Can sex stop body size growth

Hormonal treatment of adolescents with a trans identity

Summary

introduction

Since the 1990s it has been shown that hormonal therapy from puberty onwards alleviates gender dysphoria in transgender adolescents (man-to-woman, MzF; woman to man, FzM), which is why it has become a recommended standard procedure in various guidelines.

Methods

Effects and side effects of hormone therapy in adolescents (puberty arrest; menstrual suppression; antiandrogen therapy; gender reassignment therapy with estrogen / testosterone) are discussed in the light of the recent medical literature.

Results

GnRH analogs are used to suppress isosexual puberty development. Alternatively, progesterone and antiandrogens (cyproterone acetate) are used. Followed by gender reassignment therapy, this therapeutic regimen can significantly alleviate gender dysphoria and, if started early, prevent somatic stigmatization in the undesired biological sex. However, negative effects on bone health, neuropsychological development, social functioning and, in particular, fertility issues are cause for concern.

discussion

Hormone therapy in transident adolescents can effectively improve the present gender dysphoria and associated accompanying psychopathology. A highly selective diagnostic process by an interdisciplinary gender team with regular case conferences is an indispensable prerequisite for facing the numerous, individual ethical challenges.

Abstract

Background

Since the 1990s, hormonal intervention starting at puberty has been shown to alleviate gender dysphoria in transgender adolescents (male-to-female, MzF; female-to-male, FzM) and has become a standard treatment recommended in various guidelines.

Methods

The effects and side effects of therapeutic interventions in adolescents, such as blocking puberty, menstruation, or testosterone action as well as gender-affirming hormonal therapy with estrogens or testosterone, are discussed in light of the recent medical literature.

Results

GnRH analogues are used to inhibit undesired isosexual development. Alternatively, progesterone and anti-androgens (cyproterone acetate) can be used. Followed by gender affirming therapy, this therapeutic regimen has been shown to alleviate gender dysphoria and, if started early, interrupts somatic stigmatization associated with undesired biological development. However, negative effects on bone health, psychoneurological development, social functioning, as well as fertility issues are still a matter of concern.

Discussion

Hormonal intervention in transgender adolescents can effectively improve gender dysphoria and associated psychiatric comorbidity. A highly selective diagnostic process carried out by an interdisciplinary gender team that routinely meets for case conferences is a prerequisite to face the multiple, individual ethical challenges.

background

Gender incongruence / transidentity / “transgender” describes a gender perception apart from the heteronormative, gender-binary basic attitude and includes people who do not or only partially feel that they belong to their biological gender, be it the opposite sex (woman-to-man, FzM; man -zu-Frau, MzF), a gender in between, both genders are perceived or a conventional gender categorization is rejected at all [1,2,3]. Whether the growth recorded worldwide corresponds to a real increase or whether it is promoted by public awareness, media presence and the establishment of special transgender health programs is controversial. Among adolescents of secondary school age, incidence rates of 1.2% for transgender people and 2.7% for people whose self-concept deviates from typical male / female gender roles or ascriptions (“gender non-conforming”) were found [4, 5 ]. In adults, these figures are 0.3% (transgender) and 0.8% (gender non-conforming) [6]. It is noticeable that the gender ratio between MzF and FzM has reversed in children and adolescents in favor of FzM (MzF to FzM: 1 to 1.2) [7].

The choice of which gender one wants to live in is recognized as a fundamental right. In Austria, since 2009 it has been possible to change civil status without taking gender reassignment measures. The previous regulation regarding somatic treatment (hormone therapy, gender reassignment surgery) from the age of 18 after puberty led v. a. in MzF people to a "stigmatization" through body size, male habitus, deep voice and beard growth. A number of additional medical measures such as speech therapy to raise the speaking voice through to surgical shortening of the vocal folds, breast augmentation, laser epilation, facial surgery, etc. were sought afterwards [8].

After positive experiences with the puberty-locking and opposite-sex treatment of transgender adolescents had already been made in some countries, especially the Netherlands, since the late 1990s, the Endocrine Society published "Clinical Practice Guidelines" for the first time in 2009 (revised version 2017) In accordance with the “Standards of Care” of the World Professional Association for Transgender Health (WPATH), we recommend early hormonal treatment from the onset of puberty, subject to stringent psychiatric and psychological diagnostics [9, 10]. Gender reassignment operations should continue to be reserved for patients> 18 years of age.

“Gender team” / therapeutic support

Not the trans-identity per se, but the dysphoria, especially in connection with the acceptance in the living environment, has disease value and is the goal of therapeutic endeavors. The diagnosis is made by “gender teams” consisting of specialists in child and adolescent psychiatry, psychologists and psychotherapists. For this purpose, special questionnaires have been developed to record gender dysphoria in children and adolescents [11, 12]. Psychiatrists, together with psychologists and psychotherapists, ultimately also provide the indication for hormone therapy. They also advise on the time of the change of first name and civil status, which can already be carried out at this age with appropriate expert opinions. The task of pediatric endocrinologists is on the one hand to rule out a variant of gender development and on the other hand to evaluate risk factors for later hormone therapy. Furthermore, it is about the assessment of the development of puberty, the time of the start of therapy as well as clinical, hormonal and metabolic monitoring during therapy. An interdisciplinary case conference of all involved professionals takes place before each treatment step, i. This means that the indication for treatment with GnRH analogues or sex steroids is made jointly in each case by consensus. The procedure is set out in the treatment recommendations of the Ministry of Health 2017 [13].

Hormonal treatment of adolescents

A synopsis of the hormonal treatment pathway depending on age is shown in Fig. 1a (FzM) and Fig. 1b (MzF).

Puberty-Locking Therapy: GnRH Analogs

In the 1990s, a therapy to arrest the development of puberty using GnRH analogues was first applied to adolescents with trans identity (overview in [14]). When started at an early stage of puberty, it stops the further progress of unwanted physical changes. Often referred to in the medical literature as the "prolonged diagnostic phase", it can lead to a psychological relief and, as a reversible measure, save time for further diagnostic re-evaluation and long-term psychotherapeutic observation before irreversible changes are induced by the opposite-sex therapy. Treatment is started at the earliest from puberty stage Tanner 2-3. In practice, however, the group of older adolescents with advanced puberty development predominates - at least to date (Tanner 4–5). This is partly due to the fact that the diagnostic process not infrequently takes a long time, or that adolescents are more often critical or even cautious about an early body-changing intervention [15].

For treatment, a GnRH analogue (e.g. triptorelin; leuprorelin), which is established in childhood for the treatment of precocious puberty, is usually injected subcutaneously or intramuscularly at four-week intervals. There are also preparations available in higher doses with a twelve-week injection interval. The long-acting binding to the GnRH receptors of the pituitary gland prevents the pulsatile GnRH stimulation necessary for the release of LH and FSH, which leads to a downregulation of the gonadotropins. As a result, gonadal testosterone / estrogen production is throttled with a stop of further puberty development, decrease in testicular volume and sexual functions (e.g. erections in MzF), stopping of breast development and menstruation in FzM (often withdrawal bleeding after the first dose) 16].

Since germ cell maturation is blocked, an early start means that fertility is not achieved. So far it has not been possible to differentiate prepubertal gonadal tissue in cell culture, so that an - also highly invasive - surgical removal of testicular / ovarian tissue is not offered before the start of treatment. MzF adolescents at an advanced stage of puberty should be offered sperm preservation and FzM adolescents should be offered the option of egg cell or ovary cryopreservation. Among adult transgender people from Germany, the desire to have their own biological child was 25–35% [17]. In contrast, in a retrospective US study on 73 transgender adolescents, only 2 adolescents (3%) actually took fertility preservation measures before starting treatment [18].

In addition to headaches and weight gain / increase in fat mass, GnRH analog therapy can initially have effects on mood that can be attributed to the induced hormonal change. When treated at an advanced stage of puberty, FzM may experience premenopausal symptoms (e.g. hot flashes). The treatment leads to a slowdown in growth on the one hand, and to a delay in bone maturation on the other, so that effects on the final size are possible, but have not yet been systematically investigated [16, 19].

In several studies - in accordance with the essential importance of sex steroids for bone health - a failure of further increases in bone mineral density was observed during treatment [16]. In the few available studies of different designs, this deficit was largely but not completely made up for FzM and MzF under therapy with sex steroids, especially if the start of treatment was before a bone age of 14-15 years. In a study on adolescents who had been receiving gender reassignment therapy with estrogen or testosterone for two years after GnRH therapy, the volumetric bone density in the lumbar spine (Z-Score) was −1.1 and −0.66 (bone age 15 years for MzF) or −0.15 and −0.06 (bone age 14 years for FzM) [20]. There are still no studies on the question of whether a maximum individual bone mineral density corresponding to the normal population is reached later.

Negative effects on brain development have not yet been found, the executive brain functions did not differ between a GnRH and an untreated transgender comparison group [21]. However, the cohort studied was small (20 participants per group); In addition, the neuropsychological testing was not comprehensive and was only collected during adolescence. Studies regarding social development / competence under GnRH analog therapy are completely lacking. Therefore, the lack of long-term data and possible previously unknown effects must be taken into account in the clarification [22].

With regard to psychological effects, the studies available so far show a significant improvement through GnRH analogue therapy. In particular, internalizing psychiatric disorders receded, which in the course of treatment retrospectively indicated a comorbidity attributable to the trans identity and not an independent underlying psychiatric disorder [23, 24]. The extent of the gender dysphoria itself did not change.

GnRH analogue alternative at FzM

Progesterone supplements

Desogestrel or lynestrenol, used in the long cycle, can suppress menstruation to a large extent, if not always completely. Apart from fatigue, headache or hot flashes, no particular side effects were observed. The HDL / LDL ratio shifted towards a less favorable lipid profile. While the lean body mass increased (+ 8.6%), there was no significant effect on bone density [25, 26]. The target group of such a therapy are older FzM adolescents from Tanner stage B4, who experience menstruation as particularly stressful. On the other hand, there is no primary slowing effect on breast growth.

GnRH analogue alternative at MzF

Antiandrogenic progestin: cyproterone acetate

In the medical literature there is only one study in which the use of cyproterone acetate as monotherapy for 6 months in MzF adolescents from Tanner stage G4 was systematically investigated [27]. Corresponding to the mechanism of action as an antagonist at the androgen receptor and the reduction in LH secretion, there was a reduced testosterone release and effect with a decline in sexual functions (erections, libido) and a decline in the growth of body hair. Gynecomastia, corresponding to Tanner stage B2–3, was observed in one third. Side effects included fatigue, hot flashes, and increased emotionality. The body fat mass increased by 9.4%. In contrast to lynestrenol in FzM, there was a significant inhibition of the physiological increase in bone density (Z-Score −0.76 to −1.15 after 10.6 months of treatment) [26]. Since cyproterone acetate is not approved by the FDA, the mineral corticoid receptor antagonist spironolactone, which also has anti-androgenic properties, is often used in the USA.

Sex reassignment hormone therapy: estrogen, testosterone

Treatment with estrogen (MzF) or testosterone (FzM) has so far usually been carried out from the age of 16 while maintaining GnRH therapy or gestagen or anti-androgen therapy, after the indication from the supervising gender team and from the somatic side a contraindication has been ruled out. Depending on the stage of puberty at the start of treatment, the dose is gradually adjusted at six-monthly intervals, in accordance with a classic puberty induction scheme, over a period of two to three years [9]. In adolescents at an advanced stage of puberty, the starting dose is higher and the dose is increased accordingly more quickly. Testosterone (e.g. testosterone enanthate) is administered by intramuscular injection every four weeks or transdermally daily, estrogen as a tablet, e.g. B. 17-beta-estradiol, estradiol valerate, or also transdermally, especially if there is a tendency to thrombophilia. After reaching the full dose, testosterone alone is usually sufficient for FzM to suppress menstruation, and the GnRH analogue can be discontinued. On the other hand, GnRH analogue or antiandrogenic therapy is still required for MTF, since complete suppression of the endogenous testosterone effects with estradiol alone is usually not possible [9, 19]. The specific effects, time of onset and duration until the maximum effect is reached are listed in Table 1, side effects in Table 2. Depending on the age, the clinical effects and the estrogen / testosterone values, the therapy is given in terms of dose or administration interval ( Testosterone injections). Long-term morbidity and mortality were investigated in adult collectives and showed an increased rate of thromboembolic events (0–5%) in MTF receiving estrogen therapy. To what extent the testosterone-associated lowering of HDL cholesterol in FzM increases the cardiovascular risk over the long term is not yet clear [28]. The 51% increase in mortality in MzF compared to the general population was mostly not directly associated with therapy (substance abuse, infections, suicide). Testosterone at FzM in the usual hormone replacement dose was not associated with any increased mortality [29]. Psychological follow-up studies on hormone-treated adults showed an improved quality of life, although not entirely uniformly and significantly only in MzF (overview in [30]). With regard to medium-term effects in transgender adolescents, an outcome study has so far been carried out on 55 Dutch patients (MzF: 22; FzM: 33) who were born before puberty arrest (13.6 years), before the start of opposite-sex therapy (16.7 years) and one year after sex reassignment surgery (20.7 years).Subjective well-being and quality of life had improved significantly in the course of therapy up to the final examination and were the same or better compared with a non-transident, age-matched comparison group [23].

Follow-up and transition to adult care

According to the guidelines, clinical checks are carried out every three to six months at the start of puberty-locking therapy, with a survey of effects and side effects, anthropometry, blood pressure and biochemical parameters (blood count, liver values, lipid metabolism, LH, FSH, testosterone / estrogen) [9]. In practice, the hormone determination just before the next GnRH analog administration has proven its worth in order to evaluate the adequacy of the suppression towards the end of the active phase. Depending on the age, the bone age is determined annually; if it is clinically relevant, the bone density is measured at one to two-year intervals. In the case of inadequate puberty lockdown, compliance and administration intervals must be questioned. If there is a worrying decrease in bone mineral density, an earlier start of sex reassignment hormone therapy can be considered [19]. If, as part of gender reassignment therapy, the progression of puberty is inadequate, undesirable side effects occur, or the estrogen / testosterone levels are outside the target range, a change in preparation or dose can be considered. Pronounced erythrocytosis (hematocrit over 50%) or increase in liver parameters over three times the norm may require a temporary interruption of hormone therapy.

As part of pediatric care, continuous education about the necessary long-term medical monitoring should take place, so that sufficient independence and self-care are guaranteed before the transfer to adult care. Depending on requirements, the multidisciplinary team organizes further psychological / psychotherapeutic care and ideally the transfer from pediatric endocrinology directly to adult endocrinology or gynecological endocrinology takes place. In addition to the medical aspects of hormone treatment, monitoring for cardiovascular risk factors, bone density measurement and gynecological preventive examinations (breast cancer screening for MzF as well as for cis-gender women), the focus of the care is on advice on desired surgical treatments or questions about assisted reproduction if you want to have children.

Ethical challenges

One of the upper principles of medicine - “primum non nocere” - or the well-being of the child are in a special light in view of the present area of ​​tension and inevitably confront the care team with moral dilemmas and questions: Do we cause damage if we intervene early? Or do we add more (emotional) damage by waiting if a young person who experiences himself in the wrong body has to go through his own unwanted puberty and thereby stigmatize in the rejected sex? Is the risk of far-reaching impairment of mental health or of growing up happily above the risk of making body-changing, life-determining decisions before reaching psychosexual maturity, the long-term consequences of which, e.g. B. on bone mineral density or psychoneurological development are currently still uncertain? In which direction should the argument of the right to an open future be interpreted, the biological or the desired sex? What about decision-making skills among adolescents? To what extent can a young person at the beginning of puberty assess the long-term effects of hormone treatment on his / her life, in particular, for example, not being able to have biological children of their own? Is a valid informed consent in the actual sense even possible if long-term experiences are not known? In the event of parental rejection or lack of support, must the adolescent's request for treatment be given priority in terms of patient autonomy [19, 22]?

Conclusion

In terms of equality and equal opportunities, medicine is required to enable transgender people to lead a happy, fulfilling life. Although early hormonal intervention is repeatedly discussed critically and controversially in the media outside of the medical discourse, it should be recognized that gender dysphoria means great personal suffering, combined with psychiatrically relevant comorbidities up to self-harm and suicide. When weighing the benefits of hormone therapy and all reservations, the positive side can prevail in the individual case. What is essential is a standard-compliant, multi-professional, team-based decision-making process. In complex cases, interdisciplinary boards with the inclusion of medical ethics are required. Continuous accompanying research with the establishment of data registers as well as multi-center prospective studies, such as the ongoing Trans Youth Research Network [31], must be initiated.

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Funding

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Affiliations

  1. St. Anna Children's Hospital, University Clinic for Pediatrics, Medical University of Vienna, Vienna, Austria

    Dr. Stefan Riedl

  2. Department of Pediatric Pulmonology, Allergology and Endocrinology, University Clinic for Pediatrics, Medical University of Vienna, Vienna, Austria

    Dr. Stefan Riedl

Corresponding author

Correspondence to Dr. Stefan Riedl.

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Conflict of interest

S. Riedl states that there is no conflict of interest.

The authors did not conduct any human or animal studies for this article. The ethical guidelines given there apply to the studies listed.