years later with no excess testosterone? This indicates that yet unknown factors other than the current testosterone levels may be important for excellence in sports.

When also this method failed to define eligibility to compete in the female category, IAAF and IOC were facing no rules at all when in 2009 Caster Semenya, then 17 years old, won the World Championship in 800 m running, far ahead of all others. She had a quite masculine appearance, big muscles, masculine gait, which prompted some of her competitors and news media to challenge her female sex. Her competitors complained that they did not want to compete with someone with a male body. In the newspapers, questions were raised whether she is a man or a woman. The spokesman of IAAF publicly said that they would “determine her true sex”, unaware of the fact that sex identity cannot be determined by any laboratory test. Only the person herself/himself can define her/his sex identity. That made me furious as she could have been one of my patients. I protested publicly in Sweden and was called for a meeting in Monaco with the IAAF. This organization realized that it was unacceptable to have a public discussion on anyone´s sex identity. In 2009 there were no rules because all previous tests had been abandoned. I suggested testing for testosterone, as it is a key factor.

IAAF set up a small group with the task to formulate new regulations on eligibility to compete in the female category, and I was asked to join this group. My first task was to list a number of DSD conditions that might confer an advantage over other women. That proved impossible; the individual variations within all the diagnostic groups are too large.

Instead, I searched for the physiological differences between male and female athletes that make males perform better than women.

What makes testosterone a doping agent in sports? Testosterone is well known to increase muscle strength and speed. Testosterone administration increases haemoglobin levels in blood, with marked effect on oxygen transport. In some studies, testosterone administration has an effect on CNS by increasing aggressiveness, which might improve performance in elite sports. Therefore, administration of anabolic/androgenic steroids is considered a severe offence to doping regulation and is punished by harsh penalties.

What about testosterone levels? Reference values for serum testosterone for healthy women reach up to 2.7 nmol/L (with immunoassays), while the lower reference limit for healthy men is about 9 nmol/L. In other words: a woman must reach 5 SD above the mean for healthy women in order to get into the male range.  I suggested to use the lower range of the male normal range as a cutoff level; and after a long debate this was accepted (2011-2017). Hyperandrogenism of that magnitude can be reached in some DSDs, adrenal tumours and plain doping. Women with PCOS will rarely reach the male range of serum testosterone.

Are women with DSDs overrepresented in elite sports? Yes. Women with PCOS are overrepresented in successful women in sports. When Bermon et al measured testosterone levels in all 855 female athletes in the 2011 World Championships, 10 had previously unknown DSD with a mean serum testosterone concentration well into the normal male range.  In the Atlanta Olympic games, when all participating women underwent SRY analysis, 8 women were found to be SRY positive, giving an incidence of 1/140, far higher than in the general population. It is remarkable that most of these women had their testes removed at the time of testing.

Which DSDs seem to confer the greatest advantage in female sports? 5-alpha reductase deficiency is the most common cause of hyperandrogenism among elite female athletes. Most of the cases that so far have come to the attention of IAAF come from African countries with limited access to medical, and especially neonatal, diagnostic facilities. 5α-reductase deficiency type II (5αRD) is the most common diagnosis, but a few have partial androgen insensitivity (PAIS). If women with this latter condition have retained some degree of androgen sensitivity, it has been argued that these women would benefit from their high testosterone levels. However, I am of a different opinion: A new-born child with PAIS that has so little masculinization of their external genitalia that they were assigned female sex will carry this poor androgen sensitivity with them into puberty and adulthood. Therefore, even if they prove to have high testosterone levels in blood, they should be allowed to compete as women.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxyase or 11-hydroxylase deficiency might cause high levels of testosterone if untreated or undertreated. So far, no such athletes have been detected during anti-doping screening.  Finally, women with true hermaphroditism, born with ambiguous genitalia might further virilise in and after puberty. Since they are assumed to respond normally to high testosterone levels, they would fall into the same category as 5αRD.

The present regulatory rules for women with extreme hyperandrogenism are that women with testosterone levels above 5 nmol/L should be subjected to investigation. If doping can be made probable, antidoping rules will be applied. If doping is excluded, the preliminary results of endocrine screening will be reviewed by at least two members of a standing expert panel. They will make recommendation to the IAAF medical commission to proceed or not with a full DSD work-up at one of the five internationally accredited tertiary centres for DSD diagnosis. The chairman of the expert panel advises the IAAF medical commission on whether the athlete should be required or not to suppress her testosterone levels by medical means, and the modes of follow-up during suppression. If the athlete accepts suppression, she will be monitored in order to prove that her testosterone remains below 5 nmol/L for at least 6 months before she is allowed to compete again in the female category. It is known from lay press that Caster Semenya has very high testosterone levels in blood.

Paul Saenger: What was her diagnosis?

Ritzén:  Her medical diagnosis has not been publicly revealed.

Saenger: Was she CAIS?

Ritzén: It cannot be, because she would not have masculinized.

Audience: Then I wonder why testosterone should be a parameter to distinguish between male and female, because it would not catch the entire androgen insensitivity syndrome.

Ritzén: Let’s first go back to testosterone levels: if you have combination of high levels of testosterone and masculinization, it cannot be CAIS. If you have PAIS, raised as female, you then have very low androgen sensitivity. Provided that you were accepted as a girl at birth, maybe with some mild clitoromegaly, and then raised as a girl, you would probably maintain the same low degree of androgen sensitivity in puberty and later. So, I doubt personally, but I don’t have any scientific data backing this up, that anyone with PAIS raised female would ever have a benefit from testosterone. I base this on the few male patients with PAIS that I have treated outside the sports world. Even very large doses of testosterone had little effect on the  appearance of their genitalia. I don’t know if anyone of you has had similar experience.

Anyway, during the seven years that I was chairman of the expert panel for the IAAF (2011 – 2018), 15 cases brought up for evaluation and diagnosis: They were all from Africa, most with 5αRD  (all but 2).  I think this is easy to explain; they were born in villages, with low levels of medical care. We do not know the level of virilisation at birth, but they passed as females. But at puberty, when the testes start to make testosterone they start virilising.

Saenger: If the testosterone regulation on classification still holds, this problem in the South African woman is still unresolved, and I find it disheartening that the athlete continues to appear in competitions. It is interesting that she only is doing the 800 m, apparently, this advantage gets washed out if she does shorter periods, this is unheard off.  I understand why the 2-3rd athlete would complain.

Ritzén: In the official papers in 2011, she was asked to comply with the regulations that said that such high levels of testosterone, you have to reduce it for at least 6 months before she can compete again as a female. The simple way would be with the oral contraceptive pill, which would lower LH and FSH and thus lower testosterone levels.   But between 2011 and 2015 she lost most international races. Then in 2015, the regulations that were introduced in 2011 were challenged by Caster Semenya’s lawyers in the court of arbitration in sport (CAS). CAS acts as a court, where an athlete can complain about the management of their respective sports authorities. In 2015 an Indian sprinter Dutee Chand complained to CAS over the way the Indian sports organization had prevented her from competing, due to her high testosterone levels in blood. Lawyers representing Ms Chand and the IAAF presented their case, and when we broke up, all of us were convinced that the Court would go for the IAAF line, prohibiting high testosterone woman from competing in international competitions. But three months later, CAS suspended the regulation for two years, awaiting proof from IAAF that there is a quantitative correlation between testosterone levels and physical performance. The experiment to prove such a causative effect of testosterone would be to take a group of female athletes, randomize them to active compound and placebo, and give them different amounts of testosterone and see how they perform.  Such experiments would not be ethically acceptable, if enough testosterone to reach male levels would be the goal. A correlation between testosterone levels and performance in healthy elite female athletes was published in 2018, and the regulations were re-introduced, but IAAF accepted to use these only for running events 400 – 800 meters. Stephan Bermon had meanwhile proved that the correlation was valid for these events, and for 1500 meter. The latter was not included into the new regulations, since no hyperandrogenic athletes have so far been detected among the 1500 m runners. This new regulation is in effect since 2018. Presently, testosterone measurements are part of the anti-doping testing; all athletes of international competitions (World championship or Olympics) will have their testosterone levels tested. It is now easier to pick up female competitors with high testosterone levels in the male range.

Many of the athletes that after 2011 accepted to suppress their testosterone levels ended the medication after the CAS 2015 suspension of the regulations. Their athletic performance deteriorated during suppression but improved again following cessation, only to get worse again during renewed suppressive therapy.

If androgenic and anabolic hormones are administrated to athletes, it is punished as a doping violation. The effects of administered and endogenous testosterone are the same.

Strong feelings have been expressed about the IAAF regulations, both by lay people, scientists and ethicists. It is difficult to predict what direction the discussion on the regulations will take.

Ze’ev Hochberg: But Martin, is it true that females on oral contraceptives perform less well than without contraceptive?

Ritzén: Yes, we can compare the results in competition during the periods before 2011, during regulation until 2015, then a period of no regulation for 2 years after 2015, and there is a definite correlation. Semenya is the best case maybe; she was performing less well under treatment.

Saenger: But I don’t think this is a good scientific argument. To me, it is disappointing to bring lawyers that can sue for everything.

Ritzén: I am not basing this on Semenya only; all women that were found to have high levels of testosterone, before and after suppression, had better performance before suppressing testosterone. But is it not 100 cases. I think it’s pretty much proven by now.

Saenger: You talked about gender fluidity, the time is going to come when all of this gets thrown out, as there are now 3 genders in Germany, so man/woman separation does not work anymore, it becomes a challenge without the lawyers I hope, it’s clear the time will come when these things are not easily separable.

Ritzén: No, it is definitely not easily categorized. But now we’re touching on transsexuals.

Jan Lebl: Just a brief question, was a study done among male athletes? There should be a correlation between testosterone levels and performance, as there is a wide range of testosterone levels in man.

Ritzén: No, it is not that good correlation in males, and one reason may be that if a man trains very hard he will suppress his testosterone; for example, marathon runners often have low levels of testosterone.

Audience: Unless they run behind a woman!

Audience: They used to say that epitestosterone/testosterone ratio would clarify this, because in endogenous testosterone production you make both, and when you inject, there is only testosterone, and the ratio is off, so this is how you would pick out cheaters; is this correct?

Ritzén: This ratio is used in anti-doping work. However, it varies depending on ethnicity.

Arnhold: As pediatric endocrinologist, we have to take care and help patients with DSD, previously called disorders of sex development, and now it is more politically correct to say differences of sex development. Dealing with DSDs, we learned that it is a defect of nature, and we do the best that we can, but sometimes it is impossible to have an optimal result. Individuals with DSD are overrepresented in the sports field, where they are more frequent that in the general population. It is a problem for a person who was born female, lived and raised as female, excels in her sport, is a national hero, and then is told that she cannot compete anymore, or that she has to artificially lower her hormones to compete. This is a challenge.

Ritzén: I think that is the remaining difficult question: is it ethically acceptable to prevent someone from competing because she was born with a certain condition? Is it acceptable to request DSD athletes to suppress their testosterone levels, although they have not cheated, only taking advantage of their natural hormonal situation? Administration of anabolic steroids would be cheating, but she has not done so. Why should she not be allowed to compete among women? On the other hand: Is it fair to other female athletes to make them compete against women who have a male body (when it concerns muscles and haemoglobin levels)?

Arnhold: But then you also compete with other people who are taller than you, have better nutrition and socio-economic backgrounds. So there are many other factors involved.

Ritzén: But these factors are not distinguishing between male and female. Within the two categories, tallness is prevalent in both male and female. So it is not the natural definition between these two categories.

Arnhold: I looked at male and female finish times at the 800m race in the 2009 IAAF Championship: the time difference between the first male and first female (Semenya) was 10 seconds or 10%. However, the difference between Semenya and the second female was only 2 seconds or 2%. On the same race the men ran 10% faster.

Ritzén: 2 to 3 % means the difference between no 1 and no 20 in a competition.  That’s the problem. Even 2% is enough in this context.

Arnhold: We know that androgen sensitivity is very difficult to measure so we don’t have an answer.  I know that Caster lost an appeal. The limit of testosterone that was acceptable dropped from 10 nmol/L to 5 nmol/L.

Ritzén: The reason for the 10 nmol is in PCOS. There is a Canadian study studying the testosterone levels in woman with PCOS, with a pre-requisite of virilisation to accept the diagnosis. They had a mean levels of 3.5 nmol/L: so +5 SD in that group was 9 nmol/L. 5 SD means 1 in 10,000 or something like that. Now, the new limit, 5 nmol/L, is based on studies by Bermon, looking at 3 different world championships, reaching 3 SD above the normal female mean, so they ended up with 5 nmol/L. Also, it is based on tandem mass spectrometry, rather than immunoassay.

Ken Ong: So I understand and accept that T to determine eligibility is far better than karyotype and SRY: but do you think it is sufficient?  One question: 6 months of low T may not overcome all the benefits of a lifetime high T for 20 years? Even if CAIS is really complete, such individuals have normal male birth weight and male adult height. Do you think Testosterone is sufficient?

Ritzén: It is not the only factor. It is fascinating that, in the Olympic Games, there is a clear overrepresentation of the females that have been castrated early on during childhood. It looks like the Y chromosome in itself added something beneficial to the sports. We can’t cover everything; T is a factor that can be measured.

Jan-Maarten Wit: What about 17 ketoreductase deficiency? I would assume that some of your patients/athletes that perform very well would have that diagnosis: did you see many cases?

Ritzén: No we are not seeing many cases of those; they will not be caught because they don’t have high T level. They have high androstenedione levels.

Wit: But they do perform better in sports.

Ritzén: Yes, because androstenedione is also an anabolic steroid. But we can’t cover everything.

Wit: There were countries like East Germany where doping was the rule: wouldn’t it be possible to get their data and have answers to your questions? Let me just add one more issue that shows the problem: now, we also have handicapped Olympics, and we wonder how they could be compared with such different phenotypes: is there also someone investigating like gender in that area?

Ritzén: I think they are treated the same as any other competitive athletes. The first question can be answered: there is a publication (Francke and Berendonk, Clinical Chemistry 43:7;1262–1279 (1997), who reported on studies by scientists in DDR that describe doping experiments. Women athletes were given anabolic steroids or testosterone and their sports performance was measured before and during doping. One conclusion by the doping scientists was that they did not believe that anyone could win a gold medal without being doped!

Audience: At the time it was true (laugh).

Ritzén: There are diagrams showing the sky rocking difference of times between before and after doping. Some of the protocols were burned.

Hochberg: Often times there are extreme physical  differences between professional athletes and normal people: I can imagine someone with mutations that give him for instance syndactyly and he is a better swimmers, or people with genes that give them stronger muscles. Imagine people like professional American football players, they must have some special genes: would you agree to play against them?

Ritzén: There are many features that make you perform better in sports, like a tall stature, but it does not discriminate between male and female, and we are only discussing differences between males and females.  Sports is divided into female sport and male sports.

Arnhold: From a medical perspective, I can see that a female patient would want to lower her T levels for her physical attributes. But for a competitive athlete, some of them risk their lives and would do anything to get better performance.

Ritzén: Many athletes benefit from having high T levels and benefit from excelling in sports. Take Caster, she comes from a poor village in South Africa and now is making a fortune, so she would not want to lower her T levels because she does not want to lower her performance. This comes back to the ethics.

Arnhold: Caster apparently didn’t know about her condition until she was excelling in sport. If she and other patients would be diagnosed early and receive the appropriate treatment, this would not happen.

Ritzén: It’s an ethical dilemma. Shall we prevent her making money and pursue her career?

Ong: Do you apply the same criteria to transsexuals?

Ritzén: The discussion for transsexuals in sports was brought up in 2004; it was discussed by a consensus committee of five people, appointed by IOC. I was one of them. The resulting recommendation was that If you transfer from male to female, you have to wait for two years after castration. At that time, castration was the rule. Now, in Sweden and many other countries, individuals can go to the authorities and say: “now I’m a woman”, without any medical workup at all. This poses a big challenge for the sports authority.

Ong: The two years has not been challenged?

Ritzén: The reason behind the 2 years is because in a study from the group of Gooren, it was shown that muscle mass decreases during the first 15 months after castration. After that period, it remains about the same.

Lyne Chiniara: I care for trans patients at Sainte-Justine hospital, and we see less and less trans patients getting gonadectomized; what about these patients that are on androgen blockers, for instance spironolactone; their T levels would still be elevated but would not have any impact because of the medication; would they be banned from competition? What happens in this situation?

Ritzén: The regulations are being reviewed in order to get a proper scientific background, but it is not yet decided on how they should be managed if they keep their testes in place.

Audience: Last question, I know it is not the topic, but what about growth hormone?

Ritzén: There are anabolic effects of GH and many athletes dope themselves with GH. What do you think? Did you find much difference in your studies?

Audience: Highly trained athletes showed no additional effects of GH.

Ritzén: There may be a synergetic effects of anabolic steroids and GH. This has been speculated but not proven. Athletes take all kind of products. GH is now in the gym, in body-building to grow muscles and lower fat mass. They take testosterone and growth hormone together.

Michael Ranke: I have looked in the composition of GH preparations and found that there is little GH in those products. This was a Russian GH and looking at the price there should be little GH in there!

Ritzén: Unfortunately, even high quality hGH has been shown to be used as doping agents. Many athletes seem to believe in its anabolic features.

 

 

 

 

The evolving mechanisms of the Growth Hormone – Insulin-like Growth Factor (GH-IGF) axis and their causes of growth disorders

A conversation between Michael Ranke, Tübingen, Germany and Jan-Maarten Wit, Leiden, Netherlands, with contributions by Ze’ev Hochberg, Jan Lebl, Gabrielle Haeusler, Paul Saenger and Margaret Zacharin

Jan Maarten Wit: What were your ideas about the GH-IGF1 axis when you made it to the field of Paediatric Endocrinology?

Michael Ranke: Before I answer, first thank you for inviting me and thank you putting me together with my friend Jan-Maarten. To answer the first question: it’s like always when you start various aspects of your life without really knowing where it is going.

In 1972 I took the chance to continue my residency in paediatrics (which I had started in Düsseldorf under Prof. GA von Harnack) at the University Children´s Hospital in Tübingen, where Prof. Jürgen Bierich had become chairman in 1968. At that time, he was the most prominent paediatric endocrinologist in Germany. The hospital had a laboratory for hormones and biochemical and experimental research headed by Prof. Derek Gupta from London. I was convinced that Tübingen was the best place in Germany to learn the trade of paediatric endocrinology solidly. As the youngest in the group I was of course put on the kind of remnants from the more senior fellows: on the thyroid and on everything that had to do with growth hormone (GH), such as performing the RIA assay, iodination of trace, etc. Thus, I was confronted with the question: How does GH act at the cellular level? Prof. Bierich knew Prof. Bongiovanni from a visit in Baltimore, and Prof. Bongiovanni had the aspiring young professor, John Parks, in his group who had studied at the NIH. John Parks had learned about the B lymphoblastic human cell line (IM-9) from Prof. Jessie Roth. The cell line was used by various famous scientists during these years (e.g. P Gordon, CR Kahn, Pierre de Meyts, Ron Rosenfeld, Ray Hintz) for the study of insulin and GH receptors, including their regulation, internalization, and shedding. This was an exciting new area and a promising tool.

Wit:  Can you say something more about what you investigated in your time in Philadelphia with John Parks?

Ranke: I went to Profs. John Parks and Alfred Bongiovanni at the Children´s Hospital of Philadelphia (CHOP) on a grant from the German Research Foundation (DFG) in 1973. The plan was to study the effect of oestrogens on GH receptors in the human lymphoid cell line IM-9 [1], to find the mechanism of the inhibitory effect of oestrogen on growth. Although these studies were without much success, I learned a lot about assays, receptors, numerical analyses of binding, in collaboration with David Rodbard (a famous mathematician at NIH).

I also learned much about GHs (human and from other species) and prolactin. Prolactin was discovered by Henry Friesen from Manitoba, who investigated almost all aspects of prolactin with his many fellows and colleagues (P Kelly, P Hwang, B Posner, a.o.).

At the same time Charles Stanley, who much later made his name on the genetics of hypoglycaemia, did a fellowship at CHOP with Lester Baker in diabetology. He had learned how to isolate viable hepatocytes from rats for metabolic studies. We somehow collided one day and with the different experiences we decided to study the binding of human GH (hGH) and other peptide hormones to these cells. At that time the role and mechanisms of GH interaction with the liver and its role in “somatomedin” (the previous name of insulin-like growth factors) production had not been completely elucidated. It was also assumed before that hGH binds only to lactogenic receptors of the female (or oestrogen-treated male) rat. We were able to show that there are also somatogenic receptors in the rat liver mediating the effects of GH (e.g. IGF production). Interestingly, the lactogenic binding sites to which hGH binds were lost when female rats were hypophysectomized and this could not be restored by oestrogen treatment [2, 3]. These findings and my studies in the field also made me very curious about Somatomedin (SM).

Wit: Back in Germany you became a very successful investigator of Somatomedin and its binding proteins. Please tell us about that.

Ranke: During my absence from Tübingen, Prof. Dieter Schönberg had established the SM bioassay in our lab using the incorporation of radioactive sulfate (S₃₅) into porcine costal cartilage developed by Prof. Leo van den Brande [4], who had trained with JJ Van Wyk in Charlottesville. But then Schönberg had become chairman of Paediatric Endocrinology in Heidelberg, so I took it over. The SM bioassay required utilizing the cartilage from rather young pigs (approx. 3 months old), which incidentally were slaughtered at that age for other scientific reasons at the department of veterinary medicine and agriculture nearby. Thus, every Monday I went to the slaughter house to collect the material and started to measure SM activity in sera of numerous children with various disorders and from rats subjected to endocrine experiments of hormone deficiencies and hormone excess.

While during the years 1975-1980 I amassed a wealth of data with the SM bioassay and had written a PhD thesis about this, SM research had gone much further in various other research institutions. The confusion of the nomenclature (SMC, SMA, MSA, NSILA) disappeared when Rinderknecht and Humbel from the group of Rudi Froesch in Zürich published the structure of IGF-I and  IGF-II [5, 6].

By 1980 the group of Froesch (Jürgen Zapf) and Michel Binoux and others had discovered that there were binding proteins for IGF in blood (IGF Binding proteins, IGFBPs). I had established contact with the group in Stockholm (K. Hall, L Fryklund) and in Zürich (J Zapf) and the group in Charlottesville (van Wyk, L Underwood)  in order to establish modern assays for the measurement of IGFs [7].

Eventually, the development of assays for IGF-I, IGF-II, IGFBP-3 and IGFBP-2 succeeded and the study of the role of these peptides as diagnostic tools in growth disorders and their functional role in the growth process were studied from 1980 in many groups. In Tübingen this became possible by Werner Blum who was a biochemist and MD and had the “golden laboratory hands”, in collaboration with a number of other researchers in my department [8-12].

The special role of IGFBPs, in particular IGFBP-3, the most abundant IGFBP after birth, is manifested by their high structural complexity. The IGFs, Acid-Labile Subunit (ALS) and IGFBP-3 form a “ternary complex” with a size of about 150 kD, which functions as a reservoir of IGFs in the circulation, inhibits their degradation and functions as their transporter. A genetically caused impairment of ALS was later observed to cause impaired growth [13].

IGFBPs have several functional roles, many of which are associated with the functional regulation of IGFs (IGF-dependent effects), such as (a) the transport of IGFs in plasma, the control and regulation of the efflux from the vascular space and their clearance, (b) the tissue-specific direction of IGFs, and (c) the modulation of the interaction of IGFs with their receptor. For example, the multitude of possible modifications of IGFBP-3 (phosphorylation, glycosylation, proteolysis) can lead to a change in the affinity for IGFs, thus have a functional role for the effect of IGFs. In addition, some IGFBPs may have IGF-independent effects at the cellular level which are of relevance for cell proliferation, cell adhesion, cell migration and apoptosis [14].

It has been fascinating to see that primary defects of IGF production, availability or IGF-I insensitivity have been observed as distinct causes of growth disorders. Examples include GH receptor mutations, genetic alterations in components of the GH post-receptor cascade (e.g. STAT5B , STAT3 and PTPN11 mutations), and IGF1, IGF2, IGFALS and IGF1R mutations. The discovery of new defects in the area is still ongoing [15].

In addition, an excess of IGFBPs, either as a result of renal insufficiency or caused by an impaired cleavage of IGFBPs due to a genetically caused  complete absence of PAPP‐A2 proteolytic activity, was shown to diminish circulating free IGFs and consequently result in impaired growth in children [16, 17].

Wit: In your work on the complexity of the IGF/IGFBP system you became also involved in the treatment of GH Insensitivity (for example Laron syndrome). Can you tell us about your opinion about the treatment of recombinant human IGF-I?

Ranke: By 1979 hGH was cloned in E. coli [18] and in 1982 a methionyl-rhGH became available for us in Tübingen from Kabi/Sweden for a phase III study in GH deficiency (GHD). The product had been developed in collaboration between Genentech and Kabi. From 1987 onward authentic recombinant human GH (rhGH) was marketed in Europe.

Recombinant human IGF-I (rhIGF-I) was first used for treatment in primary IGF deficiency (IGFD) by Zvi Laron in 1988, who had first described GH resistance which turned out to be a GH receptor deficiency  [19]. Treatment with rhIGF-I was studied subsequently in a cohort with IGFD in Ecuador [20], the USA [21] and by a consortium in Europe which I became involved with [22].

The experience with rhIGF-I treatment, though apparently pathogenetically correct, was not very encouraging. The gain in height was only modest, children were at risk for hypoglycaemia, often developed obesity (an IGF-I effect via insulin receptors) and developed early puberty. One of the remaining problems is that the low IGFBP-3 observed in severe primary IGFD is not affected by rhIGF-I replacement. Observational studies in less severe primary IGFD are ongoing.

Wit: Let me now ask your opinion about some problems that we all have seen surrounding the diagnosis of GH deficiency. First, I would like to hear your opinion about the concept of Growth Hormone Neuro-Secretory dysfunction described in NIH.

Ranke: Soon after GH was measurable by radio-immuno-assay (RIA) in 1963 [23] it was observed that its secretion is pulsatile. Kowarski in the group of Blizzard in Baltimore [24] propagated rightly that the true secretion rate of GH could only be determined by frequent sampling. This is obviously correct, but there are practical hurdles and caveats to this approach. Still, many investigations have shown that there is a low correlation between spontaneous GH secretion over 24 hours and the GH peak after pharmacological stimuli. 

In 1984 Barry Bercu and Bessi Spiliotis at the NIH (Bethesda, USA) had described a group of children without known organic damage behaving like children with idiopathic isolated GHD (IIGHD). This condition was termed Growth Hormone Neuro-secretory Dysfunction (GHNSD)  [25] and met the following criteria: height less than first percentile; growth velocity 4 cm/yr or less; bone age two or more years behind chronological age; normal findings from provocative GH tests (peak greater than or equal to 10 ng/mL); low somatomedin-C level; and an abnormal 24-hour GH secretory patterns. One might call this “idiopathic GHNSD”. This became an enormously popular diagnosis after rhGH became available.

Not much later the idea of an impaired spontaneous GH secretion in the presence of a “normal” secretion of GH to provocation tests was stimulated by such findings in children after treatment for malignancies [26]. In light of the presumed damage to the hypothalamo-pituitary area one could call it “organic GHNSD”. However, recent investigations have shed doubt on this assumption [27].

I believe that organic GHNSD probably does exist in children after CNS trauma. Idiopathic GHNSD without anatomical CNS anomaly does probably also exist, but is rare (approx. 4% of all GHD) [28].

Wit: In the article you published last year, the frequency was almost 10%.

Ranke:  Yes, we stated that it was 10%, but this figure is not a very exact estimate. Again, in my personal opinion, I think that “idiopathic” GHNSD   is existing. However, one has to be very thorough to make this diagnosis, because it is statistically unlikely.

Wit: This will be my last question, and then we open the discussion to all participants. There are not only uncertainties about GHNSD, but also about idiopathic isolated GHD (IIGHD). What is in your opinion the best way of diagnosing IIGHD? How frequent is it, and what should be the diagnostic approach?

Ranke: This is one of those 100 Dollar questions in GHD. I do not know whether there is an evidence-based accurate answer to the question. The first reason for this is that it is difficult to establish the diagnosis of GHD. Every paediatric endocrinologist knows the problems of defining an impairment of GHD in children, due to the uncertainties surrounding the tests, cut-offs, etc. Secondly, it is also difficult to diagnose other pituitary hormone deficiencies, for example gonadotropin deficiency before puberty. Thirdly, the term idiopathic means that likely causes of a GH impairment [e.g. brain trauma (mechanic or by irradiation), specific gene defects, anatomical defects of the pituitary region] are absent.

However, despite all of this, I will try to make a reasonable guess based on long-term experience. Based on a review by Frisch [29], the number of isolated GHD in the pre-recombinant era (which was of course also a pre-MRI era) was about 50%. At that time age at GH start was about 11 yrs, mean height SDS was -4, and the GH peak to testing < 7 ng/mL. In our own series < 1987 with similar characteristics the  relative frequency of isolated GHD in so-called idiopathic GHD was 39% [30].

I would conclude that with all the additional diagnostic tools available, IIGHD is even less frequent today. In children with very severe GHD  (max GH < 3 ng/ml to tests)  and in children diagnosed very early (< age 3 years) IIGHD is likely to be less frequent [31].

Wit: Thank you very much; we open the discussion to the participants.

Ze’ev Hochberg: Despite the tremendous progress through the years in understanding the mechanisms through new molecules and their mutations and polymorphism, we still know very little about the why question. Why it is that one child is shorter than another? What we do know is that this is programmed very early in life. If you look for example at the studies of children who immigrated to America from Guatemala, you can see that within a single generation they grow taller by 4-6 centimetres, and all of it within the first three years of life. So something in the environment of the child moving to America makes it grow better than it would have grown in Guatemala. And of course we know that there is the effect of a psycho-emotional stress on the child. I think we probably overemphasize the effects of GH. We concentrated on giving GH to too many children, and lost this important question of why things happen the way they do. You have previously introduced the neuro-secretory dysfunction; this forgotten entity is probably the mechanism explaining how growth responds to the environment. So, its role may be central.

Ranke: These are complicated questions. First let me dwell a moment on the issue of what regulates height. First the observation by James Tanner that normal linear growth was directed towards a target inherited in equal parts from the parents and his subsequent theories about a central “sizostat” has influenced our thinking [32]. However, animal experiments in rats conducted in the 1980 have already suggested that catch-up growth is not associated with an increase in GH secretion [33]. Thus, the neuroendocrine theory of  CUG was not fully substantiated empirically. Nevertheless, animal experiments have shown that both systemic (liver-derived) and local IGF-I and GH are required for normal longitudinal bone growth [34, 35].

A new approach of thinking was proposed and experimentally documented by Jeffrey Baron who put the focus on the growth plate as the major determinant of linear growth. It is known that cells of the cartilage lineage undergo a transition from resting (stem) cells to proliferating chondrocytes to hypertrophic chondrocytes until calcification ends the process. The magnitude of the process – from origin to senescence – , that is the number of cell divisions, is obviously under genetic and humoral (endocrine, paracrine, autocrine) control. The normal course of the process requires an intact “milieu interne” – including nutrition, hormones etc. Baron’s amazing suggestion was that in the case of disorders inhibiting growth the process of cell senescence in the growth plate is interrupted. When the defect is corrected the “resting” system “awakes” and the missed process occurs at a faster pace, resulting in CUG [36].

So the question is what is the mechanism how adaptation to the environment takes place, and what do we mean by “environment” actually? The adaptation is to food, quantity and quality, it is to altitude, just to name few things. In the Andes people are short and the Masai are tall, despite the environmental difficulties.  What causes the adaptation I don’t know. One other area that has stimulated thoughts and some ideas about this is intra-uterine growth, and its inhibition. I found it, like you do, extremely interesting that these adaptation progresses do not occur through multiple generations, but within a short time. Another example comes from palaeontology. In Sicily there used to be African elephants, who still had the possibility to walk uninhibited over land to Sicily. When the water came into the Mediterranean and separated Sicily from Africa, the elephants were captured, and in this “extra-African” environment, that did not give them enough food.  The elephants within generations shrunk to the size of a horse. So there is “something” going on, which is not simply understood by hormone secretion or food adaptation. This “something” must occur on an adaptational level which is possibly epigenetic and is affecting hormones, the growth plate and other levels of metabolism. I can only speculate, but this is one of the things that deserve research.

Jan Lebl: You mentioned the importance of the acid labile subunit (ALS). What’s your opinion on the significance of investigating children for a defect in the gene encoding ALS (IGFALS)?

Ranke: The ALS story is really very interesting. Patients with IGFALS defects vary in stature; some of them are short, some are not. This is the interesting part. In general, measurements of ALS may be valuable in the differential diagnosis of  short children with low IGF-I and IGFBP-3 [37]. I know ALS deficiency from the literature, but I have no personal experience with such children. Perhaps somebody around the table knows more about this.

Wit: Yes, it is an important diagnosis and a specific diagnostic clue is that IGF-I SDS is low and IGFBP-3 SDS even lower. What we do as a next step in such children is perform DNA testing and check for an IGFALS defect. We found in 5 big Turkish families that they are often born SGA, so ALS deficiency should be part of the differential diagnosis of SGA as well as of ISS.

Gabrielle Haeusler: Yes, ALS is interesting not only because primary ALS deficiency has a phenotype. We decided to introduce an assay for ALS determination and developed reference data in children. We did so because we wanted to investigate the possible role of ALS determination in the biochemical diagnosis of GHD. ALS like IGFBP-3 and IGF-I is decreased in GHD, it follows the same cascade of GH signalling. What we found is that ALS determination is of no additional benefit as compared to determination of IGF-I alone. Also, routine determination of serum ALS during diagnostic work-up for short stature did not lead to diagnosis of further patients with an ALS mutation. If you suspect ALS deficiency, it’s because of low IGF-I and IGFBP-3. IGFALS is a small gene with two exons, so the genetic analysis is relatively easy and therefore preferable.

Paul Saenger: It is impossible to separate environmental impact on growth from nutritional factors. We heard about small elephants in Sicily, as an example of adaptive downsizing. There are many examples in other parts of the world. On the Channel Islands in California they found small Mammoth skeletons –  adaptive downsizing to nutritional restrictions is the guiding principle. Homo  floresiensis was very small, maybe because they lived on the tiny island of Flores (Indonesia). Eager colleagues in Pediatric Endocrinology tried to explain it as congenital hypothyroidism or even more esoteric –  as the first example of Laron Syndrome. In my opinion, this was just another example of downsizing because of nutritional limitations.

Margaret Zacharin: The question is if in children growing up here in Austria, where there is plenty of food, there is any impact of food. In children in Africa where the children have little to eat one can presume that poor nutrition has an influence on growth, but in rich countries … (?).

Ranke: I think that the impact of what you are mentioning is that some people (even paediatric endocrinologists) are selling food components suggesting that these make children grow. On the other side, this belongs to an area that has not been investigated in a scientifically sound mode. Growth plays on nutrition, but the mechanisms are obviously quite complex.

Zacharin: In IGHD, which seems to resolve in 75% of cases at the end of linear growth, good health and energy remain when demands for GH and growth factors are low, in contrast to a group of irradiated individuals who, when they cease their GH for GHD, at the end of their linear growth, feel dreadful and remain unwell until GH is replaced. Do you have an explanation?

Ranke: These are two things. Are you talking about delay of growth as a part of idiopathic short stature (ISS)? That is something that has been researched and suggested in the 1980’s.

Zacharin: I am really talking about GHD.

Ranke: I want to make this point. In delay of growth and adolescence GH secretion appears low in pre-puberty. However, in the presence of sex hormones eventually all such deviations are gone.  In contrast, when a child had a head irradiation, the GH secretory system remains defect. It might well be that these patients are not recognized during the growth phase, but are recognized as GH deficient in adulthood.

Zacharin: The adolescent who has bona fide isolated GH deficiency – not ISS – confirmed by retesting at the end of linear growth does not have associated reduced energy anywhere near the level of disability experienced by those who have radiation induced deficiencies even though other hormones are adequately replaced.  Marked resolution occurs with administration of adult levels of GH. It seems unclear as to why this should be so.

Ranke: This is true.

Haeusler: I agree that what we face is this high proportion of patients with IIGHD who reverse their diagnosis in puberty. Are you aware of any study – very complicated for ethical issues- on young children who received low doses of sex steroids, and have been investigated to see if GH secretion normalizes? And growth? The pathological GH test normalizes after giving sex steroids to a child.

Ranke: You are raising this issue when you have a child who is short, not growing well, you did all the tests and you have low GH secretion, and you assume that the child has IIGHD. And then after years, you repeat the test, and then you cannot confirm the diagnosis (according to the established criteria). Then the question is: was your diagnosis wrong in the first place, or was the diagnosis correct but did the “defect” normalise in the end? In my view there is currently a tendency in the scientific community to say that what you have diagnosed earlier in childhood was more likely wrong than correct. Indeed, there was and is perhaps a trend to overdiagnose IIGHD, caused by parents, physicians and producers of rhGH. The question is, whether this can be avoided. Perhaps by “priming” children with sex steroid before GH testing?  Some believe it, some do not. Certainly there will and need to be further expert meetings on the whole complex of establishing the diagnosis of GHD in the future.

Wit: Our time is up, thank you all.

References

1              McGuffin WL, Jr., Gavin JR, 3rd, Lesniak MA, Gorden P, Roth J: Water-soluble specific growth hormone binding sites from cultured human lymphocytes: preparation and partial characterization. Endocrinology 1976;98:1401-1407.

2              Ranke MB, Stanley CA, Rodbard D, Baker L, Bongiovanni A, Parks JS: Sex differences in binding of human growth hormone to isolated rat hepatocytes. Proc Natl Acad Sci U S A 1976;73:847-851.

3              Ranke MB, Stanley CA, Tenore A, Rodbard D, Bongiovanni AM, Parks JS: Characterization of somatogenic and lactogenic binding sites in isolated rat hepatocytes. Endocrinology 1976;99:1033-1045.

4              van den Brande JL, Du Caju MV: An improved technique for measuring somatomedin activity in vitro. Acta Endocrinol (Copenh) 1974;75:233-242.

5              Rinderknecht E, Humbel RE: The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem 1978;253:2769-2776.

6              Rinderknecht E, Humbel RE: Primary structure of human insulin-like growth factor II. FEBS Lett 1978;89:283-286.

7              Furlanetto EW, Underwood LW, Van Wyk JJ, D’Ercole J: Estimation of somatomedin-C levels in normals and patients with pituitary disease by radioimmunoassay. J Clin Invest 1977;60:648-657.

8              Blum WF, Ranke MB, Bierich JR: Isolation and partial characterization of six somatomedin-like peptides from human plasma Cohn fraction IV. Acta Endocrinol (Copenh) 1986;111:271-284.

9              Blum WF, Ranke MB, Bierich JR: A specific radioimmunoassay for insulin-like growth factor II: the interference of IGF binding proteins can be blocked by excess IGF-I. Acta Endocrinol (Copenh) 1988;118:374-380.

10           Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR: A specific radioimmunoassay for the growth hormone (GH)- dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 1990;70:1292-1298.

11           Ranke MB, Elmlinger M: Functional role of insulin-like growth factor binding proteins. Horm Res 1997;48 Suppl 4:9-15.

12           Ranke MB, Schweizer R, Elmlinger MW, Weber K, Binder G, Schwarze CP, Wollmann HA: Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children. Horm Res 2000;54:60-68.

13           Domene HM, Bengolea SV, Martinez AS, Ropelato MS, Pennisi P, Scaglia P, Heinrich JJ, Jasper HG: Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. New Engeland Journal of Medicine 2004;350:570-577.

14           Ranke MB: Insulin-like growth factor binding-protein-3 (IGFBP-3). Best Pract Res Clin Endocrinol Metab 2015;29:701-711.

15           Ranke MB, Wit JM: Growth hormone – past, present and future. Nat Rev Endocrinol 2018;14:285-300.

16           Blum WF, Ranke WM, Kietzman K, Tonshoff B, Mehls O: Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor-binding protein (IGFBP) in uraemia. Pediatr Nephrol 1991;5:539-545.

17           Dauber A, Munoz-Calvo MT, Barrios V, Domene HM, Kloverpris S, Serra-Juhe C, Desikan V, Pozo J, Muzumdar R, Martos-Moreno GA, Hawkins F, Jasper HG, Conover CA, Frystyk J, Yakar S, Hwa V, Chowen JA, Oxvig C, Rosenfeld RG, Perez-Jurado LA, Argente J: Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med 2016;8:363-374.

18           Goeddel DV, Heyneker HL, Hozumi T, Arentzen R, Itakura K, Yansura DG, Ross MJ, Miozzari G, Crea R, Seeburg PH: Direct expression in Escherichia coli of a DNA sequence coding for human growth hormone. Nature 1979;281:544-548.

19           Laron Z: Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. J Clin Endocrinol Metab 2004;89:1031-1044.

20           Rosenbloom AL, Guevara Aguirre J, Rosenfeld RG, Fielder PJ: The little women of Loja–growth hormone-receptor deficiency in an inbred population of southern Ecuador. N Engl J Med 1990;323:1367-1374.

21           Backeljauw PF, Underwood LE: Prolonged treatment with recombinant insulin-like growth factor- I in children with growth hormone insensitivity syndrome–a clinical research center study. GHIS Collaborative Group. J Clin Endocrinol Metab 1996;81:3312-3317.

22           Savage MO, Blum WF, Ranke MB, Postel Vinay MC, Cotterill AM, Hall K, Chatelain PG, Preece MA, Rosenfeld RG: Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab 1993;77:1465-1471.

23           Glick SM, Roth J, Yalow RS, Berson SA: Immunoassay of Human Growth Hormone in Plasma. Nature 1963;199:784-787.

24           Kowarski A, Thompson RG, Migeon CJ, Blizzard RM: Determination of integrated plasma concentrations and true secretion rates of human growth hormone. J Clin Endocrinol Metab 1971;32:356-360.

25           Spiliotis BE, August GP, Hung W, Sonis W, Mendelson W, Bercu BB: Growth hormone neurosecretory dysfunction. A treatable cause of short stature. JAMA 1984;251:2223-2230.

26           Rappaport R, Brauner R: Growth and endocrine disorders secondary to cranial irradiation. Pediatr Res 1989;25:561-567.

27           Darzy KH, Pezzoli SS, Thorner MO, Shalet SM: Cranial irradiation and growth hormone neurosecretory dysfunction: a critical appraisal. J Clin Endocrinol Metab 2007;92:1666-1672.

28           Maghnie M, Lindberg A, Koltowska-Haggstrom M, Ranke MB: Magnetic resonance imaging of CNS in 15,043 children with GH deficiency in KIGS (Pfizer International Growth Database). Eur J Endocrinol 2013;168:211-217.

29           Frisch H: Characteristics of idiopathic growth hormone deficiency at the start of  growth hormone therapy and the response to growth hormone. ; in Ranke MBP, D.A.; Reiter, E.O. (ed) Growth Hormone Therapy in Pediatrics. Basel, Karger, 2007, pp 108-115.

30           Ranke MB, Schweizer R, Binder G: Basal characteristics and first year responses to human growth hormone (GH) vary according to diagnostic criteria in children with non-acquired GH deficiency (naGHD): observations from a single center over a period of five decades. J Pediatr Endocrinol Metab 2018;31:1257-1266.

31           Ranke MB, Lindberg A, Albertsson-Wikland K, Wilton P, Price DA, Reiter EO: Increased response, but lower responsiveness, to growth hormone (GH) in very young children (aged 0-3 years) with idiopathic GH Deficiency: analysis of data from KIGS. J Clin Endocrinol Metab 2005;90:1966-1971.

32           Tanner JM: Catch-up growth in man. Br Med Bul 1981;37:233-238.

33           Mosier HD: The determinants of catch-up growth. Acta Pæd Scand [Suppl] 1990;367:126-129.

34           Baker J, Liu JP, Robertson EJ, Efstratiadis A: Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993;75:73-82.

35           Yakar S, Sun H, Zhao H, Pennisi P, Toyoshima Y, Setser J, Stannard B, Scavo L, Leroith D: Metabolic effects of IGF-I deficiency: lessons from mouse models. Pediatr Endocrinol Rev 2005;3:11-19.

36           Lui JC, Nilsson O, Baron J: Growth plate senescence and catch-up growth. Endocr Dev 2011;21:23-29.

37           Domene HM, Hwa V, Jasper HG, Rosenfeld RG: Acid-labile subunit (ALS) deficiency. Best Pract Res Clin Endocrinol Metab 2011;25:101-113.

 

Liverpool, May 2021

Host: Joanne Blair

Scientific program:

A conversation between Carl Roberts (Liverpool John Moores University) and Gabriele Haeusler (Vienna University) about “Motivated behavior: eating”

A conversation between Joanne Blair (Liverpool John Moores University) and Alix Douglas, a person with Turner syndrome about “TS: the burden of disease”.

A conversation between Francis McGlone, (Liverpool John Moores University), and Orit Hamiel (Tel Aviv University) about “Touch in infancy, and how it influences the developing brain”.

Venue and directions: To be added in due time

A live conversation between

Stylianos Antonarakis, iGE3 Institute of Genetics and Genomics of Geneva

and

Jesús Argente, Universidad Autónoma de MadridIssues

With contributions by George Chrousus, Ana Claudia Latronico, Stefano Cianfarani and Christos Yapijakis.

Editor: Ivo Jorge Prado Arnhold

Transcribed from the live conversation by Esther Marten

Jesús Argente: We, pediatric endocrinologists, take care of patients and follow all of the progress in genetics and all of its new brand techniques. This allows identification of new diagnosis and new therapies. Therefore, we need to deal with this new knowledge and need to study hard to better understand what genetics can offer to clinicians.

So in a very informal manner we would like to have a conversation, a discussion in relaxed manner about the relevance of the progress that genetics has made in pediatric endocrine diagnosis. To talk also about the necessity of organized genetic laboratories, how many genetic laboratories we need in one country, even in the states, how many laboratories do we really need to make any advance in the area of one specific genetic diagnosis. Also about the analysis of the different techniques, where to apply what technique. So how the clinician should decide with every patient with a genetic component, what technique could be the best, the cheapest, maybe the most important one to make a proper diagnosis, so that we analyze the sample of the patients, and the parents later. Therefore, those are all of the questions that we would like to discuss. Of course, the most important thing for us are the patients, and when we are in front of a patient, we deal with a specific diagnosis and we deal with a potential approach to this kid, in order to offer our best. So Professor Antonarakis just to break the ice, what kind of reflections do you have with this small introduction?

Stylianos Antonarakis: I will answer the best I can all of your questions but I will leave them for the question period. And I will be very brief actually because I will talk about facts and not theories. I will give you an anecdote about briefness; my mentor was Dr. Victor McKusick at Hopkins for many years, and when I became an assistant Professor, he asked me to give a talk on the Mutations in Thalassemia (1981). Then he called me into his office and said, “young man I have this talk for you, and you talk about the variance in Thalassemia”. And I was delighted and asked Dr. McKusick, how much time do I have, he said, “15 minutes.” I turned this in my head and said It will take me one hour to say what I have to say. I said 15 minutes is not that much. He looked at me and said, “young man, if you cure cancer, it will take you five minutes to say it and the whole world will change.” then I learned my lesson and said thank you very much and went out and when I was at the door, I opened the door and then he said to me, “young man, I’ll tell you something else, when you propose to your future wife, how much time does it take to say yes or no, so I will try to be brief as crystals.”

So, I talk to you about facts and I start with the most important fact in genetics, the Genome. So what is the Genome? There’s a book of instruction, of information for each one of us of our future, of our destiny, of our development and our susceptibility to disorders. The Genome is big, tremendously big. It is 3.2 billion nucleotides from haploid Genome. So each one of us has a Genome, a finite Genome of approximately 6.4 billion nucleotides. Half from the father and half from the mother. 6.2 bases of gigabytes of information. Those in this iPhone I think are about 16 gigabytes of information. So in that iPhone, if I erase everything, all your WhatsApp that are on, I can put my Genome, plus the Genome of my Dad and part of the Genome of my Mom. So to give you an idea of how big the Genome is, but also how finite the Genome is, I represent to you in a kind of a book.

As you know the Genome is divided into several Chromosomes. The Chromosomes are like buses that transport the Genome from one cell to another, and from one generation to another. And its dividing Chromosomes, the smallest Chromosome, Chromosome 21, is about 1.2% of our Genome. Let’s say 1% for the sake of argument. And I convinced the Swiss Institute of Bioinformatics (SIB), to print Chromosome 21 for me, because I work with Chromosome 21 trisomy etc. So they did it. I give you the book, so you can take a look at this and appreciate. So this is a rare copy, the only copy that exists on earth printed. Its Chromosome 21 and it has 1470 pages and it has 248 nucleotides per line, letter, per line and has 31000 nucleotides per page and the total length is 46 million nucleotides and as I said its 1.2% of the human Genome. Try to appreciate, our Genome is about 80 times bigger. 80 books, you can put it in your library to enjoy it. And I argue that this is the most important text, the most important book for us humans, written. Perhaps a little bit more important than you can see the repetitive sequences etc. The letters are a 5 or 6 size in New York times text. This book is important. However, if you compare your Genome to that book, your Genome is a bit different from this. This is what we call the reference Genome that we had put after the sequence of the Genome in the database. This does not mean that this is normal Genome, actually there is no “normal” Genome.

If you compare your Genome to this, you will be a bit different. How much is the difference? The difference is that one in every thousand letters, thousand nucleotides is different between two randomly chosen Genomes in the population. So one in a thousand. So that means that for a 3+ Billion letters, you differ from another randomly chosen Genome about 3 million letters. Between 3, 3.5, 3.8 depending on your origin. If you’re an African, you have about 4 million differences. If you’re a European, about 3 million differences etc. Because the Africans are earlier, the first stalk of humanity, and therefore they have more time to accumulate variance. And not only some letters change, but also pieces of the text change. In other words, you may have from the copy you receive from your Dad, you may have a piece of DNA from one copy and from your Mom two copies, or three copies or four or five or ten, and that’s a normal variation and so we call this copy number variation. If we add the copy number variation with a single nucleotide variation, the letter changes, our Genomes are different form each other, for 0.9%.

So we are all Homo sapiens sapiens, because we are 99.1% identical, but we are 0.9% different. And that difference is fantastic. We are all different here, different intelligence, different orientations, different likings, different appreciation of the environment, and different susceptibility to disorders. So we are all different because when we copy the DNA, from one cell to another, or from a generation to another generation, the copy mechanism is extremely accurate. Fantastic actually, it is amazing how efficient and correct the copying of one DNA to another. I am talking to you for about five minutes perhaps and millions of my cells in the blood and the gut and elsewhere have been renewed, so I have copied all this DNA right now, and I pass it from one cell to its daughter cells. The copying mechanism is accurate, but not without mistakes. Every time we copy the DNA we make some mistakes. How many? One letter change in a hundred million letters. minus nucleotide, minus division. Every hundred million letters we make one change. So a new child that’s born from two parental Genomes, he or she has between forty and a hundred new variants, new mutations. So every time we do the genetic experiment, we add to the gene pool forty or a hundred variants.  And that in long term, there are about two hundred thousand years of existence on this earth, has made us very different from each other and has given us the variability. And the variability is important because we can adapt to the ever changing environment and can evolve. If we were monomorphic, if the environment changes in a bad direction for us we would all disappear. But because we are polymorphic, then some of us, because of our genetic variation that we have, we survive.

That’s a gift of nature that the organisms that survive are polymorphic. And we should celebrate this, this is a fantastic gift. However, as you know it very well, there’s no free lunch. We pay for this. And the price that we pay for this very ability, for this possibility to evolve and adapt, is that sometimes the variation that we have is pathogenic. It gives us all the genetic disorders. And as Theodosius Dobzhansky said in a fantastic book that he wrote in 1973, Dobzhansky was a major figure in population genetics at Cal Tech. He wrote that “nothing in biology makes sense except in the light of evolution” and you can think a little bit further, “nothing in medicine makes sense, except in the light of evolution”. So because of this very ability, we can see medicine now a bit different, in a different way.

Now let me challenge you, I argue that the causes of disorders are twofold. The tree of medicine, the trunk is divided into two main branches. The branch of genomic variation, and the branch of environmental variation. Or, in the leaf of the trees, in the further branching, some of the branches go together again, and there is an interaction in the Genome and the environment. And I challenge you, you are in medicine for many years now, I challenge all of you to find one disorder or one phenotype or one trait, that is not due to genomic variation and is not due to environmental insult variation, or the interaction between the two. I tried very hard to find one and have not found any yet. So because of this, I and many others think medicine as either genetic medicine, or environmental medicine. And I’m not an expert in environmental medicine, so I’ll talk to you about genomic medicine.

What is genomic medicine? It is medicine based on the individual genetic variation. Now if you think about this individual genetic variation, some people call it personalized medicine. A tremendous misnomer in my view, because personalized medicine is not only based on the genomic variation, it could be based on other variations. For example, could give you a different personalized medicine than your genetic variation. So in my view, let’s not use this. Second, Francis Collins at the NIH convinced president Obama to use precision medicine in my view another misnomer, we always try to practice precision medicine. What has changed is the individual genomic variation that we can now appreciate and measure, and therefore, the evolution of medicine is because we understand better our Genome. The variation is extensive, and could be common, that many of us have the same variants, or could be rare. And the rare variation is the one that is of the low hanging fruit because we can identify the causes of millions of Mendelian phenotypes, and we can find what we call high impact variants, that if you have one, you have a disorder, or we can identify the low impact variants, for which you need several of those and several combinations of those in order to develop one of the late onset common human disorders.

Now the late onset of common human disorders is extremely important in medicine. Extremely important. Because people that are not pediatricians, and other specialties and the population are mostly interested in late onset disorders that they have. However, in evolutionary terms, the late onset disorders are not important. Because our species and every species, every bisexual species dies with menopause. So what happens after the age of menopause in our species is not important in evolution. That’s why we’re not protected from the common, low impact variants that predispose us or cause the common complex phenotype of adult age. And most of the pediatric endocrinologists are dealing with the rare high impact variants. Now, if you give me your sequence today and I can sequence your DNA, quite cheaply actually, if you like for me to sequence your protein coding genes, I will ask you to pay 300 dollars of reagents and wait for a day or two. If you want me to sequence your entire genome, you probably need to pay about 1200 dollars in reagents and wait about a week. But even if I had all this sequence, for how much of this sequence I can make an intelligent, medical verdict. I can say something that is useful for the patient and satisfactory for the physician because we identify the cause of a trait. 0.3% about 40 million base pairs, 40 mega base of sequence. 0.3% because if you look at the databases today, you’ll find that we know 4171 genes that that could cause if mutated in a bad manner a Mendelian phenotype. And for the other 16000 protein coding genes that we have, we don’t know, so they are not today medically reimbursed. And it’s not only that, but you and I have about 19000 non coding RNA’s and long ones and about 2000 short non coding RNA’s and we have about 70,000 promoters and have about 600,000 enhancers and transcription factor binding sites. Very functional parts of the Genome that we have a smell of, we know that they exist. However, we don’t know that their variation causes different phenotypes. So all the genetic medicine today, the sophistication that you may think we have is based on this 0.3% and so the medical genome that I call today is 0.3% and tomorrow we expect that the medical genome will cover about half of our genome (50%). Why half? half is what the encode project and several other projects, mainly funded by the NIH but also Europeans contributed to it, have identified that perhaps half of the genome may be functional. And the other half is repetitive and perhaps its important. Some people doubt that it’s important and in the next thirty years I don’t think that we will touch the repetitive elements because we expect to find more etiologies in disorders in the functional element. The 50%. The repetitive elements you could think of as of an accumulation of DNA’s over evolution.

I’ll give you an example; let’s say that I buy a house when I’m thirty and then at eighty I will die and then I accumulate things, many things in the basement, and then I give the house to my child and the child does not throw anything out because she thinks that its of value, and then she also in her lifetime accumulates another basement and then she gives it to her children, and the children continue to accumulate, and then the Genome that we have today as 50% so called “junk”. Evolutionary it’s important not to throw anything away because when we throw away, because you are blind in evolution, you may throw out something important among these things. So we accumulate, but we don’t throw out. So you see the first goal, first research goal of today, the medical goal of the Genome, is to go from 0.3% to 50%.

Of course our genome is also a history book. We can say something about our ancestry, where we come from, what is our line in time. And we can find that I have a part of my chromosome eleven, like five mega bases of Ashkenazi Jewish origin. And if I look at my ancestry I won’t find one, but if I do the calculation, the mutation rate I can predict, theorize that in 7030, there was a Jewish genome that went to my genome. To my lineage of genome and then I probably have another 2% of my genome Asian. Then in 1450, I can say because of the mutation rate and the variants in that particular genome, that I had an influence in somebody with that particular genome now entered the lineage. This is called recreational genetics. We don’t care about this in medicine, except that because of the sectorization of the populations that they’re inbreeding, several groups of people develop their own disorders sometimes.

Now, let’s go to medical issues. When you have a client, a patient, a patient is somebody that you see that has a disorder. But in genomic medicine, let’s think differently. Everybody is pre sick. Everybody has a pathogenic variation or pathogenic variation that will make her or him susceptible to develop a specific disorder. So let’s not talk about patients, let’s talk about humans. So if you have a human with a specific phenotype that you recognize, and then you give the DNA for sequencing, and we recognize the variants, if they are genomes,  we cannot interpret them except for 0.3%, and in that 0.3% there’s a variant, and I use an example; 375 variants to sustain in humpty dumpty gene, and this variant is one among 23,000 variants that are defined in the genes, in the exome as we call it. The exome means the sequence of a protein coding fraction of the genome. So 1 in 23,000 is probably causative in the phenotype that you are interested in. And all the other ones are not. So the difficulty variant to find that one variant that is pathogenic among the sea of other variants that are not. And for this we rely on prior knowledge, prior probability, and prior knowledge for this kind of exercise. The databases.

We look at the databases and we find that this variant is found in a hundred different individuals that do not have the phenotype that you are interested in. Then you do the simple statistics, and then you say that this is not the causative variant. And you can use the same Aristotelian logic if you find nobody else or if you find it on everybody that has the same phenotype, you conclude that this is the causative variant. So the point is that the argument is mainly statistics. It’s a numbers argument. So for the majority of variants that we declare pathogenic, the argument is 99% statistical. Of course there are other arguments, if you have this variant in a model organism, mouse, or yeast, or zebra fish, or any other model organism, then you can study this variant and say whether it is pathogenic or not. But this argument, the model argument, the animal model argument is not as strong as the statistical argument. Somebody did the experiment in the BRCA1 Gene that causes if mutated deleteriously breast cancer in females and in some countries in males, and ovarian cancer in females too, somebody from Seattle, made all the variants that could exist in that particular gene, all of them. And then he used a viability of haploid cells and the finding was that about 30% of the amino acid changes are deleterious in that particular cell setting. However, a fraction of them are found in normal people, without any phenotypic significance. So the model organisms are fantastic but we have to use the information with caution. And then in everyday life people use prediction programs, programs that look at the amino acid substitution isoleucine leucine and valine if you interchange them then there’s not much of a difference because the side change is almost the same but if you have an arginine to a histidine a to a small one negative charge let’s say, the mutation is very serious if you have an arginine to leucine, both of them are positively charged the polar big amino acids, there’s not much of a difference so most of the programs of the prediction programs look at the amino acid substitution, they look at the frequency in the population, they look at the domain that they occur and they also look at the evolutionary conservation. An amino acid that is important is likely to be conserved. And a place of an amino acid that is changing very frequently, then is likely not to be important.

All these programs work that way, they give you an output that this variant is likely pathogenic, pathogenic, likely benign and something in between that is the nightmare to the geneticist. A real nightmare that’s called VUS (Variants of unknown significance), which are the majority of them today. The databases that you can consult for this prior knowledge, they exist, there’s a database of about 150,000 genomes that you can access, it’s called gnomad from the Boston Poly theorem the Broad Institute, there are other databases like the Craig Venter’s database is a database of about 10,000 Genome sequences, the Europeans were trying to put a database together of about 10,000 Genomes etc. But this number of genomes, let’s say 200,000 genomes that you can find today in the databases, are really not enough. The databases are very poor. So challenge number two, in genetic medicine is to enrich the databases for millions of genomes. Now one important thing here in databases is that if you have a database of variants, they’re worth nothing, if you don’t have a phenotypic assessment on them, a phenotype link to the variant. So the effort is to populate the database with variants, but also to populate the databases with phenotypes.

Then there’s the politics of databases which is important, most of the databases are on the other side of the Atlantic, and some of the databases are on this side of the Atlantic, and other databases are in Asia. And each one, because they get the money from a national pocket, and not from the international pocket, then the databases have a flag, have a color. And I argue in science that the databases should not be national, nationalistic. But the WHO which is in Geneva and I’ve shook hands with some of them, they should take this under their umbrella, and create genotypic-phenotypic databases that are international, accepted by others, by everybody, funded by the national programs, and that will solve the problems of accessibility and the problem of privacy. Now let me say one word about privacy, of course we legislate for privacy and we legislate against discrimination. However, some people argue that privacy does not exist. And if privacy does not exist in behavior, perhaps it would be difficult to have privacy in genomic variants. but the best argument for people contributing their genomes to the world’s database is that your client, your patient, comes for a genetic diagnosis, when we find a variant, that causes a disorder, how do we find the variant. We did it; we compare this variant to the databases. So we have a diagnosis because others contributed their genomes to the databases. So this altruistic solidarian argument is the best argument I think for people who contribute their variants because if they don’t contribute their variants, we cannot make a diagnosis on an individual basis.

George Chrousos: So Professor Antonarakis, your talk is very excellent in my opinion because you’re trying to be extremely vigorous with science in this particular case applied to genetics. But there is something where I would like to ask a few questions and also permit the audience to ask any questions that they want because we don’t talk about clients, we talk about patients. We are doctors and we work in university hospitals and genetics made great progress so in the 60’s we in the 70’s we preferred PCRs, and in the 80’s and 90’s we preferred sequencing. And now we have genome and we have and some geneticists say the is dead or chromosomal abnormalities.

But we still measure glucose and we need to incorporate genetics in our work, in our daily work. Briefly, how do you consider that geneticist and clinicians should get together to organize techniques to use for what purpose interpretation of technique. I understand all of the which take all of the databases, we know where it’s going and we know that we will find an insertion producing mutation and chromomycosis and creating a stock current is highly pathogenic if a specific phenotype that we are working with.

So how should we organize, collaborate together in a clinic with a patient, with a client, a human being, Geneticist and Pediatric Endocrinologist. How? and in a country like Switzerland how many laboratories of genetics do you think you need to take care of the Swiss population in terms of monogenic decisions?

Antonarakis: Well I will start with the last question. Which is quite easy actually. Before the introduction of the Genome analysis and diagnosis, the estimation was that we need one genetic center for about 1 million people. So Switzerland has 6 million people, so 6 genetic laboratories in different places to serve the population. Now that the Genomic analysis is a reality, and the search for variants is more laborious and the genetic counseling becomes more complicated. Then we still need 6 genetic centers, one per million, but with more people per genetic center. So the answer is, the question really is not how many centers we need but how many specialists we need, because we need six centers still, but we may need fifty people per center instead of three people per center. 

Chrousos: What do you mean a specialist, you mean geneticist doing clinics?

Antonarakis: Now, when we talk about specialists, I’m talking about two different branches, one medical branch and one laboratory branch. And we consider both of them equally important. So the medical branch is MD’s and the laboratory branch is PhD’s and since you’ve mentioned the country that I work in, my adopted country also, after the US, is that we have two specialties one for MD’s and one for PhD’s and there’s always the politics etc. and I don’t want to go into this, but you need both. And now that cancer became a genetics problem, because as you know cancer is a genomic problem of somatic cells and has to do with driver variants and rearrangements in the genome, now we need more and more and more to deal with the cancer categorization, the treatment choice, the monitor of the treatment, and the change of the treatment with relapses. So the six centers that I’ve mentioned to you, you need to add one center per million people for cancer genetics. So we’re talking about twelve now with several people in each one of them.

Now let’s go to your first question. What do we do with genetic investigation? If you like to look at this holistically, the best thing to do is to sequence the genome. Sequence once, and interpret many times. And the answer to the question is also financial. If the sequence of the genome goes below $400 a genome, which may happen in two to three years, then that will be the detection of choice. And I argue and I see it that many countries will introduce neonatal genomes, so everybody that will be born will have a genome done, and databased and this will be one component of the medical record indisputable and not questionable, and then we base our medicine on additional tests beyond this. In practice though, because genome sequence is still expensive, insurances doesn’t pay in many countries for genome sequence, insurances may for exome sequencing, all the protein coding genes as we have said. Then this is the diagnostic method of choice, but if you have a very strong clinical suspicion of one gene involved, you can only do that one gene, or if you suspect clinically a chromosomal disorder, then you can do a chromosomal analysis, perhaps not with the regular karyotypes but with micro hybridization or with some kind of cheap sequencing method in which you see the copy number of chromosomes plus the junction fragments of translocations. The diagnostic thing is in flux actually and it largely depends not on technology that exists, but on the cost.

Of course this is a vicious cycle, a new technology will bring the cost down, and therefore we use that technology. The problem in medical practices is that my generation and your generation will soon disappear from medical practice, and the new generations they don’t know or they’re not used to this clinical thinking that our generation had. The new generation will do genotype first, blindly and without any thinking, and then they will start to think about it after this.

Argente: I can see the reasons actually, I can see that in Spain I can see that in the States and I can see that everywhere I go, they start thinking about medicine as genetics. So that means that if you have a specific disease or a specific phenotype you need to find out an explanation due to a mutation in one specific gene. As a monogenic disease. Of course the base can have a syndrome, the syndrome can also be explained the genetic techniques or not according to our knowledge. But today, most of the medical residents, I’m talking about my personal experience in the field, they’re not thinking in terms of physical exam, you know what happened with your family, what kind of diseases you have, but in terms of genetics immediately you know, everything should be genetics. And the geneticists say, medicine isn’t genetics, even if you have a fracture in your thigh, can’t be explained by genetics really. But the geneticist like you right now, are really more prudent and say please don’t do medicine like that at least so far, because right now we have the possibility of being wrong, we have the possibility of applying something in an appropriate manner, or maybe what we consider is appropriate, maybe tomorrow we will know that it is not. And of course we follow all of the reports from the states that we’ve acquired so far, the amount of variants, mutations, pathologic mutations that are not, and this is quite important in order to follow medicine. Don’t you think so?

Antonarakis: I couldn’t agree with you more; we do our best with whatever we have. So with the prior knowledge that we have and the knowledge that we get, as I’ve said before, one good hypothesis is that genetics is extremely important for the etiology of disorders, on the other hand if we use only genetics today, we explain 0.3% of what is out there. So because of the lack of knowledge, we cannot apply genetics only today. There was a study two years ago by an international collaboration in which they asked the question; from all the patients that will go to a hospital today, how many of them will have a genetic disorder? a problem in the genome. And this was done from many monozygotic twins in which people share the same genome in the zygote actually, when the monozygotic twins grow older, they accumulate their own variants and they diverge with age, and it was estimated that 49% of the suffering in a hospital today, with todays knowledge, is due to the genetic variation. About 50%. And for that 50%, we can identify a very small fraction of the real variants that causes them. Now, you said something very important too, that we can say something about the high impact variants. Just remember this term. High impact variant that cause the Mendelian disorders. Or the digenic disorders or the trigenic disorders, or the oligogenic disorders. However, the medium impact variants and the low impact variants, we do not know much. And this is a mega challenge in medicine, not only in my field to identify the low impact variants that contribute to disorders. I’ll give you a low impact variant that you all know, there’s a gene for apolipoprotein E, that makes a protein, the apolipoprotein Apo E, and the Apo E comes in three flavors, three colors. A blue, a red, and something in between, a red/blue, according to two amino acid substitutions in positions 112 and 154. The red/red is cysteine in those two amino acids, and the blue/blue is another amino acid. The blue we call Apo E4. And a specific fraction of the population is homozygous for this E4. They have two copies of E4. Now if you happen to have a homozygous for E4, you have a 15 times more of a probability to develop Alzheimer’s disease than the normal population, if you are Caucasian, European. So that is what we call a low impact variant. Because it increases your possibility of a disorder, but is not deterministic like the achondroplasia variant for example. Everyone that has the achondroplasia gene, there’s a mutation in one amino acid, everybody has short stature and the bone abnormality. So the determinism goes a hundred percent to fifteen times more than the population. So the high impact variants we know, we conquer all of them, the low impact variants is a tremendous challenge, not only this but the low impact variants, they don’t act in in isolation actually even the Mendelian variants don’t act in isolation. There is no really Mendelian disorder. In all our books now we call them neo Mendelian because there are modifying factors of high impact too that change the phenotype. So for the common complex phenotypes there are many low impact variants that contribute to disorders. And perhaps there is one medium impact variant that triggers the appearance of a phenotype.

Argente: Good, so let me ask you a last question before passing the microphone to all of the members here in this living room, you’re Greek, come from a Greek origin, I come from Spain and we can understand each other because we are speaking in English. My question is; do you think that most of the clinicians today speak the same language that geneticists speak? 

Antonarakis: Of course not.

Argente: So we need to do a good deal of teaching people how genetics works etc. because we are spending a lot of money. In Europe for example, the number of private laboratories, doing any kind of techniques with no bioinformatics vigorous control is amazing. And we are spending tons and tons of euros doing something that most of the people really don’t know what they’re doing. And this is not moral. This is unethical in my opinion.

Antonarakis: I agree with you partially. However, you need experts. Socrates said: don’t look at what many people think, only look at what people with knowledge think. And the geneticist is something else that happened in our generation and I’m very proud of it, it is that the geneticist now has an organ of investigations. Something. When I started, the geneticist had the phenotype. He was a helper. A helper of others. Phenotypic assessment. Short, tall, dimorphic, big ears, etc. Now the geneticist, or the genetic medicine, or medicine, has this organ that’s the genome. As the cardiologist has the heart, and the neurologist has the nervous system, and the psychiatrist has I don’t know what, the geneticist has a different organ that is big but finite, don’t forget the finite. And the computer makes the finite shorter and shorter and shorter as time goes on and artificial intelligence and machine learning makes this shorter and shorter and more approachable. So I never expect that everybody will be on the same wavelength. And why be? we’d become monomorphic again. And I think the diversity of thought is healthy, and if there is diversity of thought, there is a need for MDs to take care of the others.

Ana Latronico: Thank you very much for this very interesting and unique conversation, and I have a question about the relevance of imprinted genes, what is your view about them?  because in pediatric endocrinology, we have a lot of imprinted disorders, some of them are implicated in puberty and growth. Another point is related to animal functional studies, how they have impacted the new era of human genetics and if they are so important, as we previously thought. In the genetics of human pubertal development, mice studies did not help. More recently we have another imprinted gene, associated with precocious puberty called DLK1 on chromosome 14. Interestingly, chromosomes 14 and 15 are very similar in some aspects, especially because both contain a cluster of imprinted genes. Then I totally supported your idea about animals and we should be more careful about when we require functional studies using animals. 

Antonarakis: Thank you very much to discuss the idea of imprinting. As you probably know, imprinting means that a gene is expressed only if it comes from one of the two parents, paternally expressed if it comes only from the parent when it comes from the father and when it comes from the mother it’s not expressed. It’s a peculiar type of inheritance, there are several imprinted genes that we know, and with a large project like the GTEx, the genome tissue expression project in which transcription of thousands and thousands of cells from different tissues are studied, then we will know by the alleles that are expressed, how many total genes we have with imprinting, we don’t have that many. And most people think that we will not find many more of protein coding genes that are imprinted. They are very interesting, it’s about a hundred, if you look at a mouse 120, people expect to find no more than 200, this is an exception, but perhaps for development it is very important. The other point I would like to make is that we have genes and networks that change in different stages of our lives, in puberty for example, the regulation of genes changes, because some genes are lined up, transcription factors, and then the regulation changes. The best example perhaps in puberty you have better examples.

But the best example that we use in my community is hemophilia B. There’s a hemophilia in which there is a mutation in a promoter, one type of hemophilia B not all of them, and when the child is a child, they’re hemophiliacs. They need the transfusions, they need factor 9, they need care, they bleed etc. and when they reach puberty hemophilia B becomes very mild. Because there is a different transcription factor that lights up and then binds to this promoter area better than the one in childhood, and then it cures the hemophilia B. So there are several examples like this that the gene regulation changes throughout life. And perhaps in my stage of life, the third stage, the regulation changes yet so one needs to study us. That brings me to the mouse experimentation. We now say that each human could be a project. A research project. Human, one individual, how we change through the years, through the environmental stresses, through the networks that change within us which are also the environment, the microbiota in our gut, everything that touches us, then we need to study in each human because each human has a unique genome and a unique environment.

Stefano Cianfarani: A very short and general question about the impact of epigenetics on genome function and the impact of epigenetics in medicine.

Antonarakis; Undoubtedly epigenetics is important to give you the short answer, you’re talking to someone who is biased or is the variation of the genome. There are many experiments that concluded, and the evidence is mounting, that a good fraction of epigenetic variation is based on the genetic variation. So in other words, your epigenetic marks are probably different from mine, and you can say that the environment makes them. However, a good fraction of them is because of your genetic variation that predisposes or allows the epigenetic mark to be on you and not on on me. But this is a biased opinion.

Christos Yapijakis: A very short but philosophical question. Do you think there is evidence in the human genome supporting the theory of intelligent design in evolution? 

Anotonarakis: I will give a short answer. Probably not. There are two forces that work in the evolutionary process; chance and necessity. Mutations and selection. There’s nothing else that matters. Variants occur in nature, wakes up in the morning and has mutations, notes them down in a book in some genome and then necessity comes in selection and says it’s not useful for me. If it’s not useful, you have it, you die with it. If it’s useful, I like to have it myself too. So if there’s intelligence on this, you answer.

Argente: Thank you very much Prof. Anotonarakis, it has been a great pleasure to be here with you, I never thought that one day I could be at your house with a geneticist like that with an excellent great phenotype.

 

 

Epicurean Philosophy and Modern Science and Life

A live conversation between

Christos Yapijakis, geneticist and philosopher, National and Kapodistrian University of Athens, Greece

and

Stefano Cianfarani, University of Rome ‘Tor Vergata’, Italy

Transcribed from the live conversation by Uri Klempner

With contributions by Ze’ev Hochberg, Alan Rogol, George Werther and Jesús Argente

Stefano Cianfarani: A short historical introduction to the topic starting from Socrates and his most brilliant student Plato who founded here in Athens the Academia, and one of Plato’s students was Aristotle who founded the school named Lyceum here in Athens. Notably, still now Academia describes the University and Lyceum denotes the best high school in many countries including Italy. We are talking about Plato in 5th century BC, Aristotle in the 4th Century BC. Then we have Epicurus who is considered a philosopher of the Hellenistic era. Let me remind you that Aristotle was the tutor of Alexander the Great. We consider the Hellenistic era the period of time coming from the death of Alexander the Great up to the Roman Empire. The interesting thing today is to talk about Epicurus as a precursor of modern science and Professor Yapijakis is going to tell us what the link is between Epicurus’ philosophy and modern science. Let me remind that Epicurus founded here in Athens the Garden school of philosophers and one of the main issues of this school was the empirical observation of nature what we can say the evidence-based knowledge which can be considered a precursor of evidence-based medicine in some way.

Christos Yapijakis: First of all, I would like to thank Professor Chrousos and Professor Hochberg for the invitation and Professor Cianfarani for the conversation. This is a great opportunity for me to discuss Epicurus’ philosophy and his relevance today with such distinguished thinkers and doers. Hopefully this philosophical discussion may be a fascinating and enlightening experience for us all.

I am a geneticist, clinician and scientist, and a friend of Epicurean philosophy. I will do my best to present the scientific basis and the humanistic values of Epicurean philosophy as a pragmatist scientist, not as an Epicurean. Our way of thinking in this modern world is basically eclectic, combining different ideas and belief systems. Therefore, I will stick to the facts and I will present my opinion like a modern scientist with humanistic values based on the available evidence. Of course, personal beliefs should always be respected as long as they do not harm other people.

I will present a short introduction of the Epicurean philosophy in relation to three points: its scientific value, its past influence, and its humanistic value today. I will stress the current need for a universal humanistic scientific philosophy, and I will emphasize the fact that the Epicurean ethical philosophy is based on human neurobiology and biological psychology by giving you some examples. I will end up with some thoughts on healthy developmental education of children.

My first point is the scientific value of the Epicurean philosophy. It is the only ancient philosophy that is so much compatible with modern Science, due to its empirical evidence-based method. I will start saying that Epicurus had three philosophy teachers, a Platonist, an Aristotelian, and a Democritean, but he was mostly influenced by Democritean physics and Aristotelian biological ethics. Epicurus was very much interested in observing and understanding nature with the aim of achieving serenity and happiness. His study of nature was not theoretical. He thought that we need science in order to be happy. He thought we need the study of nature as a means of avoiding myths, fears of the unknown and superstition. For this purpose, he introduced the methodology of Canon according to specific criteria of truth. In Greek, Canon means “ruler”, an instrument we use in order to measure something. Canon was an empirical methodology of enquiry consisting of observation by the senses and drawing inferences of the unknown based on the analogies observed. So Epicurus used certain criteria of truth: everything that we sense is true, we should believe it; concepts in our minds are based always on past sense observations; emotions are another criterion of truth because whatever pleases us is friendly to our nature and whatever causes us pain is unfriendly.

Epicurus combined the atomic physics of Democritus and the biological ethics of Aristotle correcting their inconsistencies and errors using observations and the Canon. This approach made Epicurean philosophy very comprehensive and among all ancient philosophies by far the most compatible with modern scientific findings. Epicurus taught that one should propose many possible different theories to explain a phenomenon, and not accept as true a theory until one has observational facts. This is another thing that is common with modern science. Epicurus and his students introduced several notions that were reaffirmed by scientific inquiry in the last four centuries. For example, the atomic weight; this is how Dalton in the early 1800s proved that the atomic theory was correct by measuring the weight of the so-called atoms. Another example is the emerging new properties of chemical substances based on their atomic structure. Epicurus was the first to speak about the chemistry laws, that atoms have certain characteristics but when they are combined into forming a molecule, the molecule will have emerging properties and different characteristics than the atoms it contains. His philosophy even predicted that diseases have a molecular basis. Epicurus also wrote about the multitude of worlds in the universe, while, for example, Aristotle said that there was only one world. When two Swiss astronomers in 1995 discovered the first exoplanet, they wrote a paper with the title “Epicurus was right, other planets exist outside the solar system”. Epicurus spoke about the atomic nature of sense perception almost like a neurobiologist would describe it today, that atoms come from the environment, either straight like the photons that we see or in waves that we hear. He spoke about the evolution of species based on natural selection; Darwin was influenced by Epicurus through his grandfather, that’s why he was prepared to observe what he observed in Galapagos Islands. Epicurus was a champion for the existence of free will, based on the observation that there is chance in the universe. According to him, if there wasn’t any chance then every event would be predetermined and we would not have free will. Free will is not caused by chance, but its mechanism is allowed to happen because the universe is not deterministic. Epicurus was the first philosopher to introduce the concept of justice as a social construct, the progress of civilization and many other notions including the existence of extraterrestrial life on other planets that science is still investigating.  This is the scientific basis of Epicurean philosophy.

The second point I would like to make is Epicurus’ past influence based on historical facts. The rediscovery of the Epicurean philosophy in Renaissance helped humankind to evolve during Empiricism, Enlightenment and Modern Era of Science.  After about a millennium of imposed silence during the Middle Ages, in 1417 the discovery of the great poem in 7400 verses “On the nature of things” of the Roman Epicurean Lucretius made a great impact in disseminating the philosophy of Epicurus during the Renaissance. Many philosophers of Empiricism and Enlightenment were influenced by Epicurus, including Locke and the French encyclopaedists. One of the major political figures of the Enlightenment was self-declared Epicurean Thomas Jefferson, the third president of the United States, the author of the American declaration of independence, who introduced the human right of the pursuit of happiness, the first time after Epicurus. Jefferson was also the founder of the first public American university, the University of Virginia. Before that American universities were either religious or private for wealthy men. Several modern philosophers were influenced by Epicurus; among them the utilitarian Jeremy Bentham and John Stuart Mill should be mentioned. Several early scientists recognized the influence of Epicurean influences in their work, including Galileo, when he saw planets with satellites. An astronomer friend of Galileo, a Catholic priest named Gassendi, was the one who reinstated the Epicurean philosophy. Other noted early scientists with Epicurean influences include Boyle the early chemist, Newton with gravity, Dalton with atomic weight. Several life scientists and physicians discovered biological mechanisms proposed by Epicureans, including Darwin (evolution by natural selection), Pasteur (life derives from life), Mendel (the laws of genetics that were first observed by Epicureans as Lucretius’ poem attests), Freud (psychotherapy) and Garrod (the molecular basis of disease). The Epicurean philosophy has a scientific value, thus in the past it has influenced and helped humanity to stand on its feet during Empiricism, Enlightenment and the modern era of Science.

The third point I would like to make is the humanistic value of Epicurus’ philosophy. The Epicurean philosophy constitutes an ethical system based on observed human nature and not on abstract ideas. It is based on common human biology and psychology and constitutes the basis of modern secular humanism. Epicurus thought that the purpose of philosophy was to increase human happiness; otherwise, it is a useless endeavor. For him, philosophy is a useless endeavor if it doesn’t make people better in order to live a happier life in harmony with other people. He mentioned that the right philosophy based on naturalism cures the anxieties of the soul in a similar manner that the right medicine cures the pains of the body. Epicurus observed that we are naturally inclined towards pleasure which is measured by the absence of pain. He defined happiness as a condition in which the body does not feel pain and the soul is not anxious. He tried to free people from superstition and unsubstantiated fears of the unknown. He observed that there is chance in the world and no destiny; thus, he taught that the existence of chance atomic movements permits free will in people. He offered a four-part remedy (the Tetrapharmacos) for mentally curing the anxieties of the soul in order to live a pleasant, virtuous and fearless life. The first part of the Tetrapharmakos states “do not fear god”. According to Epicurus, gods do exist but they are not fearful.  Since nothing comes from nothing in Epicurean philosophy, the existence of gods may be inferred by the fact that people have the notion of a god as a happy and everlasting being. But as all of us observe, the world is so imperfect because obviously gods are not concerned with people or celestial bodies. For Epicurus it is absurd and unrespectable to be afraid of the gods instead of admiring them as examples of perfect happiness. The Epicurean philosopher tries to live like a god among people. Epicurus advises us to have God as a guiding example worthy of admiration, not fear. The second part of the Tetrapharmakos states “death is nothing to us”. Death destroys our material body and material soul, because all we are is a structure of composite molecules. The composite molecules have a lifespan and then are destroyed into atoms; the atoms are eternal. So death destroys our soul and senses, therefore as long as we live we will never experience it. So we don’t have to be afraid of death. Instead of wasting our lifetime worrying about something that we will not experience, we may be armed with the right philosophy, prudence and friendship and always remember the last two parts of the Tetrapharmakos: “all necessary good is easy to achieve”, while “all bad is easy to endure”. These are the four medicines of Epicurus. The message of Epicurus was that all people (including wealthy and poor men, women, even slaves) may achieve happiness if their way of living is based on prudence, virtue, justice, friendship and scientific knowledge. Without scientific knowledge about how the world works we cannot be happy, Epicurus says. He was the first philosopher that laid the foundations of Enlightenment in the modern era style.

Numerous recent studies have shown that people feel happier when they satisfy their basic needs and have meaningful relationships with their relatives and friends regardless of economic or social status. So the basic values of modern humanism, secular humanism, are all shared with Epicurean philosophy: friendship for all humans (philanthropy in Greek), naturalism and realism, social contract (justice as a human agreement), freedom of belief including freedom of religion (first established in the modern world by Thomas Jefferson). Jefferson was the one who proposed that any person could adore any god in any religion that he or she prefers without persecution. He thought that humans have a central value because they are humans and have human rights.  A human is the central value and no abstract ideas can justify human suffering. So there is a humanistic value in Epicurean philosophy.

Let me now comment on why we need a basic humanistic scientific philosophy today. I think that many problems of the world today stem from the current schizophrenic situation that evidence-based knowledge is separated from belief. We know by empirical experience in scientific observation that humankind faces problems such as tribal conflicts, socioeconomic crisis, religious and political fanaticism, as well as mounting environmental hazards. But the majority of humanity still analyzes the data subjectively (in a ‘metamodern’ personal way) and not objectively. Science by itself can provide exquisite knowledge, but its proper use requires a moral and emotional philosophy, that is ethical philosophy, that is missing both in science and in today’s society. We need a basic humanistic scientific ethical philosophy, I would call it an Epicurean-like, that teaches us both the scope of science which is evidence-based knowledge of reality in order to be happier and create more humane societies and realistic in a scientific way of thinking based on observation. The Epicurean philosophy constitutes a sound basis for dealing with everything from interpreting nature to everyday decision making by offering practical advice. It places the highest value on life within the limits of Nature, human happiness based on knowledge, friendship and virtue. What unites us all people includes humanistic values (the ‘right to pursue happiness’) and scientific observation of reality. The main issue is how many people will understand this before a possible major catastrophe. Education of younger generations may be the solution.

My last part of the initial presentation of Epicurean philosophy is that the Epicurean ethics is based on human neurobiology and biological psychology. I will stick to not too many details but to the main points of course because you all know parts of this, but I will try to connect how the human brain works with the Epicurean philosophy and human nature. You know that all living organisms originate from a common ancestor and all current biological structures derived from alteration or improvement of ancestral biological structures. So the human brain actually consists of three different interconnected brains that arose during evolution: a) the ‘reptilian brain’, mainly the hypothalamus that controls the instincts of hunger, thirst, sexual drive etc.; b) the ‘mammalian brain’ which corresponds mainly to the amygdala and the hippocampus and it controls the emotions, pleasure, fear, love, anger, hate etc.; and the ‘brain of primates’ of higher apes and humans that corresponds mainly to the grey matter of the cerebral cortex, representing about two thirds or more of the total size of the human brain. It controls as you know the cognitive functions, logical thinking and imagination. Cognitive functions develop during childhood and adolescence in humans, while in apes they remain relatively stable. The three parts of the human brain are interconnected and interact with synaptic neural networks, and for example, a sense experience that we have stimulates the hippocampus and the amygdala. Hippocampus manages the short-term memory; the amygdala determines the positive, neutral or negative emotional experience. If the experience is strongly positive or strongly negative, then it is stored in the cortex in the primate brain. So it is the emotional choosing of our brain that stores our memory. This is how Epicurus described that: “Pleasure is the starting point and goal of living blessedly for we recognize this as our first innate good. This is our starting point for every choice and avoidance.”

The reptilian brain corresponds to the instincts and their desires. If I’m thirsty I desire to drink, if I’m hungry I desire to eat etc. But because our desires may be other than instincts Epicurus recognized that there are three forms of desires. One form is for natural and necessary things. If I’m thirsty I have to drink, so I can drink water and I will not be thirsty anymore. The second form includes natural and unnecessary desires; for example, if I’m thirsty to drink champagne of 30 years old. The third for includes unnatural and unnecessary desires which is vanity, for example to put my name on a sign on a tall building. Epicurus said that the only way that our body will suffer is when we avoid the natural and necessary desires. If I’m thirsty I cannot postpone forever to drink water. Every time that I feel I have a natural and necessary desire I will have to satisfy this desire. Otherwise my body will be in pain. Regarding the unnatural and unnecessary desires for fame, fortune, vanity and fancy things, Epicurus counsels us to forget them. To obtain them is hard, they will create us more pain than good, so it is better to forget them all the way. While the natural and unnecessary desires, for example to drink champagne when I’m thirsty, Epicurus says that we don’t need them but if we go to a dinner with other people and we are offered champagne then we may drink it and enjoy it but without any strife, because people who don’t need this kind of natural and unnecessary desires they enjoy them better. Only the natural and necessary desires, which correspond to the instincts, we should always satisfy otherwise we’ll feel pain.

Epicurus determined the purpose of life on emotional grounds: to be happy, to live a pleasurable life, aiming at the blissful state of physical lack of pain and mental lack of agitation and anxiety. Above all Epicurus considers prudence, the practical wisdom which is part of the cognitive faculty in the primate brain, as the supreme regulator of conscious selection of what brings happiness with wise satisfaction or physical needs and instincts and preservation of emotional balance by tasting those pleasures that do not result in greater pain instead of pleasure. The problem in humans is that while the biological system of desire is in the reptile brain (namely the reward system, the dopamine system), the pleasure system is in the mammalian brain, corresponding to a bath of endorphins. The important point is that desire and pleasure have a different biological background and therefore this distinction may create psychological problems in humans, since they usually do not readily distinguish them. The average person confuses desire to obtain something with a belief of pleasure upon fulfillment of one’s wishes. This is how advertising works. I see a car with a happy man inside, and I believe that if I buy this car I will be happy, which is not the case. In addition, the biological system controlling the emotion of fear is in the mammalian brain. But with the primate brain, with cognitive function with prudence, we can understand that most fears are only imaginary and unsubstantiated. For example, if I walk in the street and I see a car coming towards me I have to be fearful of the car so that I will move and avoid it. But if I think while I’m sitting in a building that if I exit the building a car will run over me, this is a phobia. I create a scenario into my brain and I fear because of this scenario. The important thing to always remember is that both the reptilian brain, the instincts, and the mammalian brain, the emotions, are for now. It’s absurd and useless for me to say that in next year on October 20th at 5:13 in the afternoon I will be thirsty, or that I will be fearful. The emotions are a system that evolved in mammals in order to change their behavior because of the environment.  Whatever we like and gives us pleasure we continue to do it. Whatever makes us feel pain, we have to stop it and then do something else. For example, when a monkey finds a fruit that is very tasteful, if he is on a tree, then he will eat it and find pleasure in it. But if he is on the ground and there is a lion coming, the monkey will be fearful and look for shelter before eating the fruit. We have to recognize this biological basis of emotions, because our mind has the capacity for past memories, understanding the present and planning the future, therefore if we create fearful scenarios we may end up with fear emotions like phobias.

The Epicurean approach of psychotherapy that was used in the School of Epicureans in the ancient times was called the therapy of the soul: “psyches therapeia”, psychotherapy, exactly as we call it today and is based on human nature. It reveals the absurdity of unsubstantiated fears by curing mental agitation with facts. It aims for a serene blissful state achieved by engaging prudence, practical wisdom, by free will. Modern existential cognitive psychotherapy which seems to be more effective than other approaches focuses on the identification of one’s fears and negative thoughts revealing their absurd character and then proposes their systematic engagement with pleasurable activities. Therefore, we need evidence-based and narrative-based psychotherapy, therapy of the soul, with friendly frank criticism based on empirical observations, as the Epicureans needed it 2000 years ago, because our human nature remains the same.

Cianfarani: Let me be a little bit provocative. Going back to the modern science. First of all, I’d like to remind you that despite the fact that Epicurus wrote more than 300 papers, just three letters, and a few fragments are left to us from Epicurus. Most of all we know about Epicurus comes from the Roman philosopher of the first century Lucretius, who reports the Epicurean vision of life and nature in his masterpiece “De Rerum Natura”.   As you know Democritus was the founder of atomistic philosophy. But his point of view was a deterministic atomistic view of nature. Epicurus goes even farther as for Epicurus just chance and necessity regulate nature, recalling us the famous book of the Nobel prize winner in 1965 Jacques Monod: “Chance and Necessity”. On the other side, Aristotle believed in the purpose, in the aim behind any natural phenomena, including human life. So the description of nature according to Aristotle was based on common laws regulating all nature facts or nature appearances. The question is, don’t you think that there are limitations in the view of Epicurus based on chance and necessity. Translating that into our common practice as physicians. To give you an example, if we look at the effectiveness of a new therapy, we can discover a new drug just by chance or by necessity, and we can say that this drug is effective in curing Mr. X with a disease but also Mr. Y and Mr. Z with the same disease. The conclusion is based on the facts that this new drug, which was discovered by chance, is effective in curing different subjects with the same disease. But the next step would be: why? If we just base our knowledge on empiricism, on the facts or senses like Epicurus, we don’t go beyond what we see. The next step would be the reason; why? To quote what Einstein said about that: “Imagination is more important than knowledge, for knowledge is limited whereas imagination embraces the entire world, stimulating progress, giving birth to evolution.”

Yapijakis: Thank you very much for raising this point. First of all, I would say that Democritus spoke about atomic physics in an intellectual way. He didn’t believe in observation. He thought that senses should not be trusted. On the other hand, Aristotle was the first philosopher that was using the empirical observation. He had two teachers. We always recall his teacher Plato. But Aristotle had another teacher before Plato, his father Nicomachus, who was a physician. Although he was trained in Plato’s Academy his original medical observational and empirical study helped him overcome the Platonic idealistic philosophy. Aristotle wrote somewhere that Plato and the truth are friends but I prefer the truth. Aristotle was the first observational philosopher, because as we all know physicians empirically observe the symptoms and make a diagnosis.

Aristotle used this observational empirical method for living organisms but he thought that some ideas, some concepts, should be reached by logic alone. By logic alone he said that since women are inferior to men they should have fewer teeth. Instead of observing and counting the teeth of women and changing his belief that he reached by logic, he preferred to write in two places that women and female animals have fewer teeth than males. Another belief of Aristotle was teleology; that everything in Nature has a purpose. There is a scope in the universe and the last event is the purpose of the previous events. As if I would say to you that the purpose of your lives was to come here today to listen to my talk. Which is not the truth of course. So the basic problem of Aristotle was that he had these beliefs that by observation an objective scientist like Epicurus would easily overcome. I would say in response to your comment that Epicurus lets free the people to make any hypothesis that they want, any hypothesis explaining a phenomenon using imagination is justified. But the hypothesis has to be judged by the observation, by the facts, in order to be considered correct or be disregarded, like any modern scientist would do. We can make whatever hypothesis we want but it’s the actual experiment that will show us that if our hypothesis is correct or not. Actually in the Garden of Epicurus most probably the first experiments started. We don’t know this for sure, but we know that the leader of the Aristotelian School at that time Strato of Lampsacus, who coexisted with Epicurus in Athens for twenty years, certainly started doing experiments. Strato most probably learned this from Epicurus, but there is no proof of this yet. This is a hypothesis. We know that Strato conducted experiments, so he disregarded the teleology of Aristotle, he accepted that everything is composed by individual bodies and void, and he started a scientific tradition in the Hellenistic time with Eratosthenes, Archimedes etc. of philosophers that performed experiments. So this was the difference between Aristotle and Epicurus. Aristotle was a great philosopher and without him probably Epicurus would not be that great. But I think that Epicurus became even greater than the great Aristotle and much more humane.

Cianfarani:   Can we agree with the Emmanuel Kant’s statement that “concepts without percepts are empty and percepts without concepts are blind”?

Yapijakis: Well, yes and no, it depends because Kant is a subjective philosopher. Kant thinks that every person understands nature in a different way, which is of course right at a certain point – for example, a guy like me with myopia will see differently without contact lenses or glasses. But we basically see the same things, we may understand the same things and we can have an objective way of communicating, which is science. Of course, there are differences in opinions and perspectives but we can see and hear nature as it is. To answer your question, we may communicate objectively if we use the concepts in their original meaning coming from the senses. This is what Epicurus insists that we should do in order to communicate. We should use the term ‘table’ for what it originally means. Not as a roundtable in a symposium, let’s say, or any poetical, allegoric, other symbolic meaning. Because in this way we could not communicate. Epicurus insisted that natural philosophers, like scientists today, should use the terminology that corresponds to the things that we can perceive by senses. Otherwise, we’ll end up talking about things in different meanings, as often is done by rhetoricians, by politicians, by poets and then we cannot communicate.

Ze’ev Hochberg:  In the Hebrew language, we use the phrase “Epikoros” when we want to talk about somebody who is not a believer. If somebody is God forbid a scientist and does not believe in God, he is called an Epikoros.  The phrase Epikoros was coined many years ago – in the second century, in the time of the Mishna, known as the “Oral Torah”. During that time the Jews were expelled from Palestine by the Romans, and only a few scholars remained. They started to discuss philosophy, and for them Epikoros was a dirty word. And when I listened to you I understood why. A very important part of Judaism is fear from God. The same is true for Christianity. In Christianity suffering is a high virtue; people intentionally suffer. And this is different from Epicurus’ strive for happiness.  I have a question for you Christos. How is Epicurean philosophy different from hedonism? We speak quite a lot about hedonism as a mechanism for childhood obesity. We have a special center in the frontal brain for hedonism; for Epicureanism?

Yapijakis: I will answer your interesting thoughts in two parts. First regarding the Jewish name of Epicurus and then on hedonism. First of all, it’s a historical fact that the Epicurean philosophy was the first international secular humanistic philosophy that spread in the Hellenistic world. It was not dedicated only for Greeks but it proselytized Syrians, Jews, Egyptians, Romans, and Celts. There were even Carthaginians. Because it is a philosophy that address all humans, not only Greek. Second, during the Hellenistic period there was a political religious strife between the Pharisees and the Sadducees. The Sadducees were the priests of the temple in Jerusalem at that time, and they were heavily Hellenized. They dressed like Greeks, they spoke Greek fluently, and they were mostly influenced by Epicureanism, which was in fashion at that time. So they believed that God wants us to live a happy life and that there is no afterlife. The best way to obey God’s will according to the Sadducees was to enjoy life and be virtuous, friendly to others and things like that. There is a book in the Bible called “Ecclesiastes” (Greek for “Qohelet” in Hebrew) that suggests that every major dream is vain, one should enjoy every day and not expect the future things. This book was written probably by a Sadducee, an Epicurean-influenced Jew. And the opposing fraction was the Pharisees, from the word Farsi meaning Persian. The Pharisees were the priests that collaborated with the Persians during the Persian occupation before the Greeks came to Israel. They introduced into Judaism Zoroastrian ideas which were dualistic Platonic ideas, for example that there is a good God and a bad devil; there is after life with punishment for the sinners and things like that. Those teachings did not exist in Judaism before the Pharisees. Today’s Judaism is a Pharisaic Judaism. The Pharisees called their rivals “Epicureans” as a curse against the Sadducees, and the word Epikoros remained in Hebrew as a name for nonbeliever, agnostic, atheist. This is a remnant from the political history of things. Later in the beginning of the Roman era, there was a Jew called Philo of Alexandria who was a Hellenized Jew and a Platonist who somehow combined Judaism and Platonism. Thus, Judaism, Christianity and to a certain extent Islam are very Platonic religions.

In order to answer about the hedonism, I would have to say that hedonism was first proposed by another philosopher before Epicurus, Aristippus. He was a student of Socrates. The students of Socrates included Plato, Xenophon, Antisthenes the Cynic and Aristippus. Aristippus believed that there is no happy life, so everybody can live their life looking for pleasure all the time, and especially eating, drinking and having sex in a promiscuous way. Everything is subjective and there is no ethics in reality. We cannot understand nature, because each one of us has a different subjective perspective – the Kantian way. All that exists is looking for pleasure, as much pleasure as possible. Aristippus became a council of a tyrant in Syracuse in Sicily. He became a philosopher entertaining a tyrant in order to have a lot of pleasure. This is what we call extreme hedonism. This mindless hedonism, as we Epicureans call it, would not lead us to happiness. This is the kind of hedonism that modern Western society promotes with the money and the advertisements and consumerism – making people to look for hedonism in material things as a substitute for real happiness. On the opposite, the Epicurean hedonism is prudent, since our goal is not pleasure of the moment but a happy life, a pleasurable life. The Epicurean hedonism is a different kind of hedonism. In order to have a pleasurable life you have to be virtuous. Virtue is not a goal; it’s a means for a happy life. If you’re not virtuous and you are aggressive with other people you will not feel safe. If we seek only pleasure for its own sake, we will be self-destroyed sooner or later. But if we understand our nature, then we may know that pleasure simply informs us that something is good for us. But we have to think that if we continue doing this pleasurable thing will I get more pleasure or more pain? For example, if I like chocolate and I eat 10 kilos of chocolate, my stomach will ache. I have to use my prudence to understand what this pleasure will bring to me, which is more pain. Epicurus says that a pleasure that leads to more pains should be avoided. We should select instead pains that would lead to greater pleasures. For example, if I’m a student I will have to read and lose a weekend of pleasure to study, but I’ll succeed in my exam on Monday, and I will live a pleasurable week and be happy.

Alan Rogol: I’ve spent four decades at Mr. Jefferson’s University in Virginia. He lived at Monticello, which was up the mountain, he took a spyglass and designed the university. But on his grave he never said that he was president of the United States. He was most proud to be author of the Declaration of American independence, author of the statute of Virginia for religious freedom, absolutely unheard of at those times, and the father of the University of Virginia.

Yapijakis: This was because of Epicurean influence as he said in his letters. “I am an Epicurean” he wrote, that’s why I believe it. The Epicureans like the great Thomas Jefferson wanted to make a revolution but not the revolution with guns and knives and things like that. But the revolution of the mind. That’s a kind of enlightenment. That’s why what they did was they taught the science of their times freely to everybody. This is what the French Epicurean encyclopaedists did. They printed an encyclopedia with all the knowledge of that time for everybody to share. And this is what Jefferson did when he founded the first public university for everybody, men and women to be there. And the same was done by other Epicureans in other countries. Jeremy Bentham in England founded the University College London, which was the first public university in England that accepted women and men, Catholics, Protestants, whatever. Because the other universities accepted only Protestants, only Catholics, only men and things like that. Also in Russia another Epicurean, the scientist Lomonosov created the first public University of Moscow.

George Werther: I understand that Epicurus was not completely areligious, he believes that gods had a role but in fact his philosophy was at odds with the modern theological thinking. So my question is how does Epicurean philosophy in the current age contrast with modern theology and say Christianity or Judaism which say essentially all our morality and ethics has to be based on religion whereas this is not.

Yapijakis:  First of all Epicurus was certain, he did not just believe, he was certain that there were gods. He was certain because of his Canon, the method he used to understand nature. He used this method for the gods as well. But he also thought that all religions were fake, since they were based on myths and literature. In addition, he observed that religions did not respect the gods.  The Platonists relied on myths so they thought that Epicurus was not religious enough for their like. The same opinion they had for Aristotle.  For about a thousand years during the Middle Age Aristotle was mostly considered an atheist. And that’s why when his tomb was found in his home town Stagira about a couple of years ago, it was also discovered that it was destroyed by the then Byzantine Romans of the sixth century to build a fortress, because Aristotle was considered an atheist. Because he didn’t believe in God in the same manner the Platonists would believe. Aristotle was fortunate enough to be liked by the Islamic world. There were some Epicurean influenced and Aristotelian influenced Islamists, mostly Persians and Arabs, who created the Arabic renaissance in the 8th and 9th century; all the great Muslim astronomers, physicians and philosophers were of that period. Omar Khayyam is such an example of a renowned Epicurean influenced astronomer, mathematician, physician and poet of that era. If you read his poems you will see the Epicurean influence. The Arabic renaissance lasted 2-3 centuries until a Platonic Islamic clergy said that these scientific endeavors were works of the devil. After that the Islamic world remained mostly in the Middle Ages until today.  In Europe Aristotle was revived by the Italian Catholic priest Thomas Aquinas in the 12th century. Thomas Aquinas managed to Christianize Aristotle, so the modern Roman Catholic Church is mostly Aristotelian. Platonic Aristotelian but mostly Aristotelian, while the Greek Orthodox Church remains Platonic. A few centuries later, in late Renaissance, another Catholic priest, the Frenchman Pierre Gassendi revived the Epicurean philosophy around 1650. He influenced many people because after him the Enlightenment started. Gassendi also Christianized the Epicurean philosophy but probably not enough because Epicurus was not accepted by the Catholic Church. He was accepted mostly by some Protestants in England, like Hobbes and Locke; later he inspired the French philosophers of the Enlightenment.

Today, because of freedom of thinking, freedom of speech, and the perseverance of scientific thought in the modern world, all religions have started to include humanistic environmental thinking and try to say things about things that science discovers. For example, the Catholic Church has something to say about evolution of living organisms, namely that there was a divine providence for evolution. I’m proposing that we should use the Epicurean philosophy not as an anti-religious dogma or an alternative religion, but as a common humanistic scientific philosophy that would unite us all Christians, Muslims, Jews, Hindus, Buddhists, agnostics, atheists etc. based on a pragmatic and scientific basis. Whatever I believe in my private life it’s my right but I will not impose my opinion to you. This is what Jefferson said because of Epicurus. This is what I think the United Nations say today.

Cianfarani: Aristotle founded metaphysics. He founded a need of going beyond the physics, trying to discover the laws beyond it. The question is going back to the modern science and scientific method. But if everything according to Epicurus is just regulated by chance, so why should we study biology or physics?

Yapijakis: Chance is a rare phenomenon. But necessity also exists of course. And necessity most often make things happen. There are lots of necessary laws of nature.  Rarely ever a chance phenomenon happens. But because there are many different phenomena happening at the same time chance more often influences reality than if there was only one phenomenon.  For example there is gravity, so a cup stays on its place on a table. But there is also atomic movement inside a cup, and there is a slight possibility that the majority of the atoms of the cup may go towards one side direction and the cup may fall without anybody touching it. There is this probability but it’s very rare. A physicist said that in a human life twice or three times something like this, an unexpected phenomenon, will happen within our range of three meters. But mostly we’ll be sleeping or not paying attention or will think that something fell because its position was unstable or whatever. Chance exists in the universe and we know that from experiments. What you are saying is how we can live our lives if there is chance. This is the beauty of it, because we’re free beings. We are free to destroy ourselves and this planet or free to be happy living together. Maybe there is a divine providence in the universe that we haven’t seen so far. I’m not against that theory. I’m saying that we should communicate, we should understand nature and our nature, and use our best of our capabilities in order to have a happy life. All of us. Every person is entitled to happiness on their own merit.

Jesus Argente:  You mentioned Epicurus about his address in brain function. And I would like to ask you what the main concept of the brain was that he had at that time?

Yapijakis: At that time there was the concept that the brain is the center of our soul, as first proposed by the Pythagorean physician Alcmaeon. That concept was accepted by Plato, because he was under Pythagorean influence. But Aristotle, who did a lot of anatomy studies in animals, thought that the brain was only freezing the blood. So he said that the heart was the center of the soul. Because Epicurus trusted the great scientist of that time Aristotle, and not the theoretician of that time Plato, he made the same mistake. Epicurus believed Aristotle and he said that the center of the soul is the heart. But he said that the soul has a center part and another part that is peripheral all over the body. The center part decides where to send the directions and the peripheral part sends information to the center part.

Maybe it is the right time to say something about children. You all know that Finland is one of the best countries regarding education for decades. Finland is in the northern part of Europe as you know. I looked for a text on education and philosophy from a Finnish perspective. I found a Finnish text on the historical perspective of teaching philosophy to children, which starts with Epicurus and his philosophy. That is because Epicurus was the first philosopher who said that we should not teach our children unnecessary and useless things, but to teach them about their nature and nature in general in order to learn how to live a good life. According to Epicurus there is never too early for philosophy because there is never an early time to be happy. Therefore, some of the education approaches used in Finland are influenced by the Epicurean philosophy or related concepts.

Coming to the end of our conversation. I would like to present you a diagram derived from Carlo Cipolla’s ‘The basic laws of human stupidity’. The horizontal axis corresponds to the action of one person that acts in a positive way for him or her, or in a negative way for him or her, and what influence this actions has on others; positive or negative more or less. So if I would do an action that will cause me to gain but others will lose, I’m a crook. If do an action that I will lose and others will gain I will be a victim, if I do it all the time. If I do something that I will lose and others will lose, I’m stupid. Like some terrorists that kill themselves and other people. But if I do something that I will gain and others will gain at the same time I’m clever. To combine this way of thinking with the possibly corresponding anxiety or the lack of anxiety that Epicurus wants, the only person that remains calm is the clever person who is in the win-win situation, as I have mentioned in my essay ‘Epicurean egoistic altruism’. The victim has the anxiety of recognition: “I always put myself behind others, they never recognize my mighty sacrifice”. The stupid has the anxiety of uncertainty. The crook has the anxiety of punishment. It doesn’t matter if he or she remains without punishment. The crook will never be sure that he or she will avoid punishment, as Epicurus mentioned. So the only way to be happy is to always try to act cleverly in win-win situations. This fact may be easily taught to younger generations.