How do the endocrine interventions ‘puberty blockers’ and ‘cross sex hormones’ work?

While often described as merely a ‘pause’ button for children with gender dysphoria, there is growing evidence that puberty blockers permanently alter the normal trajectory for psychosexual development.

Puberty

Puberty is defined as the period of maturation during which adolescents reach sexual maturity and become capable of reproduction. It is a critical period of time for development, when all bodily systems are growing, and brain function and cognition undergo changes. The bodily changes of puberty make it a period of distinct transitional physiology (Viner, Allen and Patton, 2017).

The time of puberty, or adolescence, marks a process of maturing from being a dependent child to an independent adult. Socially, puberty carries significance: there are many ‘rites of passage’ that occur through the ages and different cultures where bonding with peers, journeying separately, learning a place in the world or passing some tests of maturity or even painful genital procedures. Physically, it is associated with maturation of secondary sexual characteristics, but also of brain, bone, muscle mass, fat layers etc. The rapid changes in height and development of hair, breast buds, dropping of voice pitch and so on can be welcomed or much disliked by many young people. The onset of menstruation for girls can be particularly difficult as blood and periods carry negative connotations or taboos in many societies. 

Puberty blockers

Puberty blockers are a powerful class of drugs that interfere with the normal release of signals called luteinising hormone (LH) and follicle stimulating hormone (FSH) from the brain (pituitary gland), which tell the gonads (ovaries or testes) to make sex hormones (oestrogen and testosterone). Normally, the brain releases gonadotropin releasing hormone (GnRH) in short pulses to stimulate the pituitary gland to make LH and FSH. Puberty blockers deliver this same GnRH signal continuously. 

When delivered in this way, the pituitary gland will no longer respond to this signal. The effect of blocking LH and FSH release is similar to the effect on sex hormone production achieved by surgical removal of the ovaries or testes (‘castration’) or their ceasing (like a menopause). The pharmacological name for this class of drugs is gonadotropin releasing hormone agonists/analogues (GnRHa).  

Due to extensive testing in controlled clinical trials over many years, GnRHa have been approved for use in the treatment of adults with some forms of cancer. They are also approved for children who experience puberty at an abnormally early age (‘precocious puberty’) but will be stopped so that normal puberty can unfold and take place at the typical age of onset (Bangalore Krishna et al., 2019). Any particular drug will have a different risk:benefit profile depending on the indication (reason) it is given for a particular disease. It is wrong (if not pharmacologically unintelligible) to think that a drug being safe in precocious puberty means it will be safe when used for gender dysphoria to block pubertal development and plan to start lifelong exogenous opposite sex hormones. (For example, insulin can be life saving in diabetic ketoacidosis, and fatal in a healthy euglycaemic person.) There is no disease of normal puberty in gender dysphoria. There is no hypothesis nor causally understood mechanism by which an opposite sex hormone corrects a ‘hormone deficiency’ in a person transitioning (as implied by the term ‘hormone replacement’). There is no ‘second puberty’, despite the bodily changes from cross sex hormones sometimes being described as such by people undergoing transition. No doubt the drugs are powerful, effect major mood and physical alterations and many people feel their lives have been transformed, but there are complications and unwanted effects associated with every medical intervention. There are currently no ongoing nor published robust studies (i.e. randomised controlled trials) evaluating the long-term safety and effectiveness of puberty blockers for gender dysphoria (SBU, 2019; NICE, 2021). The vast majority of children put on GnRHa for reasons of gender identity go on to take cross-sex hormones (Brik et al., 2020; Carmichael et al., 2021). 

The use of puberty blockers for children who experience discomfort due to a perceived mismatch between their identity and their biological sex presents several unique risks. Since puberty normally occurs together with adolescence, a challenging but critical phase of child psychosocial development, artificial interruption of physical sexual maturation must lead to changes to the time-dependent stages of human development, many irreversible. Preventing the gonads from normal maturation, particularly when followed by cross-sex hormones, will adversely affect fertility and may lead to permanent sterility: “A special group of individuals are prepubertal or pubertal adolescents who will never develop reproductive function in their natal sex due to blockers or cross-gender hormones. At this time there is no technique for preserving function from the gonads of these individuals“ (Coleman et al., 2012). Halting normal puberty will also affect a child’s linear growth. This is a critical time of life for strengthening bones. Disruption or delay of this process results in lower peak bone density, which markedly increases the risk for osteoporosis later in life (SEGM, 2021).  

Less well studied are the effects of puberty blockers on normal human brain development, which continues into the third decade of life. There has been some animal work (in male sheep) that shows puberty blockage with GnRHa impacts brain function (memory and cognition) (Hough et al., 2017). GnRHa may adversely influence learning, memory, mood, and psychosexual maturation. Depression and suicidal ideation are included on the lists of potential side effects of puberty blockers (Drugs.com, 2021).   

While often described as merely a ‘pause’ button for children with gender dysphoria, there is growing evidence that puberty blockers permanently alter the normal trajectory for psychosexual development. In the UK, it appears that 98% of children started on GnRHa in early puberty go on to take cross-sex hormones (Carmichael et al., 2021).  Some clinicians are concerned that children cannot give legitimate consent to these drugs, particularly as their effects will alienate functions that children simply cannot understand before adulthood (like sexual enjoyment and fertility). There have been legal cases around the world regarding the use of puberty blockers for gender dysphoria, notably Bell v Tavistock in the UK, a case where the Judicial Review findings were overturned on Appeal (EWHC 3274, 2020; EWCA Civ 1363, 2021) but where light was shone on a number of medical practices that “surprised” the Judges. While law should not unduly interfere with medical practice, nevertheless these legal proceedings raise questions about the quality of healthcare, scientific unknowns, lack of data on long-term outcomes, safeguarding and ethical concerns surrounding puberty blockers. It is possible that patients may wish to sue services for unsatisfactory practices in the future. 

Cross-sex hormones

Most people understand oestrogen as the ‘female sex hormone’ and testosterone as the ‘male sex hormone’.  Both hormones are normally present in both sexes, but at markedly different levels.  Sex hormone levels also vary in amount throughout life, and are usually low in young children.  Maturation of the ovaries in females or testes in males at the time of puberty leads to increased sex hormone production and release. These rising levels of sex hormones are responsible for the observed bodily changes during adolescence that lead to reproductive maturity, development of secondary sex characteristics, acceleration and eventual completion of linear growth, increased bone density, and important changes in brain development.  

Sex hormones work by altering the expression of genetic signals within cells throughout the body.  Use of the opposite, or ‘cross-sex’ hormones for the treatment of gender dysphoria generally consists of the administration of testosterone to females desiring to appear (or be treated) as men and oestrogen to males desiring to appear (or be treated) as women. The dosages of exogenous hormones aim to achieve levels that correspond to the opposite sex. When given to females, testosterone causes growth of the clitoris, the development and growth of facial hair, deepening of the voice through growth of the larynx (voice box), increased muscle mass and strength, and increased number of red blood cells in the body. It can also lead to hair loss, acne, aggressive behaviour, elevated blood pressure, and cardiovascular disease. When given to males, oestrogen causes growth of breast tissue (gynaecomastia), increased weight gain and body fat, decreased sperm production, decreased sex drive (libido), impotence (inability to have an erection), enlargement of the prostate gland, and mood changes (depression, anxiety, and irritability, tiredness).  It also increases the risk of blood clots and stroke, swelling of the hands and feet, and type 2 diabetes.  Due to sex determined differences within DNA itself and from alterations that affect the ability of cells to read this genetic information, the way the body responds to the sex hormones differs between females and males. Thus, giving testosterone to females is not the equivalent of giving it to males (whether they are men with abnormally low levels, in say hypogonadotrophic hypogonadism, or men with normal levels). Likewise, giving oestrogen to males is not the equivalent of giving this same hormone to females. 

Many of the immediate effects of cross-sex hormone administration, such as impact on fertility, are well recognized. The long-term consequences of these drugs, particularly when given to adolescents, are largely unknown. 

For individuals who later decide to ‘detransition’ (i.e. re-identify themselves in accordance with their biological sex), some of the bodily changes induced by cross-sex hormone exposure are expected to be irreversible. Specifically, males exposed to oestrogen will continue to have gynaecomastia. Females exposed to testosterone will continue to have facial hair, clitoral enlargement, and a deepened voice. In both sexes, fertility may be permanently impaired.  For treated adolescents, hormone effects on height cannot be changed once the growth plates have fused.

References:

Bangalore Krishna, K. et al. (2019) ‘Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium’, Hormone Research in Paediatrics, 91(6), pp. 357–372. doi: 10.1159/000501336.

Brik, T. et al. (2020) ‘Trajectories of Adolescents Treated with Gonadotropin-Releasing Hormone Analogues for Gender Dysphoria’, Archives of Sexual Behavior, 49(7), pp. 2611–2618. doi: 10.1007/s10508-020-01660-8.

Carmichael, P. et al. (2021) ‘Short-term outcomes of pubertal suppression in a selected cohort of 12 to 15 year old young people with persistent gender dysphoria in the UK’, PLOS ONE. Edited by G. L. Santana, 16(2), p. e0243894. doi: 10.1371/journal.pone.0243894.

Coleman, E. et al. (2012) ‘Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7’, International Journal of Transgenderism, 13(4), pp. 165–232. doi: 10.1080/15532739.2011.700873.

Drugs.com (2021) Triptorelin Side Effects. Available at: https://www.drugs.com/sfx/triptorelin-side-effects.html.

EWCA Civ 1363 (2021) Quincy Bell and Mrs A v. The Tavistock and Portman NHS Foundation Trust. Available at: https://www.judiciary.uk/wp-content/uploads/2021/09/Bell-v-Tavistock-judgment-170921.pdf.

EWHC 3274 (2020) R (on the application of) Quincy Bell and A -v- Tavistock and Portman NHS Trust and others. Available at: https://www.judiciary.uk/wp-content/uploads/2020/12/Bell-v-Tavistock-Judgment.pdf.

Hough, D. et al. (2017) ‘A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep’, Psychoneuroendocrinology, 77, pp. 1–8. doi: 10.1016/j.psyneuen.2016.11.029.

NICE (2021) Evidence review: Gonadotrophin releasing hormone analogues for children and adolescents with gender dysphoria, National Institute for Health and Care Excellence. Available at: https://arms.nice.org.uk/resources/hub/1070905/attachment.

SBU (2019) Gender dysphoria in children and adolescents: an inventory of the literature, SBU 2019/427. Available at: https://www.sbu.se/307e.

SEGM (2021) The Effect of Puberty Blockers on the Accrual of Bone Mass, Society for Evidence Based Gender Medicine. Available at: https://segm.org/the_effect_of_puberty_blockers_on_the_accrual_of_bone_mass.

Viner, R. M., Allen, N. B. and Patton, G. C. (2017) ‘Puberty, Developmental Processes, and Health Interventions’, in Disease Control Priorities, Third Edition (Volume 8): Child and Adolescent Health and Development. The World Bank, pp. 107–118. doi: 10.1596/978-1-4648-0423-6_ch9.