A Retrospective Study of the Use of Gonadotropin-Releasing Hormone Analogs and Testosterone in Transgender Boys: Who, What, When, and for How Long?

Abstract

A retrospective review of gender-affirming hormone therapy was conducted in 101 transgender boys followed in the pediatric endocrine clinic. Eighty-seven percent were postmenarchal at the initial visit. Of the 44% prescribed gonadotropin-releasing hormone analogs (GnRHas), insurance coverage was denied in 34% and an average of 4.5 months elapsed before treatment could be started in the remainder. Patients prescribed GnRHas were younger than those who were not, 13.7±2.1 versus 15.5±2.0 years, p<0.001. Continued menstrual bleeding was reported by patients receiving testosterone alone at doses ranging from 50 to 200 mg every 2 weeks.

Introduction

Gender dysphoria (GD) is characterized by distress associated with incongruence between one's sex assigned at birth and experienced gender.¹ Consensus guidelines recommend the use of puberty blockers to suppress the hypothalamic–pituitary–gonadal (HPG) axis in adolescents with GD.^2,3 The recommended timeframe for initiation of puberty blockers is at Tanner Stage 2. This prevents the development of secondary sexual characteristics along with the concurrent increase in emotional angst typically experienced by youth with GD during puberty.^4,5 Early initiation of puberty blockers also allows for less-invasive gender-affirming treatment later.^6,7

Although there is controversy around the use of puberty blockers in youth, it is a fully reversible intervention that improves mental health and does not increase rates of subsequent gender-affirming hormone use.⁸ Furthermore, patients who choose to start gender-affirming hormones as adolescents tend to continue treatment into adulthood, suggesting that they are mature enough to make decisions regarding this aspect of their health care and identity.⁹

In both transgender (TG) girls and TG boys, gonadotropin-releasing hormone analogs (GnRHas) are the gold standard for blocking puberty.¹⁰ However, most youth with GD present for initial evaluation well beyond Tanner Stage 2. The role of GnRHas in postpubertal adolescents with GD is not well defined.¹¹ Similarly, the success rate of prescriptions for these costly medications in this patient population are unclear. In TG girls, endogenous testosterone production requires a puberty or androgen receptor blocker even after estrogen is started.¹² While testosterone alone is sufficient to suppress the HPG axis in TG boys, the dose required to cause cessation of menses is unknown.¹³ In this study, our goal was to characterize the use of GnRHas and testosterone therapy in a cohort of TG boys.

Methods

Study design: retrospective

After Institutional Review Board (IRB) approval, medical records of transmasculine patients followed in the pediatric endocrine clinic were reviewed. An institutional waiver of informed consent was granted by our IRB for this exempt study. Variables evaluated included age, ethnicity, pubertal status, type of GnRHa, time between prescription and initiation of therapy, and length of therapy. In patients receiving testosterone alone, information about menses was recorded. Comparative analyses of patients prescribed GnRHas versus those who were not were performed using independent samples t-test and descriptive statistics, including means and standard deviations, were also calculated.

Results

A total of 101 transmasculine patients were included in the study. Patients were evaluated by a clincal psychologist with extensive experience in gender and all were deemed as meeting formal criteria for GD. Patients were referred to pediatric endocrinology for medical treatment of their GD. The average age at initial consult was 14.6±2.3 years (range 7.9–17.8 years) and average duration of follow-up was 1.8±1.5 years (range 0.0–7.0 years). At presentation, 87% had reached menarche.

Forty-four percent of the patients were prescribed GnRHas. Patients prescribed GnRHas were younger than those who were not (13.7±2.1 years vs. 15.5±2.0 years, p<0.001). There was no difference in menarchal status between groups, with menarche having occurred in 80% of patients prescribed GnRHas and in 93% of patients who were not (p=0.054). Of the patients prescribed GnRHas, 34% were unable to obtain the medication due to insurance denial and high cost. Among the 29 patients who were able to start a GnRHa, the average lag time between prescription and initiation of treatment was 136 days (range 16–804 days). As seen in Table 1, the most common GnRHa prescribed was 3-monthly leuprolide. Patients received GnRHas for an average of 1.4±0.5 years (range 0.5–2.2 years).

Table 1.

Cohort Characteristics and Gonadotropin-Releasing Hormone Analog Use

All patients, n=101
Age (years), mean±SD (range)	14.6±2.3 (7.9–17.8)
Ethnicity, n (%)
Caucasian	85 (84)
Unknown	7 (7)
African American	6 (6)
Asian	2 (2)
Hispanic	1 (1)
Menarchal status, n (%)
Premenarchal	13 (13)
Postmenarchal	88 (87)
Patients prescribed GnRHa, n (%)	44 (44)
Patients denied insurance coverage of GnRHa, n (%)	15 (34)
Types of GnRHas used, n=29
Monthly leuprolide, n (%)	2 (7)
3-Monthly leuprolide, n (%)	18 (62)
6-Monthly triptorelin, n (%)	1 (3)
Histrelin implant, n (%)	8 (28)

GnRHa, gonadotropin-releasing hormone analog; SD, standard deviation.

Of the 101 patients, 71 (70%) were also receiving testosterone therapy as of their most recent visit. The average age of initiation of testosterone was 15.8±1.1 years (range 13.9–17.9 years). No difference in average age was seen between patients started on testosterone and those who were not (16.2±3.9 years, p=0.51). However, more patients who initiated testosterone had reached menarche than those who had not started testosterone at the time of the analysis (97% vs. 67%, p<0.001). Median testosterone dose at the time of the review was 275±100 mg divided over 1 month (range 50–400 mg). Most patients were receiving every 2 weeks injections, and doses of testosterone were generally increased by 50–100 mg per total monthly dose approximately every 6 months if desired by the patient.

In patients receiving testosterone therapy only (n=43), the lowest dose at which cessation of menses was reported was 50 mg every 2 weeks and the highest dose at which continued menses was reported was 200 mg every 2 weeks. Additional effects of testosterone reported by patients included voice deepening, increased body hair, acne, muscle development, and “bottom growth.” While not systematically collected, anecdotal behavioral and emotional changes expressed by transboys after starting testosterone included craving meat and not being able to cry as easily as before. At the time of the review, the average duration of testosterone therapy was 3.2±1.7 years (range 0.04–8.09 years).

Discussion

In recent years, many endocrinology clinics have seen increased numbers of referrals for GD in pediatric patients.^14,15 Despite this trend, many pediatric TG patients present to the endocrine clinic in their teens, often after completing puberty, suggesting continued delays in the diagnosis of GD and/or referral for treatment. Ideally, patients with GD should be referred to a behavioral health specialist with experience in gender to receive a formal diagnosis, followed by a referral to endocrinology for potential initiation of puberty blockade, with all of these steps taking place before or in early puberty (Tanner Stage 2). Unfortunately, current care falls significantly short of that recommended by most professional organizations.

In our cohort of TG boys, most were postmenarchal at presentation and there was no difference in menarchal status between patients who were prescribed GnRHas and those who were not. Potential barriers to diagnosis and referral include patients' lack of vocabulary to describe their GD to others, fear of coming out to parents, and concerns about health risks associated with treatment.¹⁶ Concerted efforts are needed to increase the number of TG patients who are referred early in puberty rather than in later stages.

Additional delays in treatment for GD arise in relation to initiating puberty blockers. Many insurance companies do not consider the diagnosis of GD as an indication for treatment with GnRHas, despite clinical practice guidelines. The process of obtaining insurance approval for GnRHas can be lengthy and requires a considerable amount of effort from parents, clinic staff, and physicians.¹⁷ High medication costs and difficulty with insurance approval lead to the strikingly long interval between prescription and initiation of GnRHa treatment experienced by many TG patients. Indeed, our data show that the average interval was 136 days, or more than 4.5 months. Alternatively, many TG boys are unable to ever receive GnRHa treatment and instead must rely on other forms of menstrual suppression such as Depo-Provera or progestin-only pills.

Interestingly, this cohort of TG boys only received GnRHa treatment for ∼1.5 years on average. This briefer-than-expected treatment time is mostly due to the delayed age at which these patients start treatment. Among those desiring gender-affirming therapy, most started testosterone within 1–2 years of initiating GnRHa treatment. Difficulty maintaining continued insurance approval for GnRHas was also a contributor, forcing patients to rely on testosterone alone for menstrual suppression.

Once testosterone is initiated, there is large variability in dosing and escalation rates. The dose of testosterone at which patients can safely stop other forms of menstrual suppression is unknown.¹⁸ In our patients, doses as low as 50 mg every 2 weeks was sufficient to suppress menses in some, whereas other patients reported continued bleeding on adult doses of testosterone.

Limitations

Limitations of our study include the retrospective design and the potential for missing or incomplete information in the medical records. The generalizability of our results to other regions of the country is unknown.

Conclusion

In conclusion, our results indicate that significant delays in diagnosis of GD, referral to endocrine clinics, and initiation of puberty blockers continue to exist despite clinical consensus guidelines in TG health. These findings highlight the need for further research to identify best candidates for pubertal blockade and determine the ideal length of treatment with GnRHas, particularly among those patients able to initiate treatment early in puberty. Increased advocacy for GnRHas as the gold standard for treatment of GD to aid in decreasing the barrier of insurance approval is key to providing improved health care for TG youth.

Abbreviations Used

GD

gender dysphoria

GnRHa

gonadotropin-releasing hormone analog

HPG

hypothalamic–pituitary–gonadal

IRB

Institutional Review Board

SD

standard deviation

TG

transgender

Authors' Contributions

E.J.K. performed data collection, curation, and formal analysis, and wrote the original draft. J.S.F. assisted with data validation and review and editing of the article. E.A.E. was responsible for conceptualization of the study, supervision of all aspects of the project, and review and editing of the article.

Author Disclosure Statement

The authors have no conflicts of interest to disclose.

Funding Information

No funding was received for this article.

Cite this article as: Kain EJ, Fuqua JS, Eugster EA (2023) A retrospective study of the use of gonadotropin releasing hormone analogs and testosterone in transgender boys: who, what, when and for how long?, Transgender Health 9:4, 357–360, DOI: 10.1089/trgh.2022.0156.