Severe Hyperandrogenism Secondary to Polycystic Ovarian Syndrome in a Gender-diverse Adolescent

Abstract

The development of gender identity takes place under the influence of a complex interplay of social, psychological, and biological factors. Studies in individuals with disorders of sex development have suggested that exposure to androgens during fetal development and across the lifespan may contribute to a more masculine gender identity. We describe here an individual designated female at birth who presented with severe hyperandrogenism (total testosterone 337 ng/dL, 11.7 nmol/L) (reference range, 6-50 ng/dL [0.21-1.74 nmol/L]) and virilization secondary to polycystic ovarian syndrome in the setting of gender identity exploration. On presentation the patient endorsed a masculine gender identity, and after GnRH analog therapy reduced total testosterone to the cisgender female range, endorsed a feminine gender identity. This case adds to what is known about the possible range of androgen excess in polycystic ovarian syndrome and demonstrates the diagnosis and treatment of polycystic ovarian syndrome in a gender diverse adolescent.

Introduction

Gender identity formation begins in childhood and develops throughout adolescence. The development of gender identity is complex with social, biological, and psychological factors all likely contributing [1]. Studies of individuals with differences of sex development (DSD) have revealed potential biological underpinnings of gender identity, including that endogenous androgen exposure may contribute to the formation of a masculine gender identity [1]. For example, most 46, XY individuals with complete androgen insensitivity syndrome identify as female [2]. Conversely, 46, XX individuals with congenital adrenal hyperplasia (CAH), who are exposed to higher levels of androgens during fetal development and throughout their lifespan, have a higher rate of masculine gender identity than 46, XX individuals without hyperandrogenism [1, 3]. These reports cannot separate social factors that may impact how individuals who physically appear more masculine or feminine are treated or reared from biological effects, nor isolate the influence of androgen exposure during fetal development from exposure in adolescence or young adulthood. Our understanding of the influence of sex steroids on gender identity into adolescence, especially as they interact with the psychosocial elements of gender identity formation, is still developing [1, 4, 5].

Polycystic ovarian syndrome (PCOS), a syndrome of excess androgen production in people designated female at birth (DFAB), is estimated to affect between 5.0% and 19.9% of people DFAB [6-9]. The prevalence of PCOS in transmasculine individuals may be elevated compared to cisgender patients, though dated diagnostic criteria and inadequate considerations of other androgen sources in older studies complicate a consensus [10]. Recent research remains divided; 1 study found increased biochemical hyperandrogenism in transmasculine patients but no higher PCOS prevalence, whereas another reported a slightly elevated prevalence (23.8%) of PCOS in transmasculine adolescents presenting for gender-affirming care [11, 12].

We present an adolescent DFAB with severe hyperandrogenism in the setting of gender identity exploration. This case demonstrates significantly elevated androgens resulting from PCOS and the diagnosis and treatment of PCOS while allowing gender exploration. Health care providers caring for adolescents with hyperandrogenism must consider both the goals of the patient as well as the possible causes and health risks of elevated androgens.

Case Presentation

A 12-year-old patient DFAB was evaluated for secondary amenorrhea. At presentation, the patient was uncertain about their gender identity and used they/them pronouns. The patient reported beginning experimenting with masculine social presentation at age 10 years. The patient's mother was supportive of the patient's gender, but the patient had not discussed their gender with their father. At presentation, the patient expressed a desire for more masculine features and more facial hair. They had achieved menarche at age 10 years and following 2 regular menstrual cycles developed oligomenorrhea for the subsequent 2 years. They had developed hair on their abdomen, back, chest, and face around the age of menarche and deepening of their voice over the past year. They denied personal use of or possible exposure to testosterone or androgen-containing medications or supplements.

Diagnostic Assessment

At presentation, their height was 157.7 cm, weight was 80.6 kg, and body mass index was 32.4 kg/m² (99th percentile). On physical examination, they were found to have hirsutism (Ferriman-Gallwey score 19; Fig. 1), clitoromegaly (clitoral length 3.0 cm), and Tanner Stage 5 breast development. First morning laboratory evaluation revealed mildly elevated 17-hydroxyprogesterone (279 ng/dL, 844.3 nmol/L) (reference range, 20-265 ng/dL [60.5-801.9 nmol/L]), significantly elevated total and free testosterone (337 ng/dL, 11.69 nmol/L and 40.7 pg/mL 141.1 pmol/L, respectively) (free testosterone reference range, 0.9-6.8 pg/mL [3.1-23.6 pmol/L]), and elevated dehydroepiandrosterone sulfate (374 μg/dL, 1015 μmol/L) (reference range 44-248 μg/dL [119.4-673.1 μmol/L], Table 1). Thyroid function, gonadotropins, and prolactin were normal. A karyotype was 46, XX. Abdominal ultrasound and magnetic resonance imaging showed no adrenal or ovarian masses and noted that the ovaries appeared symmetrically enlarged with multiple follicles. An adrenocorticotropic hormone stimulation test was not consistent with CAH (Table 2). Oncologic markers, cancer antigen 125 (CA-125), ɑ-fetoprotein, and β-human chorionic gonadotropin were negative (Table 1).

Figure 1.

Hair growth on the abdomen (A) and back (B).

Table 1.

Summary of the relevant laboratory values

	Reference range & unitsa	Initial presentation	Repeat labs	On OCP	After discontinuation of OCP	After GnRH analog
Total testosterone	6-50 ng/dL (0.21-1.74 nmol/L)	337 ng/dL (11.69 nmol/L)	280 ng/dL (9.72 nmol/L)	289 ng/dL (10.03 nmol/L)	203 ng/dL (7.04 nmol/L)	31 ng/dL (1.08 nmol/L)
Free testosterone	0.9-6.8 pg/mL (3.1-23.6 pmol/L)	40.7 pg/mL (141.1 pmol/L)	34 pg/mL (117.9 pmol/L)	24.6 pg/mL (85.3 pmol/L)		4.7 pg/mL (16.3 pmol/L)
Estradiol	19.5-356.7 pg/mL (71.6-1310 pmol/L)		46 pg/mL (168.9 pmol/L)		64.3 pg/mL (236.1 pmol/L)	12.2 pg/mL (44.8 pmol/L)
Luteinizing hormone	0.3-23.0 IU/L (0.3–23.0 mIU/mL)	11.7 IU/L (11.7 mIU/mL)	10 IU/L (10 mIU/mL)		13.6 IU/L (13.6 mIU/mL)	1.2 IU/L (1.2 mIU/mL)
Follicle stimulating hormone	1.0-9.1 IU/L (1.0–9.1 mIU/mL)	5 IU/L (5 mIU/mL)	4.4 IU/L (4.4 mIU/mL)		4.4 IU/L (4.4 mIU/mL)	2.7 IU/L (2.7 mIU/mL)
Androstenedione	0.24-1.73 ng/mL (0.84-6.04 nmol/L)		6.95 ng/mL (24.3 nmol/L)	4.72 ng/mL (16.5 nmol/L)	5.89 ng/mL (20.6 nmol/L)	1.45 ng/mL (5.1 nmol/L)
DHEA	0.890-6.210 ng/mL (3.09-21.5 nmol/L)		10.809 ng/mL (37.5 nmol/L)
DHEA-S	44-248 μg/dL (119.4-673.1 μmol/L)	374 μg/dL (1015.0 μmol/L)	428 μg/dL (1161.6 μmol/L)	553 μg/dL (1500.8 μmol/L)	481 μg/dL (1305.4 μmol/L)	338 μg/dL (917.3 μmol/L)
17-OH progesterone	20-265 ng/dL (60.5-801.9 nmol/L)	279 ng/dL (844.3 nmol/L)	337 ng/dL (1019.8 nmol/L)
Thyroid-stimulating hormone	0.5-4.8 mIU/L (0.4–4.8 μIU/mL)	2.6 mIU/L (2.6 μIU/mL)
Prolactin	3-24 ng/dL (0.03-0.24 μg/L)	11.7 ng/dL (0.117 μg/L)
CA-125	0-30.2 U/mL (0–30.2 kU/L)				5.8 U/mL (5.8 kU/L)
Lactate dehydrogenase	100-220 IU/L (1.67–3.67 μkat/L)				208 IU/L (3.47 μkat/L)
α-fetoprotein	0-10 ng/mL (0-10 μg/L)		2.2 ng/mL (2.2 μg/L)		1.9 ng/mL (1.9 μg/L)
β-hCG	0-5.0 mIU/mL				<2.0 mIU/mL
Karyotype					46, XX

Abbreviations: CA-125, cancer antigen 125; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; GnRH. gonadotropin releasing hormone; OCP, combined oral contraceptive pill; β-hCG, β-human chorionic gonadotropin.

^a Reference ranges provided are for cisgender females.

Table 2.

ACTH stimulation test for evaluation of adrenal steroid biosynthesis disorders

	Baseline (t = 0 minutes)	Stimulated (t = 60 minutes)
17-hydroxyprogesterone	189 ng/dL (5.72 nmol/L)	320 ng/dL (9.68 nmol/L)
Cortisol	12 μg/dL (331 nmol/L)	25 ng/dL (690 nmol/L)
Dehydroepiandrosterone	757 ng/dL (26.3 nmol/L)	2150 ng/dL (74.5 nmol/L)
11-deoxycortisol	33 ng/dL (0.95 nmol/L)	124 ng/dL (3.6 nmol/L)
Androstenedione	592 ng/dL (20.7 nmol/L)	612 ng/dL (21.4 nmol/L)
Progesterone	16 ng/dL (0.51 nmol/L)	38 ng/dL (1.2 nmol/L)
17-hydroxypregnenolone	239 ng/dL (7.19 nmol/L)	1695 ng/dL (51.0 nmol/L)
Deoxycorticosterone	4.3 ng/dL (0.13 nmol/L)	14.0 ng/dL (0.42 nmol/L)
Total testosterone	242 ng/dL (8.39 nmol/L)	198 ng/dL (6.87 nmol/L)

Treatment

The patient was prescribed a combination oral contraceptive pill (OCP; norgestimate-ethinyl estradiol). At a follow-up visit 14 months after the initial presentation, the patient endorsed a male gender identity. They inconsistently took the OCP due to ambivalence regarding the estrogen component and difficulty with daily administration. Androgen levels remained elevated, but lower than initial presentation (Table 1). The patient was referred to a clinic specializing in the care of transgender and gender diverse (TGD) youth where the estrogen-containing OCP was discontinued, and GnRH analog therapy (leuprolide) was initiated.

Outcome and Follow-up

One month after GnRHa administration, the patient's androgens decreased to the cisgender female range, ruling out an oncologic source of excess androgens. At a clinic visit 4 months after beginning GnRHa therapy, the now 14-year-old patient began endorsing a female gender identity, using she/her pronouns, and presenting with typical female gender expression, which has persisted over 10 months to the present. The patient also began shaving to remove unwanted body hair. Fourteen months later, the patient continued endorsing a female gender identity and elected to start estrogen therapy. Given the patient's initial presentation with oligomenorrhea and hyperandrogenism, and the response to leuprolide therapy, lack of progression over several years of follow up, and imaging findings ruling out other causes of hyperandrogenism, a clinical diagnosis of PCOS was made in accordance with the international recommendations for the diagnosis of PCOS in adolescents [13, 14].

Informed consent was obtained from the patient and their family for the publication of this case report, including the use of clinical details.

Discussion

We present an adolescent DFAB with severe hyperandrogenism and virilization secondary to PCOS in the context of gender identity exploration. On presentation, the patient endorsed a nonbinary gender identity that transitioned to a masculine gender identity in the same period when androgen levels were elevated. In the time period when androgen levels decreased, their gender identity and expression became more feminine leaning. For this patient, the use of GnRHa to reduce endogenous sex steroids allowed gender identity exploration and was a key component of their gender-affirming medical care.

Based in part on studies of individuals with DSD, androgen exposure has been hypothesized to influence gender identity formation. In a review of 250 46, XX individuals with CAH reared as females, 5.2% experienced gender dysphoria, a prevalence that is ∼2 to 10 times higher than the reported prevalence of TGD individuals in the general population (0.5%-2%) [3, 15]. Individuals with CAH are exposed to high levels of androgens during fetal life and may be exposed to persistently elevated androgen levels throughout their lifetime, which may cause more masculine physical appearance (ie, hirsutism, deeper voice) and/or genital appearance (ie, clitoromegaly to full Prader V genital appearance) [16].

Similarly, 46, XY individuals with 5ɑ-reductase deficiency are born with atypical genitalia resulting from decreased dihydrotestosterone levels in fetal life. The rise in testosterone and 5ɑ-reductase levels at puberty increases dihydrotestosterone production, leading to virilization and a more masculine genital appearance. Many individuals with 5ɑ-reductase deficiency who are initially DFAB and reared as females begin endorsing a male gender identity at puberty, suggesting an ongoing role for androgen exposure in male gender identity formation in adolescence, though other factors associated with a 46, XY karyotype or environmental and social influences may also impact this gender transition. However, early reports of this phenomenon may have inaccurately documented prepubertal gender identity [17-19].

Notably, the literature cited here on gender identity in individuals with DSD is based on a binary interpretation of gender exclusive of non-binary gender identities. Nevertheless, these studies of patients with DSDs suggest that sex hormones contribute to the biological component of gender identity formation [4].

The pathogenesis of PCOS is characterized by excessive androgen production leading to a complex syndrome which in addition to the effects of hyperandrogenism such as hirsutism and menstrual irregularity, can include features of metabolic syndrome including hyperinsulinemia, insulin resistance, and obesity [20-22]. The degree of elevation in testosterone seen in our patient is uncommon in patients with PCOS, where total testosterone levels rarely exceed 100 ng/dL (3.47 nmol/L) [20, 23]. Most reports of extremely elevated testosterone in patients DFAB are caused by androgen-secreting tumors [24]. The patient's response to GnRHa therapy helped rule out an oncologic source of hyperandrogenism.

The prevalence of PCOS in transmasculine patients presenting for gender-affirming care may be higher than that reported in cisgender female patients [12, 25, 26]. However, inconsistency in the criteria used to define PCOS and/or elevated androgen levels has led to large variability between studies [10, 27, 28]. These findings may suggest that the increased androgens that are quintessential of PCOS are associated with a more masculine gender identity; however, there have not been any large studies of gender identity among DFAB individuals with PCOS making estimates of gender identity among patients with PCOS difficult to confirm.

In this report, the patient endorsed a female gender identity after testosterone levels fell to the cisgender female range following GnRHa therapy. Pubertal suppression using GnRHa is the standard of care for TGD youth experiencing gender dysphoria and is associated with improvements in social life, reduced symptoms of depression, and decreased incidence of suicidal ideation [29, 30]. Here, the use of GnRHa to pause endogenous sex steroid production allowed the patient to explore their gender identity without the influence of excess androgens. However, as androgens are one of many factors influencing gender identity, and many transmasculine individuals have testosterone levels within the cisgender female range, the change in gender identity may be coincidental. It is impossible to untangle the change in gender presentation from the experience of excess testosterone exposure. Additionally, the patient is treated by a multidisciplinary team specializing in the care of TGD youth, including individually tailored medical and mental health care and interventions. The guidance of the gender specialty team and the space provided for gender exploration without predetermined directionality may have also contributed to the evolution of the patient's gender journey.

We describe a rare occurrence of marked hyperandrogenism caused by PCOS in an adolescent exploring their gender identity. This case adds to what is known regarding the range of testosterone elevation possible in PCOS and demonstrates the utility of GnRHa therapy for diagnosing and treating hyperandrogenism in youth with PCOS who wish to explore their gender identity.

Learning Points

• This case adds to what is known about the possible range of androgen excess in PCOS and demonstrates the diagnosis and treatment of PCOS in a gender-diverse patient.

• The use of GnRHa to pause endogenous sex steroid production permitted both the exclusion of malignant sources of the androgen excess and the patient to explore their gender identity without the influence of excess androgens.

• The treatment by a multidisciplinary team specializing in the care of TGD youth and space for gender exploration without predetermined directionality likely contributed to the evolution of the patient's journey.

Contributors

All authors made individual contributions to authorship. K.M., K.S., and J.B.Q. were involved in the diagnosis and management of the patient. D.S. and K.M. conducted the literature review and drafted the manuscript. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient's relatives or guardians.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.