Clinical pharmacology in adolescent transgender medicine

Abstract

Adolescent transgender medicine is a growing clinical field. Gender-affirming medications for transgender youth may include gonadotropin-releasing hormone (GnRH) agonists, gender-affirming hormones or both. To evaluate the potential effects of GnRH agonists (puberty suppression) on pharmacokinetic processes for transgender youth, we searched PubMed from inception to May 2024 for publications on the effects of GnRH agonists on drug absorption, distribution, metabolism or excretion for transgender adolescents or effects on hormones (including gonadotropins, adrenal androgens, sex steroids) that are associated with changes in drug metabolism during puberty in the general adolescent population. No publications discussed the effects of GnRH agonist treatment on pharmacokinetic processes for adolescent transgender people. Sixteen publications observed marked decreases in gonadotropins and sex steroids for both adolescent transgender men and adolescent transgender women and slight effects on adrenal androgens. During GnRH agonist treatment, changes in body composition and body shape were greater for adolescent transgender people than for cisgender adolescent people. Further research is needed to better understand the effects of GnRH agonists on drug metabolism and other pharmacokinetic processes for transgender adolescents receiving GnRH agonists and other gender-affirming medications.

1. Introduction

Transgender, nonbinary, and other non-cisgender, hereafter referred to as transgender, adolescents are an increasingly visible population globally, yet gaps in pharmacologic knowledge exist for this population. Not every transgender person desires medical interventions to meet their gender expression goals. But for those who do, medication therapies, such as gonadotropin-releasing hormone (GnRH) agonists, are one part of the standard of medical care for transgender youth who desire pubertal suppression.[1, 2] In this narrative review, we examined the potential effects of GnRH agonist treatment on pharmacokinetic processes for transgender adolescents.

1.1. Global demographics and clinical cohorts of transgender youth

Between 2012 and 2017, several population-based surveys of high school-aged youth globally represented transgender youth, including 1.2% of 8166 students in New Zealand,[3] 1.8% of 131,901 students in the US,[4] and 4.1% of 940 students in Germany.[5] Two prospective clinical cohorts that have increased available knowledge about the demographics and clinical outcomes for transgender youth receiving gender-affirming medical care are the Amsterdam Cohort of Gender Dysphoria[6, 7] and the US-based Trans Youth Care study.[8] Located at the Center of Expertise on Gender Dysphoria at the Vrije Universiteit University Medical Center Amsterdam, the Amsterdam Cohort of Gender Dysphoria includes one of the largest clinical cohorts of transgender people worldwide.[6, 7] In the US, investigators in three US states (California, Massachusetts, and Illinois) launched the Trans Youth Care-United States study from 2016 to 2018.[8] In addition to these cohorts, investigators in Europe developed the European Network for the Investigation of Gender Incongruence in adolescents that will systematically assess physical outcomes, laboratory studies and the psychological well-being of adolescents receiving gender-affirming medications based on clinical need.[9] This is an ongoing multicenter prospective cohort study that started in 2021 at three medical centers in the Netherlands, Belgium and Italy.[9]

The Vrije Universiteit University Medical Center, Amsterdam has offered comprehensive mental health care and medical care for transgender children and adolescents for >20 years. In certain cases, adolescent transgender people nearing 18 years of age received mental health care and medical care through the Vrije Universiteit University Medical Center Amsterdam in the early 1970s. Between 1997 and 2018, 1766 transgender children and adolescents had an initial visit at the Vrije Universiteit University Medical Center, Amsterdam. Of these patients, 1077 (61%) were assigned female at birth, and 689 patients (39%) were assigned male at birth.[6] Among the patients who started GnRH agonist treatment, the median ages were 14 years (patients assigned male at birth) and 15.5 years (patients assigned female at birth). For those patients on gender-affirming hormones, the median age at which estrogen treatment was started was 16 years, and 16.7 years for those receiving testosterone treatment.[6] From this cohort, investigators have published several prospective and retrospective analyses on the effects of GnRH agonist treatment on skeletal health, body composition and cardiometabolic markers among transgender adolescents.[10–12] Outcomes reported from this cohort have included decreased bone resorption marker concentrations and no change in apparent bone mineral apparent density,[10] and increased fat mass and decreased lean body mass during GnRH agonist treatment.[13]

The Trans Youth Care study was a prospective, observational, longitudinal study of approximately 400 transgender youth at four US academic medical centers.[8, 14] Investigators evaluated the physiologic and psychosocial effects of gender-affirming medications for transgender youth, specifically GnRH agonist treatment (for puberty suppression) or gender-affirming hormones (testosterone or estrogen treatment), based on clinical need. Among 90 transgender youth receiving a GnRH agonist, the average age was 11 years, and 49% were assigned female at birth; among 301 transgender adolescents on gender-affirming hormones, the average age was 16 years, and 67% were assigned female at birth. Transgender youth in the Trans Youth Care study were racially and ethnically diverse: Among those receiving GnRH agonist treatment, 78% were White, 20% were Hispanic or Latino, 13% were multiracial, and 3% were Black; among those on gender-affirming hormones, 63% were White, 22% were Hispanic or Latino, 5% were Asian, 4% were Black, 1% were American Indian or Alaska Native, and 3% were multiracial.[8]

The effects of GnRH agonist treatment on mental health, psychological well-being, and metabolic and physiologic parameters among participants in the Trans Youth Care study have not yet been published.[8] In the Trans Youth Care study among youth on gender-affirming hormones for two years, investigators observed decreased depression scores using the Beck Depression Inventory-II (−1.47 points; 95% CI, −2.15 to −0.80) and anxiety symptoms based on the Revised Children’s Manifest Anxiety Scale (−1.27 points; 95% CI, −1.98 to −0.57) and increased psychological well-being based on the National Institutes of Health Toolbox Emotion Battery scales (2.31 points; 95% CI, 1.65 to 2.99) compared with baseline assessments before starting gender-affirming hormones.[15]

1.2. Health disparities, co-occurring medical conditions and prescription medication use

Across the life course, transgender people face stigma, discrimination and barriers to healthcare access.[16] Of nearly 3000 transgender high school-aged respondents in the 2017 US Youth Risk Behavior Survey (131,901 total students), transgender students reported 6.4 times the prevalence of sexual dating violence, 2.3 times the prevalence of being bullied at school and 2.9 times the prevalence of prescription opioid misuse compared with cisgender male students.[4] In a 2018 survey of more than 200 transgender youth 12 to 26 years of age who received clinical care at two gender clinics in the northeastern US, up to 63% of respondents experienced non-affirming interactions with healthcare providers in various healthcare settings.[17] Respondents’ experiences included interacting with healthcare providers who misused patient names or pronouns, who refused to discuss gender-related health concerns with patients, or who used hurtful or insulting language when talking about patients’ gender identities. Nearly half of respondents felt disrespected by a healthcare provider.[17] Overall, non-affirming experiences in healthcare settings were associated with increased rates of healthcare avoidance among respondents in this cohort.[18]

Based on the gender minority stress framework, in which the unique stressors experienced by members of a minority group are linked with adverse health outcomes, transgender youth may face a disproportionate burden of health disparities relative to cisgender youth.[19] As one example, investigators observed an association between bullying and higher odds of substance use among transgender youth compared with cisgender youth.[20] Transgender youth have a higher prevalence of mental health concerns, including depression and anxiety compared with their cisgender peers.[21–23] Transgender youth have up to a three times higher risk of depression and anxiety disorder compared with cisgender peers, and investigators have hypothesized that this risk is associated with social stressors such as family rejection, violence, and discrimination.[24]

Transgender people have higher odds of HIV compared with the general population ages 15–49 years.[25, 26] Investigators have observed a higher burden of HIV risk-related behaviors among transgender youth relative to cisgender peers.[4] Among transgender youth ages 13–24 years, investigators have observed an association between accessing gender-affirming medical interventions (gender-affirming hormones and surgery) and greater odds of lifetime testing for sexually transmitted infections and awareness of HIV pharmacologic prevention interventions.[27] Because HIV testing and HIV pharmacologic prevention interventions are associated with decreased transmission of HIV,[28] these services are an important part of medical care for transgender youth.

Transgender adolescents may take prescription medications to manage co-occurring medical conditions, yet knowledge is limited about patterns of prescription medication use among transgender youth. In the general population of US youth, an analysis of the 2011–2014 US National Health and Nutrition Examination Survey (NHANES), a nationally representative US survey, observed that nearly 26% of 2700 participants 12 to 19 years of age were on at least one prescription medication within 30 days of being interviewed.[29] Asthma medications, antibiotics, and attention deficit hyperactivity disorder medications were the most common medication classes.[29] NHANES does not collect information on gender expression beyond “male” or “female,”[30] which limits knowledge about prescription medication use among transgender people.

An analysis of the US Military Health System Data Repository, a centralized database of inpatient and outpatient care and outpatient prescriptions for active members and retirees for the US Armed Services and their dependents, evaluated claims data for approximately 3700 people <18 years of age with at least one clinical visit with a transgender health-related care diagnosis code.[31] Within this cohort, nearly 90% of transgender youth had a clinical visit with a mental health-related diagnosis code for anxiety, adjustment disorder or attention-deficit hyperactivity disorder. Three-quarters of this cohort used a psychotropic medication such as antidepressants (e.g., selective serotonin reuptake inhibitors), stimulants or antipsychotic medications.[31] Because adolescent transgender people may be prescribed medication therapies for co-occurring acute and chronic medical conditions, increased pharmacologic knowledge is needed to support safe and effective use in addition to gender-affirming medications.

2. Methodology

2.1. Language in this review

In this review, we used the term “adolescent transgender people” to characterize people between the ages of 12 and 25 years with gender identities that differ from their sex assigned at birth. A list of terms in this review is available in Table 1. There is diversity in the lived experiences of transgender people, and it is important to use language that minimizes assumptions about these experiences. This includes recognizing that the diversity of gender identities extends beyond a binary man-woman construct.[32] Additionally, although we focused on the pharmacologic considerations for adolescent transgender people receiving GnRH agonist treatment with or without subsequent estrogen or testosterone treatment, not all transgender youth desire these interventions and, even among those who do, few are able to access them.

Table 1.

Language in this review

Term	Definition
Sex	A categorization of various physical characteristics including hormonal expression, genitalia and gonads. Sex is typically socially assigned to an individual at birth as male, female or intersex based on the appearance of external genitalia.
Gender / Gender identity	A social construct that describes behavioral, psychological and social traits present in a culture, typically with gender categories such as man, woman or nonbinary. The construct of gender may vary by culture. Gender identity is an individual’s personal understanding of their place in that social construct.
Gender-affirming medical care	Medical interventions such as medications or surgery that a person may or may not choose to meet their gender expression goals. For example, a trans youth may access hormone therapy to suppress puberty and the development of undesired secondary sex characteristics.
Transgender or trans	An umbrella term describing a person whose gender differs from the cultural expectation of their sex assigned at birth. This umbrella includes trans women, trans men and nonbinary people.
Cisgender or cis	A term describing a person whose gender aligns with the cultural expectation of their sex assigned at birth; not transgender.
Transgender man / transmasculine adolescent	A man/adolescent identifying along the masculine spectrum who was assigned female at birth.
Transgender woman / transfeminine adolescent	A woman / adolescent identifying along the feminine spectrum who was assigned male at birth.
Nonbinary	An umbrella term describing people with a gender identity outside of the cultural binary of “man” or “woman.” Some labels people may use to describe themselves include: nonbinary, genderfluid, genderqueer, agender, and bigender.

2.2. Approach

To examine the potential effects of puberty suppression on pharmacokinetic processes for transgender adolescents, we performed literature searches on the following topics: 1) the effects of GnRH agonist treatment on drug absorption, distribution, metabolism or excretion for transgender youth, 2) the physiological or hormonal factors that contribute to changes in pharmacokinetic processes during puberty; and 3) laboratory studies and physiological measures for adolescent transgender people receiving GnRH agonist treatment for puberty suppression (such as histrelin, leuprolide or triptorelin). We summarized the changes in physiological and hormonal laboratory studies and linked these outcomes to the available literature on drug absorption, distribution, metabolism and excretion for the general adolescent population. Because we focused on the effects of puberty suppression on pharmacokinetic processes, we limited our discussion on gender-affirming hormones (i.e., estrogen or testosterone treatment, including antiandrogens such as spironolactone or cyproterone acetate) to information available from publications that also discussed effects of puberty suppression.

2.3. Selection criteria and search terms

We searched PubMed from its inception to May 2024 for English-language publications using the following search terms: “drug absorption,” “drug distribution,” “plasma protein,” “drug metabolism,” “drug excretion,” “pharmacokinetics,” and “drug metabolizing enzymes,” “drug transport*,” “kidney function,” “creatinine,” “hormones,” with “adolescent,” “adolesc*,” “teen*,” “puberty.” We searched for terms related to gender-affirming medications using the World Professional Association for Transgender Health Standards of Care and the Endocrine Society clinical practice guidelines: “gonadotropin-releasing hormones,” “blockers”, “GnRH analogs.”[1, 2] We combined these terms with “adolescent,” “adolesc*,” “teen*,” “puberty,” and transgender person-related search terms (“gender dysphoria,” “transgender persons,” “gender identity,” “transsex*,” “transgender” “nonbinary”).

We extracted the following laboratory studies from publications based on our literature review of hormones and laboratory studies associated with changes in drug metabolism among adolescent people[33–38]: Luteinizing hormone, follicle stimulating hormone, estradiol or testosterone, adrenal androgens (dehydroepiandrosterone sulfate [DHEAS], androstenedione), growth hormone and insulin-like growth factor 1 (IGF-1) concentrations, and plasma proteins including sex hormone binding globulin. We extracted kidney function biomarkers (serum creatinine) and body composition estimates (e.g., body mass index) from available publications.

We excluded cross-sectional studies, as we wanted to evaluate laboratory studies and other physiologic factors for adolescent people before and during GnRH agonist treatment, and publications that evaluated gender-affirming medications not included in the World Professional Association for Transgender Health Standards of Care or the Endocrine Society guidelines (e.g., regimens containing the antiandrogenic medication bicalutamide or lynestrenol), as well as case reports or case series.

3. Gender-affirming medications for transgender adolescents: An overview

Clinicians have provided care for transgender adolescents for nearly 50 years.[39] Two global professional organizations, the World Professional Association for Transgender Health (WPATH) and the Endocrine Society, have published standards of care and clinical practice guidelines, respectively, for gender-affirming medical care for transgender people across the life course.[1, 2] For transgender children and adolescents, gender-affirming medications may include the following medications based on a person’s developmental stage: 1) GnRH agonists that suppress the hypothalamic-pituitary-gonadal axis (puberty suppression),[2] and 2) gender-affirming hormones including testosterone or estrogen treatment that induce secondary sex characteristics aligned with a person’s gender expression goals.[1, 2] The Endocrine Society recommends gender-affirming medications no earlier than Tanner stage 2,[2] and some adolescents may initiate GnRH agonist treatment later in puberty (Tanner stages 4 or 5).[40] Although guidance on how to provide gender-affirming medications for transgender adolescents is outside the scope of this review, we recommend reviews by Lee and Rosenthal (2023)[41] and Mahfouda et al. (2019)[42] for overviews of the available medical interventions and models of clinical care for transgender youth.

Of note, transgender youth who are prescribed a GnRH agonist based on clinical need may or may not continue on to take gender-affirming hormones. As an example from the US Trans Youth Study, among 315 participants enrolled who were starting gender-affirming hormones (testosterone or estrogen treatment) based on clinical need, only 25 (7.9%) had previously received puberty suppression treatment.[15]

3.1. Puberty suppression

The Endocrine Society recommends GnRH agonists as a class to suppress endogenous puberty.[2] The GnRH agonists, which are available as depot formulations or implants, stimulate the production and release of gonadotropins from the anterior pituitary gland. Continuous GnRH agonist administration subsequently suppresses the secretion of luteinizing hormone and follicle-stimulating hormone into the systemic circulation.[43] GnRH agonists do not affect the frequency or amplitude of hypothalamic GnRH pulses,[43] contributing to the reversible effects of GnRH agonists on the hypothalamic-pituitary-gonadal axis.[2] In US clinical settings, GnRH agonist treatment includes the histrelin subdermal implant and subcutaneous or intramuscular leuprolide injection.[40, 44–46] In Europe, subcutaneous or intramuscular triptorelin injection is available for GnRH agonist treatment.[47] GnRH agonists are not metabolized via cytochrome P450 (CYP) enzymes.[48]

3.2. Gender-affirming hormones

Gender-affirming hormones include testosterone or estrogen treatment. Testosterone treatment may include testosterone gel or injectable testosterone esters (testosterone cypionate or testosterone enanthate).[2] Testosterone treatment typically suppresses menstruation within six months of initiation,[49] but clinical providers may prescribe adjunctive medications such as progestin-only pills, depot medroxyprogesterone acetate or combined oral contraceptives to facilitate more reliable menstrual suppression prior to, or in combination with, testosterone treatment.[1, 2, 50] For example, in a clinical cohort of more than 200 transgender adolescents undergoing more than one year of testosterone treatment, a quarter of the cohort had an episode of breakthrough uterine bleeding.[51] Estrogen treatment regimens typically include 17β-estradiol preparations (tablet, patch, or injectable esters including estradiol valerate or estradiol cypionate).[2] During estrogen treatment, clinicians may also prescribe an antiandrogenic agent, including spironolactone, cyproterone acetate or a GnRH agonist to suppress endogenous testosterone production and activity.[2] Spironolactone and cyproterone acetate antiandrogenic effects include inhibiting endogenous androgen activity by binding to androgen receptors and blocking the binding of endogenous androgens.[2]

Estradiol and testosterone are metabolized via CYP enzymes, including CYP3A, CYP2B6, and CYP2C9.[34] Additionally, the antiandrogenic agents spironolactone and cyproterone acetate as well as progestogens may contribute to potential drug-drug interactions.[34] However, knowledge about drug-drug interactions is limited for the adolescent transgender population. Data from small pharmacokinetic analyses have observed that clinically significant drug-hormone interactions are unlikely between gender-affirming hormones and medications for pharmacologic HIV prevention (tenofovir disoproxil fumarate and emtricitabine) among transgender adolescents.[52, 53] However, additional work remains to understand the potential pharmacologic effects of GnRH agonists, estradiol and testosterone treatment on the maturation of major drug-metabolizing enzymes and drug transporters during puberty.

4. Pharmacologic considerations for transgender adolescents on gender-affirming medications

We identified no publications investigated the potential effects of puberty suppression on pharmacokinetic processes for adolescent transgender people. Sixteen publications reported the concentrations of gonadotropins, sex steroids, adrenal androgens or IGF-1 before and during GnRH agonist treatment, with or without subsequent gender-affirming hormones (Table S1).[13, 44, 45, 47, 54–65] Cohorts were located in the Netherlands, the US, Israel, Denmark, Turkey and Italy. The durations of follow-up during puberty suppression in selected publications ranged from 2 months to 65 months.

4.1. Drug absorption

Physicochemical changes affect oral medication absorption and bioavailability during early development, although most of these effects reach adult values in infants and young children. Several factors influence the drug absorption rate and extent for infants and young children.[66] For example, developmental changes in gastric pH and gastrointestinal motility may influence oral drug absorption, potentially decreasing the bioavailability of weak acids such as phenytoin, phenobarbital and ganciclovir.[67] However, most age-related effects disappear within the first few years of life. For instance, the gastric pH is similar to that of adults (pH 2–3) at two years of age, and by three years of age, the gastric acid excretion rate per kilogram of body weight is similar to that observed for adults.[68] Intestinal transit time is longer in neonates than for infants or young children due to decreased motility and peristalsis.[69] The gastric emptying rate is low in neonates and reaches adult rates by approximately eight months of age.[69, 70] Finally, sex-related effects influence gastric pH and gastrointestinal motility among adults. For example, cisgender women, on average, have a slower gastric emptying time and lower gastric acid secretion than cisgender men.[71]

Drug-metabolizing enzymes and efflux transporters (P-glycoprotein) in the gastrointestinal tract influence drug absorption. Investigators have observed mixed effects of age-related changes on duodenal CYP3A mRNA expression, protein levels and activity for children through 17 years of age.[72] Investigators have also reported mixed observations for age-related developmental effects on the P-glycoprotein mRNA and protein levels in the duodenum.[72] Based on the apparent oral clearance of fexofenadine, a P-glycoprotein substrate, investigators have observed maturation of the apparent activity of intestinal P-glycoprotein at six months of age.[67] No conclusions can be drawn about the potential effects of puberty suppression on drug absorption for transgender youth at this time.

4.2. Drug distribution

Total body water, extracellular and intracellular water and protein binding affect the volume of distribution of medications. Changes in body composition during adolescence may alter the volume of distribution for specific drugs. As one example, when considering changes in the ratio of total body water to total body fat across the life course, neonates and infants have a higher ratio of total body water to total body fat, contributing to an increased volume of distribution of hydrophilic medications including certain antimicrobial agents (gentamicin and linezolid).[67] Additionally, increased total body fat may increase the volume of distribution of lipid-soluble drugs like lidocaine or benzodiazepines.[35]

Lean body mass and total body fat increase during adolescence, and sex-related effects contribute to differences in the rate and extent of these changes.[36] Clinicians assess body weight relative to height using the BMI for adolescents, children and adults.[73] Based on the US Centers for Disease Control and Prevention 2000 growth charts, the BMI for the general population increases after 6 years of age, likely reflecting increased body fat. For cisgender boys at the 50^th percentile, the BMI-for-age curve increases from 15.4 kg/m² at 6 years of age to 23 kg/m² at 20 years of age. For cisgender girls at the 50^th percentile, the BMI-for-age curve increases from 15.2 kg/m² at 6 years of age to 21.7 kg/m² at 20 years of age.[73] Although growth charts are sex-based which may limit the utility for adolescent transgender people, investigators are exploring the role of age-adjusted, non sex-specific growth charts for transgender youth.[74] Seven publications estimated body composition (using BMI) before and during GnRH agonist treatment with or without subsequent gender-affirming hormones (Table S1).[13, 47, 54, 56, 61, 63, 65] Three publications reported statistically significant increases in BMI for adolescent transgender men,[47, 63, 65] and two reported a statistically significant BMI increase for adolescent transgender women.[47, 63] The remaining publications did not directly compare BMI before and during GnRH agonist treatment or gender-affirming hormones.

Klaver et al. reported that estimates of body composition and body shape changed toward those values of one’s affirmed gender at 22 years of age after receiving GnRH agonist treatment and subsequent testosterone or estrogen treatment.[13] Among 71 adolescent transgender women receiving GnRH agonist treatment and estrogen treatment (Table S1), the total body fat percentage increased (+9%, 95% CI: 8 to 11, P<0.001), lean body mass decreased (−9%, 95% CI: −11 to −8, P<0.001) and the waist-to-hip ratio decreased (an estimate of adiposity, −0.04, 95% CI: −0.05 to −0.02, P<0.001).[13] Among 121 adolescent transgender men receiving GnRH agonist treatment and subsequent testosterone treatment, total body fat percentage decreased (−3%, 95% CI: −4 to −2, P<0.001), lean body mass increased (+3%, 95% CI: 2 to 4, P<0.001), the waist-to-hip ratio increased (+0.03, 95% CI: 0.01 to 0.04, P<0.002).[13] These changes remained significant even after investigators adjusted for Tanner stage and baseline BMI. Klaver et al. concluded the extent of these changes in body composition and body shape was greater for adolescent transgender people than for adolescent cisgender people. The effect of these changes on drug disposition for adolescent transgender people remains to be determined.

Plasma protein binding influences medication distribution and changes in plasma drug binding can either increase or decrease free drug exposure. Plasma drug-binding proteins include albumin, α₁-acid glycoprotein and globulins, with albumin and α₁-acid glycoprotein observed to increase nearly two-fold during puberty.[38] Plasma protein concentration measurements were lacking for transgender adolescents. In one retrospective cohort, Stoffers et al. reported sex hormone binding globulin concentrations (SHBG) for 62 adolescent transgender men receiving GnRH agonist treatment and subsequent testosterone treatment (Table S1).[56] SHBG concentrations decreased significantly during testosterone treatment relative to baseline (25.9 nmol/l vs. 50.3 nmol/l, respectively, P<0.001). No other plasma protein concentrations were characterized in available studies. Whether potential changes in SHBG or other plasma drug-binding protein concentrations among transgender youth track with those for cisgender youth remains to be determined. We are unable to draw conclusions about the relationship between protein concentrations and drug disposition for adolescent transgender people.

4.3. Drug metabolism

No publications discussed the effects of puberty suppression on drug metabolism for transgender youth. Experts have observed marked variability in drug-metabolizing enzyme activities during adolescence, but specific regulatory mechanisms contributing to the maturational changes of drug-metabolizing enzymes remain to be established in vivo.[33, 37] Two examples of CYPs with apparent changes in activity for adolescents that emerged from our literature search include CYP3A4 and CYP1A2, which we will discuss further.

CYP3A is a clinically significant drug-metabolizing enzyme in phase I metabolism that metabolizes more than 50% of medications biotransformed by the CYP superfamily.[75] Investigators have noted that apparent activities of drug-metabolizing enzymes, including CYP3A, decrease during adolescence.[37] The timing of these changes correspond with increased systemic concentrations of gonadotropins, sex steroids, adrenal androgens and growth hormone concentrations during puberty.[33] As one example, investigators have observed age-related variability in the disposition of carbamazepine, an antiseizure drug and a CYP3A substrate.[33, 76] CYP3A4 metabolizes carbamazepine to its active metabolite carbamazepine-10,11-epoxide, with minor contributions from CYP2C8.[76] In a clinical cohort of more than 70 patients on carbamazepine monotherapy for acute seizure management (average age 9.5 years; range: three months to 29 years), investigators observed a small but statistically significant positive correlation between the carbamazepine plasma steady-state concentration-dose ratios and age (r=0.18, P<0.01).[77] A separate analysis of 15 patients (ages one to 15 years) observed a moderate positive correlation between carbamazepine plasma steady-state concentration-dose ratios and age (r=0.44, P<0.001).[78]

In addition to CYP3A, investigators have observed age-related effects on CYP1A2 activity. CYP1A2 metabolizes several medications, including the antidepressant medication duloxetine and the antipsychotic medication olanzapine.[75] Investigators observed higher apparent CYP1A2 activity during pre-pubertal or early Tanner stages relative to later Tanner stages among cisgender adolescent people.[33] Based on the caffeine breath test among more than 60 people (ages three to 20 years), in which caffeine was used as a model probe substrate for CYP1A2,[79] apparent CYP1A2 activity was higher for participants in Tanner stages 1 through 4 compared with adults.[80] Investigators have also observed that the weight-normalized apparent oral clearance of the bronchodilator theophylline, a CYP1A2 substrate,[79] was ~45% lower among adolescents who had completed puberty than among those who were prepubescent.[33] Although the exact mechanistic underpinnings for these changes remain to be established, investigators have suggested that hormonal changes, including those of gonadotropins, sex steroids and adrenal androgens, may contribute to changes in drug-metabolizing enzyme activity during adolescence.[33]

Eleven publications reported longitudinal changes in gonadotropin concentrations, most of which observed decreased luteinizing hormone and follicle-stimulating hormone concentrations, and decreased estradiol and total testosterone concentrations, during GnRH agonist treatment (Table S1).[13, 44, 45, 47, 54, 56, 58, 60, 62–65] For adrenal androgens, three publications reported a statistically significant increase in DHEAS concentrations during GnRH agonist treatment for adolescent transgender men (Table S1).[56, 59, 63] However, DHEAS concentrations typically increase during endogenous puberty,[33] and the final concentrations were aligned with those observed for people of a similar age not receiving gender-affirming medications.[59] For adolescent transgender men, androstenedione concentrations were lower during the first year of GnRH agonist treatment than at baseline.[59] In one analysis, authors observed that five of 67 adolescent transgender men had mildly elevated androstenedione concentrations before treatment and suggested that polycystic ovary syndrome, which may have contributed to the overproduction of adrenal androgens, could not be ruled out.[59] No clinically significant changes in adrenal androgen concentrations were observed for adolescent transgender women receiving GnRH agonist treatment and estrogen treatment.[59, 63]

IGF-1 is a growth hormone-responsive protein produced by the liver that can be used as a surrogate marker of changes in growth hormone concentrations.[34] Growth hormone increases during adolescence,[33] and the growth hormone-IGF-1 axis is stimulated by adrenal androgens.[81] As an example of changes in growth hormone during adolescence, among cisgender adolescent men, growth hormone concentrations increase during late puberty (13–14 years of age), followed by a decrease in concentrations in early adulthood to those concentrations observed before puberty.[82] Several publications provided narrative summaries of IGF-1 concentrations during puberty suppression, focusing specifically on gender-affirming medication’s effects on growth and adult height attainment.[55, 57, 64] No publications reported clinically significant changes in IGF-1 concentrations during GnRH agonist treatment for adolescent transgender men or adolescent transgender women. However, oral estradiol treatment was associated with a slight decrease in IGF-1 concentrations among adolescent transgender women.[55, 64]

The effects of either GnRH agonists or gender-affirming hormones on the apparent activities of phase I drug-metabolizing enzymes for transgender adolescents are unclear. However, several drug-metabolizing enzymes in the CYP enzyme superfamily exhibit sex-related differences in apparent activities between cisgender women and cisgender men. These differences include lower apparent CYP1A2 activity among cisgender women than cisgender men and higher (~35%) apparent CYP3A activity for cisgender women than cisgender men.[35] Although most publications reported marked decreases in gonadotropin concentrations and an associated decrease in sex steroid concentrations for adolescent transgender people receiving GnRH agonist treatment, the extent to which these changes may contribute to altered CYP activities remains to be determined.

4.4. Drug excretion

The kidney is a major organ for drug excretion. Investigators have established that the glomerular filtration rate reaches adult values within the first year of life.[66] Although clinical knowledge is limited about the effects of either GnRH agonist treatment, testosterone or estrogen treatment on kidney function in transgender adolescents, the effects of gender-affirming hormones on kidney function is an active area of investigation.[83] Two publications reported serum creatinine concentrations during GnRH agonist treatment (Table S1).[47, 56] The serum creatinine concentration was not significantly different before and during GnRH agonist treatment for adolescent transgender women. One study observed a slight but statistically significant decrease in serum creatinine concentrations among adolescent transgender men at 12 months of GnRH agonist treatment compared with pre-treatment baseline (0.77 mg/dL vs. 0.83 mg/dL [68 vs. 73 umol/l], respectively, P<0.01).[47] Of note, the authors observed no correlation between lean body mass and the change in serum creatinine concentrations.[47]

In a separate cohort of adolescent transgender men undergoing testosterone treatment after GnRH agonist treatment, serum creatinine concentrations increased significantly at 12 months of testosterone treatment relative to the concentrations during GnRH agonist treatment (0.70 at baseline vs 0.84 mg/dL during testosterone treatment [62 vs. 74 umol/l], P<0.001).[56] In an analysis of 194 participants receiving testosterone treatment in the US Trans Youth Care study (median age 16.2 years),[8] investigators also observed a slight but statistically significant increase in average serum creatinine concentrations over six months of testosterone treatment relative to baseline concentrations (0.68 mg/dL at baseline to 0.79 mg/dL during testosterone treatment [60 vs. 70 umol/l], P<0.001) and an average serum creatinine of 0.82 mg/dL (72.5 umol/l) at 12 months of testosterone treatment.[84] Because increased lean muscle mass may contribute to non kidney-related increases in serum creatinine concentrations,[83] investigators used BMI (based on sex assigned at birth) to estimate body composition in this cohort. The average BMI was 25.7 kg/m² at 12 months among people receiving testosterone treatment (from 25.1 kg/m² at baseline). Separately, among adolescent transgender women in the Trans Youth Care study (median age 17.3 years), investigators observed a slight but statistically significant decrease in serum creatinine concentrations at 6 months of estrogen treatment compared with baseline concentrations (0.83 mg/dL at baseline to 0.76 mg/dL during estrogen treatment [73 to 67 umol/L], P < .001). At 12 months of estrogen treatment, the average serum creatinine concentration was 0.74 mg/dL (65 umol/L), and the average BMI at 12 months was 25.2 kg/m² (up from 23.9 kg/m² at baseline).[84]

Overall, the above observations suggest clinically significant changes in kidney function may be unlikely during GnRH agonist treatment, but gender-affirming hormones may lead to marked changes in kidney function estimates. In the Trans Youth Study, the investigators used the 2021 Chronic Kidney Disease in Children under 25 (CKiD U25) equation to estimate glomerular filtration rate among patients under 25 years of age,[85] and observed that patients undergoing testosterone treatment had a slight increase in estimated GFR at six months of testosterone treatment relative to baseline: 8% (female modifier used in estimating equation) or 10% (male modifier used in estimating equation).[84] The investigators also noted a slight increase in estimated GFR when using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) kidney function estimating equation: 3% (male modifier) or 7% (female modifier).[86] Participants undergoing estrogen treatment had a decrease in estimated GFR at six months of treatment relative to baseline using the CKiD under 25 equation: −12% (female modifier) or −14% (male modifier). The estimated GFR using the CKD-EPI 2021 equation was −12% (female modifier) and −7% (male modifier).[84] Experimental, clinical and population-based studies have reported mixed findings regarding the effects of sex hormones on kidney function.[87] Additionally, creatinine-based kidney function estimating equations include a binary sex-related modifier.[85, 86] To better estimate kidney function for transgender youth receiving GnRH agonists or gender-affirming hormones, and to determine potential effects on renal drug elimination, prospective, longitudinal studies using an exogenous filtration marker (e.g., iohexol) are needed. No conclusions can be drawn about any effect of gender-affirming medications on kidney function or implication for drug excretion at this time.

5. Considerations for inclusive pharmacologic research for adolescent transgender people

Increased clinical pharmacological research is needed to ensure medications are safe and effective for transgender adolescents. Several unique considerations must be weighed to appropriately engage adolescents in research. For transgender people, barriers toward participating in research include concerns about privacy and exploitive or opportunistic research[88] and mistrust of medical and research communities.[89] Community advisory boards and research teams that include members of the transgender community are two key strategies that have been successfully used by researchers.

6. Conclusions

No publications discuss effects of GnRH agonists on pharmacokinetic processes for adolescent transgender people. During GnRH agonist treatment, changes in body composition and body shape were greater for adolescent transgender people than for adolescent cisgender people. Gonadotropins and sex steroid concentrations decreased markedly during GnRH agonist treatment. However, only slight effects were observed on adrenal androgen concentrations and IGF-1 concentrations, and these changes probably aligned with typical hormonal changes that occur during puberty. Increased research is needed to characterize and evaluate the potential effects of gender-affirming medications on drug disposition for transgender youth.