Claudio Rubiliani is a member of the OPS Board of Directors. He is an honorary lecturer in Organismal Biology, Doctor of State, Visiting Professor at Duke University Marine Lab (North Carolina, USA) and former Inspector of French Education in Germany.
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Les bloqueurs de puberté et les traitements hormonaux administrés aux enfants et aux adolescents : modalités d’action et interrogations. Une brève synthèse.
Reminder
The functioning of the reproductive system in humans requires a long maturation process and follows a rigorous chronology. Any desynchronizing intervention will result in disruptions to its functioning, some of which may be irreversible, and in consequences for other bodily functions, since the reproductive system is not a "closed" system..
Throughout life, six phases of endocrine regulation of the reproductive system can be distinguished :
A prenatal phase of sexual differentiation begins in the embryo between weeks 5 and 7. In boys (XY), activation of the SRY gene on the Y chromosome triggers a chain reaction, including testosterone synthesis by the testes and activation of the Anti-Müllerian Hormone (AMH) gene. These hormones shape the male reproductive system. Male germ cells are latent (spermatozoa will not be produced until puberty).
A perinatal phase, in the weeks following birth, when the cerebral control center (hypothalamo-hypophyseal axis) is activated and sex hormones are synthesized in large quantities. This short phase, nicknamed "minipuberty", is still rather mysterious, but appears to be essential for the maturation of the reproductive system.
A phase of latency and maturation = childhood, when the endocrine mechanisms regulating the reproductive system are at their lowest.
An explosive phase = puberty, which begins on average at around 10-11 years of age in girls, and 11-12 years of age in boys, but there are major disparities (between 8 and 13 years of age in girls / 9 and 14 years of age in boys). Its onset is initiated by the action of complex neuroendocrine mechanisms. During this period, hypothalamic-pituitary control changes radically: in boys, its regular functioning is reflected in sperm production and numerous morphological changes. In girls, a cyclical, menstrual function is established, with oocytes regularly entering the final phase of maturation = ovulation. The uterus, too, enters a cyclical process of transformation. At the same time, the body also transforms to reach adult morphology.
An adult phase of regular, cyclical function in women, continuous function in men (see diagrams).
A phase of senescence, after around 40 years of operation, resulting in a gradual decline in testosterone production in men, but more drastic changes in women: the menopause and the end of cyclical operation.
In red: puberty blockers and other hormone treatments
AMH = Antimüllerian Hormone
GnRH = Gonadotropin Releasing Hormone FSH = Follicle Stimulating Hormone LH = Luteinizing Hormone
The use of hormone therapy, and in particular puberty blockers, in the context of sexual transitions is in fact an "opportunistic therapeutic detour".
In fact, the substances and protocols developed for hormone therapy have been used to treat - with a few exceptions, which we'll come back to later - adults, notably for hormone-dependent cancers (prostate, breast, ovary...) or various disorders such as endometriosis or infertility.
Puberty blockers and action on brain hormones.
The hypothalamic-pituitary hormones (GnRH, FSH, LH) are the same in men and women. What differs are the target organs and their own hormonal responses, inducing continuous function in adult men and cyclical function in adult women.
The main puberty blockers act on the hypothalamic hormone GnRH. They may be GnRH antagonists (blockers), whose reversibility is not guaranteed, even in adults, or agonists (=mimetics). The aim is to reduce secretions of the pituitary hormones LH and FSH and, by chain reaction, to reduce all steroid hormone secretions.
The use of GnRH blockers is very delicate, but is currently enjoying a certain success among specialists, in the hope that it's not just a fad.
This is one of the rare cases where a protocol is available for children: in the case of precocious puberty (onset before age 8 in girls, before age 9 in boys).
This hormonal desynchronization blocks skeletal growth, and growth plate resorption can accelerate. In this case, treatment is limited to 2 years and must be discontinued before the age of 12, precisely in order to resynchronize the various hormonal circuits.
GnRH agonists (or homologs) act in an a priori paradoxical way. GnRH is continuously synthesized in the hypothalamus and, at puberty, is suddenly secreted abundantly and pulsatile (with pulses every 60 to 90 minutes, rapid pulses stimulating LH secretion, slow pulses FSH secretion). The principle of action of agonists is that high-dose, continuous administration short-circuits the pulsatile mechanism and, by negative feedback, stops GnRH secretion and, consequently, LH, FSH and steroid secretion. This delicate technique generally results in a short episode of stimulation and hence overproduction of GnRH, before a sharp drop in production (known as the "flair-up" effect). This particular protocol generally results in transient but normally reversible side-effects. It still raises many questions.
All validated protocols concern adults or, as we have already mentioned, children whose puberty has started early. However, in the context of early transitions, the Dutch Protocol recommends the use of puberty blockers at around age 12, and crossover hormone therapy from age 14.
The administration of GnRH analogue-type puberty blockers to children who have not yet entered puberty and whose hypothalamic-pituitary axis has not yet reached structural and functional maturity appears dangerous for several reasons:
Pre-pubertal, i.e. early, blockage of the hypothalamic-pituitary axis in no way presages reversibility of the reproductive regulatory systems.
Animal experiments have shown that the cerebral maturation process of GnRH neurons takes place in "partnership" with the maturation of surrounding neurons. An early blockade of GnRH would thus induce a deficit in other neurotransmitters essential to the cognitive system, such as prostaglandins and glutamate.
Dopamine, the main neurotransmitter of the "reward circuit", is also a modulator of GnRH secretion in vertebrates. Dopaminergic circuits are therefore affected by GnRH inhibition.
As a result, the hypothesis of a "feel-good" effect induced by puberty blockers seems totally undermined by these inevitable interactions with neuromediators. Many questions remain about these interactions and their impact on cerebral maturation, which is only acquired around the age of 24, i.e. at the end of puberty.
Moreover, as the entire reproductive regulatory circuit is inhibited by these blockers, there will be repercussions on many other functions dependent on normal steroid hormone secretion. Thus, experience with GnRH blockers in oncology gives us a range of side effects common to all representatives of the GnRH antagonist or agonist class, such as :
Depressive tendencies, hot flushes, asthenia, weight gain, muscle loss, gynecomastia, testicular atrophy, impotence, loss of libido, hair loss, nausea, vomiting, headaches, anemia. Hyperglycemia and diabetes - Osteoporosis - Increased risk of myocardial infarction - Transient elevation of AST/ALT. They can also cause a reduction in bone mineral density.
In conclusion, it appears that the administration of puberty blockers to children or adolescents as part of a transition process is done, on the whole, in complete ignorance of the consequences !
Actions on natural sex steroid production: inhibition, substitution, supplementation.
In the context of sexual transitions, for both young people and adults, treatments involve inhibiting natural sex steroids and replacing them with steroids from the opposite sex (= hormone substitution or cross-sex hormones), in addition to hypothalamic-pituitary hormone inhibition. It should be remembered that the target organs of the opposite sex have little or no suitable hormone receptors, hence, for example, the frequent induction of polycystic ovaries following testosterone administration.
Since no natural hormone of the desired sex can be secreted, it is clear that hormone replacement therapy will have to be continued indefinitely, with all the health consequences that this implies.
Various studies, including one published in October 2021 in the Annales d'Endocrinologie, provide an initial assessment of the situation.
The masculinization process.
The most classic process consists of a triple treatment:
Blocking estrogen production by using an antiaromatase (which inhibits the action of the aromatase enzyme that converts the steroids androsterone or testosterone into estrogens). This inhibitor may be steroidal and irreversible, such as exemestane, or non-steroidal and reversible, such as anastrozole or a closely related molecule.
A supply of exogenous testosterone or a derivative such as testosterone cypionate, nicknamed the "bodybuilder's magic bulge". Whatever the form of administration (daily pill, fortnightly intramuscular injections or quarterly injectable testosterone undecanoate with delayed effect), the dosage is inevitably high and the whole metabolism is involved.
Supplementation with a synthetic progestogen to prevent menstruation (it acts like a contraceptive pill, mimicking stabilization of the menstrual cycle in the post-ovulatory phase).
This treatment will have an obvious impact on liver function, as the liver is the basic organ for the metabolism of cholesterol, the "raw material" for all steroids.
Through its close interaction with other natural steroids synthesized by the adrenal glands (androsterone, corticoids), this treatment will also affect the cardiovascular system (hypertension, atheromatous plaques, heart rhythm disorders, thrombosis...).
Bone mineralization dysfunction and vertebral deformities have also been observed in adults treated with these substances in oncology.
In addition, there is a risk of developing cancers of natural non-target organs (ovaries, uterus).
The feminization process.
The classic process also consists of a triple treatment:
Antiandrogens block testosterone production, but also have a strong impact on adrenal steroids such as androstenedione. Among these antiandrogens is cyproterone acetate, one of the components of the 5th generation pills which have since been suspended by ANSM (risk of meningioma and pulmonary embolism, among others).
Inhibitors of the enzyme that converts testosterone into dihydrotestosterone (DHT) or DHT competitors. The latter hormone is mainly active on the organs of the male genital tract outside the testicle, as well as on the skeleton and muscles.
Exogenous estrogen to feminize the body.
The risks associated with estrogen intake are well-documented: clotting disorders, ischemic strokes, thrombosis and cardiac disorders.
Interfering with normal steroid metabolism also has the same consequences as in the masculinization process mentioned above: hepatic, cardiac and bone risks. Added to this is the impact on adrenal function, aggravating problems of skeletal mineralization and blood fluidity. Interaction with corticoids also has an impact on the body's defenses, which are diminished, and can lead to depression.
The risk of tumor development is also very high.
In addition to adventurous medical prescriptions and ill-advised "advice" from influencers or trans lobbies, these treatments are easily accessible via Internet sites, without any medical supervision.
The consequences of these ill-considered administrations on children and adolescents are unfortunately obvious!
Principales références bibliographiques.
- HAS.- Note de cadrage. Parcours de transition des personnes transgenres. 07/09/2022.
- Botella, C. et al. - Méningiomes intracrâniens et utilisation prolongée d’acétate de cyprotérone à dose conventionnelle chez la femme : à propos de deux cas de régression tumorale après arrêt du traitement. Neurochirurgie 61-5, p.339-342, 2015.
- Sharif, A. & Prévot, V. - Les neurones produisant la gonadolibérine sculptent leur environnement neuroglial dans la petite enfance. Médecine/Sciences 38-5, p.428-430, 2022.
- Yelehe, M. et al. – Les effets indésirables du traitement hormonal chez les personnes trans genres : analyse des cas rapportés dans la base de données nationale de pharmacovigilance. Annales d’Endocrinologie, 82(5), p.275 2021.
- Hjaltadottir, H. - Les effets des manipulations hormonales chez les enfants, adolescents et jeunes atteints de dysphorie du genre.Declaration on Women’s Sex-Based Rights, 2021.
- McLachlan, R.I. et al.- Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys and man. Recent Prog Horm Res, 57- p.149-179, 2002.
- Smids, J. & Vankrunkelsven, P. – Uncertainties around the current gender case : five problems with the clinical lesson’ Youth with gender incongruence ‘. Ned Tijdschr Geneeskd. Nov1 : 167 : D7941, 2023.
- Clayton, A. The Gender-Affirmative treatment model for youth with gender dysphoria : A medical advance or dangerous medecine ? Archives of Sexual Behavior, 51(2) p.691-692, 2022.
- Levine, S.B. & Abbruzzese, E – Current Concerns About Gender-Affirming Therapy in Adolescents. Current Sexual Health Reports, 15, p.113-123, 2023.
- Laidlaw, D.K. – The Pediatric Endocrine Society’s Statement on Puberty Blockers Isn’t Just Deceptive, It’s Dangerous. The Journal of Witherspoon Institute. Public Discourse. 13/01/2020.
- Corman, V. & Legros, J.J. – Le traitement hormonal des patients transsexuels et ses conséquences métaboliques. Annales d’Endocrinologie, 68, p.258-264, 2007.
- Zioueio, I. et al. – Complications de l’hormonothérapie anti-androgénique du cancer de la prostate. Can. Urol. Assoc. J., 8(3-4), p.159-162, 2014.
- Garcia, V. & L’Hospital, A. – Transgenres : les dérives des traitements pour changer de sexe. Enquête. L’Express Hebdo, 23/02/2023.