A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience

Abstract

Background: Androgen blockers are an essential part of gender affirming care in post-pubertal transfeminine patients. Bicalutamide is a highly potent androgen receptor blocker that is used primarily in adults. We aimed to review our experience with the use of bicalutamide in transgender adolescents who were assigned male at birth. Methods: A retrospective review of medical records of transfeminine patients treated with bicalutamide during an 8-year period was conducted. Results: Forty patients, aged 15.5 ± 1.55 years were identified, of whom 21 (53%) were started on bicalutamide alone and 19 were started concurrently on estrogen. In patients on bicalutamide alone, 90.4% reported breast development at their first follow up visit, which occurred at a median of 7.1 months. Patients were treated for 29.4 ± 18.2 months. No episodes of liver toxicity related to bicalutamide were seen. Conclusions: Although these results are preliminary, bicalutamide appears to be a safe option for androgen blockade in transgender girls.

Introduction

Gender-affirming care in transfeminine patients requires the use of medications to suppress testosterone production or block its effects (Hembree et al., 2017). While gonadotropin-releasing hormone analogs (GnRHas) are recommended as puberty blockers at Tanner stage 2 in youth with gender dysphoria (Krebs et al., 2022), their use in post-pubertal patients is debated (Coleman et al., 2022). GnRHas are also expensive, and coverage is frequently denied by insurance companies (Kain et al., 2023). Therefore, post-pubertal transgender girls are typically treated with androgen receptor blockers with concurrent estrogen as part of the process of physical transition (Chew et al., 2018).

Bicalutamide is a potent non-steroidal androgen receptor blocker with peripheral selectivity due to poor penetration of the blood brain barrier (Furr & Tucker, 1996). While used primarily in cisgender men with prostate cancer, bicalutamide has also been used in rare forms of peripheral precocious puberty in boys (Haddad & Eugster, 2019). There is preliminary evidence that bicalutamide may also have a role in the treatment of transfeminine patients, in whom it causes breast development due to the peripheral conversion of testosterone to estrogen (Neyman et al., 2018). However, familiarity with bicalutamide in this setting is extremely limited and concerns about the potential for liver toxicity have dampened enthusiasm regarding its use. Our goal was to report our experience to date with the use of bicalutamide in transfeminine adolescents.

Methods

This retrospective, single center study was conducted at Riley Hospital for Children between 2014 and 2022. The study was approved by the Institutional Review Board of Indiana University School of Medicine and was deemed exempt. Inclusion criteria included transgender patients assigned male at birth who were followed in the pediatric endocrine clinic and were treated with bicalutamide. No patients treated with bicalutamide were excluded from the study. Bicalutamide was prescribed at the discretion of the treating pediatric endocrinologist. In many cases, this was because of an inability to obtain insurance approval for a GnRH analog. The experimental nature of bicalutamide was explained to parents and caregivers and our experience using this medication in pediatric patients was shared. The medical records of all patients meeting inclusion criteria were individually reviewed for each variable of interest, and all available data were collected. Variables analyzed included age, Tanner stage, gender affirming hormone treatment, dose and length of bicalutamide treatment, liver enzymes before and during bicalutamide use, and subjective reports of decreased male secondary sexual characteristics. Descriptive statistics as well as two- sample t-tests were performed for data analysis.

Results

Forty patients (85% White) aged 15.5 ± 1.55 years (12–18) were treated with bicalutamide for 29.4 ± 18.2 months (1–69). All patients were initially prescribed 50 mg of bicalutamide PO q d which was increased to 75 mg PO q d in one and 100 mg PO q d in another. Twenty-one patients were started on bicalutamide alone, and ten were started simultaneously on estrogen. Nine patients were already on estrogen when bicalutamide therapy was initiated. These patients had previously been on a GnRHa or were attempting to start one. They were ultimately switched to bicalutamide when they were no longer able to obtain a GnRHa due to high cost and/or insurance denial. At the time of their last visit, all but four patients (10%) were on both bicalutamide and estrogen.

Of the 21 patients initially receiving bicalutamide alone, 90.4% had breast development ranging from Tanner stage II-V at the first follow up visit. The median interval between starting bicalutamide and the first follow up visit was 7.1 months. Although not objectively assessed, twenty-two patients reported experiencing one or more anti-androgen effects while on bicalutamide. The most common of these was a decrease in facial hair growth (Table 1). Liver function tests (LFTs) were measured at random intervals during treatment in 37 patients and were normal in all except one who had attempted suicide by drug overdose 1 month prior to the visit. The average AST was 17.4 ± 3.51 IU/L at baseline (n = 13) and 18.6 ± 3.20 IU/L on treatment (n = 35), p = 0.24, whereas ALT was 17.6 ± 9.41 IU/L at baseline (n = 13) and 17.8 ± 9.41 IU/L on treatment (n = 35), p = 0.94. The mean baseline testosterone (n = 12) was 265 ng/dl ± 197 and the mean testosterone level on bicalutamide treatment (n = 22) was 614 ng/dl ± 289, p = 0.00025. Few of the patients had baseline estradiol levels, but the mean estradiol on bicalutamide treatment increased from 15.3 ± 9.24 pg/mL at baseline (n = 3) to 44.4 ± 19.4 pg/mL on treatment (n = 17), p = 0.0068. These results are seen in Table 2, whereas individual data for each of the 40 patients are seen in Table 3.

Table 1.

Clinical characteristics.

Clinical variable	n (%)
Assigned male at birth	40 (100)
Ethnicity  White  African American  Asian  Unknown	34 (85) 1 (2.5) 1 (2.5) 4 (10)
Started bicalutamide alone Started bicalutamide plus estrogen Estrogen prior to bicalutamide	21 (53) 10 (25) 9 (22)
aBreast development at first f/u visit	19 (90.4)
aMedian time between bicalutamide start and first follow up (months)	7.1
Anti-androgen effects  decreased facial hair  decreased acne  softer skin  decreased erections	17 9 4 2

^aIn patients started on bicalutamide alone.

Table 2.

Biochemical characteristics.

Laboratory studies		p-value
AST (IU/L)
Baseline, n = 13  On treatment, n = 35	17.4 ± 3.51 18.6 ± 3.20	0.24
ALT (IU/L)
Baseline, n = 13  On treatment, n = 35	17.6 ± 9.41 17.8 ± 9.41	0.94
Testosterone (ng/dL)
Baseline, n = 12  On treatment, n = 22	265 ± 197 614 ± 289	0.00025
Estradiol (pg/mL)
Baseline, n = 3  On treatment, n = 17	15.3 ± 9.24 44.4 ± 19.4	0.0068

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Reference ranges: ALT: 7-52 IU/L, AST: 13-39 IU/L.

Table 3.

Individual patient characteristics.

Patients on bicalutamide alone	Age (yrs)	Breast Tanner stage baseline	Breasts Tanner Stage first f/u visit (months)	Time to first f/u visit (months)	Dose of bicalutamide (mg)	Duration of bicalutamide (months)	#Anti-androgen effects*
1	16.7	1	3	7.7	50	14.5	SS
2	16.4	1	NR	25	50	2.8
3	17.9	1	3	7	50	43
4	13.7	1	2	6	50	45	H
5	15.6	1	4	7	50	42
6	15.3	1	3	6	50	45.8	H, A
7	15.4	1	3	7.7	50	49.8	H, A, SS
8	13.4	1	3	19.9	50	69.3
9	15.5	1	1	5	50	6.3	E
10	12	1	2	7.1	50	63.7	H
11	17.9	1	2/3	11.7	50	16.7
12	17.8	1	3	6	50	56.8	H,
13	16.7	1	3	6	50	45
14	17.7	1	5	4	50	35.9	H, A
15	17.9	1	3	6.6	50	24.1
16	14.4	1	3	6.2	50	57.3	A
17	13.6	1	3	12.3	50	54.6
18	20.2	1	3	8.3	50	15.1	H, A
19	16.9	1	3	6.3	50	13.8
20	17.4	1	2	8.5	50	23.5
21	18.4	1	NR	6	50	20.2	H, A, SS
Patients on estrogen and bicalutamide	Age (yrs)				Dose of bicalutamide (mg)	Duration of bicalutamide (months)	#Anti-androgen effects*	17 beta estradiol therapy (mg)
1	17.3				50	17.8		OR 2
2	17.3				50	9.4	H	TD 0.025
3	16.5				50	8.9	H	TD 0.025
4	15.5				50	17.4		TD 0.0375
5	17.7				50	0.4	H	TD 0.0375
6	15.5				50	7.3		TD 0.075
7	17.7				50	6.5		OR 0.5
8	16				50	13.6	H	TD 0.025
9	17.5				50	26	H	TD 0.075
10	17.9				50	28		TD 0.025
11	16.3				50	30	H, A, SS, E	TD 0.0375
12	16				50	31	H, A	TD 0.050
13	18.7				50	5.5	H	TD 0.0375
14	16.9				50	11.8		TD 0.025
15	15.7				50	37.1		OR 0.5
16	17.3				50	43.8		OR 0.5
17	17.6				50	34.3	H,	OR 0.5
18	17.5				50	23.9	A	TD 0.050
19	17.7				50	20.9		TD 0.025

NR-not recorded, #SS-softer skin, H-decreased facial hair, A-decreased acne, E-fewer erections, TD-transdermal, OR-oral *not systematically assessed.

Discussion

Bicalutamide has primarily been used in the treatment of men with prostate cancer. However, it has also been used in the treatment of rare forms of precocious puberty in boys, including familial male precocious puberty (Reiter et al., 2010) and McCune-Albright syndrome (Neyman & Eugster, 2017). In 2017, we reported our initial experience (as an abstract) with bicalutamide in the treatment of transfeminine adolescents (Neyman et al., 2018). This paper represents an expansion of that initial report.

Gynecomastia is a known side effect of bicalutamide (Sieber, 2007). However, this is a welcome characteristic of the medication in transgender girls, who wish to experience physical traits more aligned with their affirmed gender. The alternative androgen blocker that is used in most gender clinics is spironolactone which is far less potent than bicalutamide and does not typically result in feminization (Rose et al., 2023).

Post-marketing studies of bicalutamide in men with prostate cancer have identified liver toxicity as a rare but serious potential adverse event (Hussain et al., 2014). To our knowledge, there has never been a case of hepatic toxicity in a pediatric patient being treated with bicalutamide, and liver enzymes were reassuringly normal in our cohort of transfeminine patients. Nonetheless, it is important to monitor liver enzymes in patients on therapy and to inform parents that using bicalutamide in adolescents is considered experimental. Additionally, since the breast development caused by bicalutamide is considered only partially reversable, it should only be used in transgender girls who are deemed developmentally mature enough to provide informed consent.

An important area of concern in the treatment of gender dysphoria in youth is the long-term effect of puberty blockers on bone mineral density (BMD). This is particularly salient for transfeminine patients, who have been found to have lower BMD z-scores on average than their cis-gender peers even before gender-affirming hormones have been prescribed (Schagen et al., 2020). The effect of bicalutamide on BMD in transgender patients is unknown. It is possible that it could even be protective due to the increased aromatization of testosterone to estrogen that results from blockade of the androgen receptor.

Limitations of our study include the small sample size, that it was retrospective and that information in the medical record could have been inaccurate or incomplete. While good compliance is suggested by the finding of breast development in our patients on bicalutamide monotherapy, adherence to therapy was not formally assessed. Likewise, anti-androgen effects experienced by patients were not systematically elicited and should be considered anecdotal. The small number of patients who had baseline values drawn limited our comparison between pre- and post-bicalutamide testosterone and estrogen levels. However, as expected, both testosterone and estrogen significantly increased on bicalutamide as a result of androgen receptor blockade (Nabhan & Eugster, 2019).

In conclusion, no evidence of hepatotoxicity has been seen in our transfeminine patients treated with bicalutamide during the past 8 years. To our knowledge, ours is the largest study reporting the use of bicalutamide in youth with gender dysphoria. Large-scale prospective studies are needed to further investigate bicalutamide as an androgen blocker in transgender girls.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Authorship contribution statement

ES performed data collection and curation and formal analysis and wrote the original draft. JSF assisted with data validation and review and editing of the manuscript. EAE was responsible for conceptualization of the study, supervision of all aspects of the project and review and editing of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).