Gender diversity in adolescents with polycystic ovary syndrome

Abstract

Objectives:

The objective of our study was to describe the prevalence of gender diverse (GD) youth among adolescents with polycystic ovary syndrome (PCOS).

Methods:

We conducted a retrospective chart review on patients who met NIH criteria for PCOS in our Multidisciplinary Adolescent PCOS Program (MAPP). We compared those with PCOS to MAPP patients who did not meet PCOS criteria as well as to non-PCOS patients from the Adolescent Specialty Clinic (ASC). Variables analyzed included gender identity, androgen levels, hirsutism scores, and mood disorders. We used chi-square, Fisher’s exact, t-tests, and Wilcoxon rank sum tests to compare groups. Gender identities self-reported as male, fluid/both or nonbinary were pooled into the GD category.

Results:

Within the MAPP, 7.6% (n=12) of PCOS youth self-identified as GD compared to 1.8% (n=3) of non PCOS youth (p=0.01, chi-square). When compared to non-PCOS GD adolescents from ASC (4.4%; n=3), the difference to PCOS youth was no longer significant (p=0.56). Among MAPP patients, gender diversity was associated with higher hirsutism scores (p<0.01), but not higher androgen levels. In PCOS, depression/anxiety was higher in GD vs cisgender youth (100% vs. 37.6%, p<0.01 and 77.8% vs. 35.8%, p=0.03 respectively).

Conclusions:

Gender diversity was observed more commonly in those meeting PCOS criteria. PCOS GD youth were more hirsute and reported more depression/anxiety. Routine screening for differences in gender identity in comprehensive adolescent PCOS programs could benefit these patients, as alternate treatment approaches may be desired to support a transmasculine identity.

Introduction

Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects up to 11% of adolescent natal females with significant reproductive, metabolic, and psychological comorbidities [1]. Diagnostic features in adolescents include menstrual irregularity combined with clinical and/or biochemical hyperandrogenism. In adolescents, clinical hyperandrogenism is based on the presence of hirsutism or severe acne and biochemical hyperandrogenism as defined by an elevated total or free testosterone. Menstrual irregularity can be diagnosed as early as one-year post menarche [2] and is a risk for developing endometrial hyperplasia/cancer and/or subfertility/infertility. Alongside reproductive dysfunction, several metabolic comorbidities such as insulin resistance, weight gain, type 2 diabetes mellitus, and non-alcoholic fatty liver disease are associated with PCOS [3]. Furthermore, PCOS in adult women [4] and adolescents [5, 6] is associated with anxiety/depression, independent of any metabolic or reproductive comorbidities. The current clinical approach to PCOS management is primarily aimed at menstrual regulation and reduction of hyperandrogenism while evaluating for, preventing, and treating metabolic comorbidities [7].

To provide more comprehensive care for youth with PCOS at our institution, the Multidisciplinary Adolescent PCOS Program (MAPP) was established by the Pediatric Endocrinology and Adolescent Medicine Divisions in 2015. While pediatric endocrinology focuses on the metabolic and endocrinologic aspects of the condition, adolescent medicine addresses psychosocial concerns, including reproductive and mental health needs. Within the first 1–2 years of the clinic, it was noted that a higher-than-expected proportion of patients self-identified as transgender or gender diverse (GD). Among U.S. adolescents, the current estimated prevalence of transgender and gender nonconforming individuals in natal females is up to 3.6% [8].

To date, there is a paucity of research describing the relationship between gender dysphoria and PCOS in adolescents. While some studies suggested an increased prevalence of PCOS in adults seeking transmasculine care [9, 10], others did not find a higher prevalence of PCOS in transmasculine individuals [11]. None of these studies focused on adolescents [12].

Since GD adolescents with PCOS may have different treatment goals than cisgender adolescents with PCOS, we examined the prevalence of gender dysphoria in adolescents being evaluated by MAPP clinicians. To this end, the objective of this study was to compare the prevalence of GD adolescents in a cohort of natal female teens diagnosed with PCOS to the prevalence of GD youth in natal females who do not carry the diagnosis of PCOS. Additionally, we aimed to examine how differences in gender identity in those that have PCOS may relate to clinical characteristics such as hormonal/metabolic profile and psychosocial wellbeing. To our knowledge, this is the first study examining gender identity in adolescents being evaluated for PCOS.

Subjects and methods

Setting

A retrospective chart review was conducted at a tertiary pediatric care center in the Midwestern United States and included teens seen at the MAPP or the Adolescent Specialty Clinic (ASC) between January 2015 and March 2020. The ASC was chosen as the reservoir for selecting a non-PCOS comparison group, since this clinic routinely elicits and records sexual history and gender identity.

Study design

We conducted a cross-sectional study using data obtained from the electronic medical records (EMR) of patients who were evaluated at the MAPP and ASC. Clinical information extracted from the EMR included patient demographics, menstrual and puberty information, gender identity, sexual orientation, history of sexual activity, mental health history, medication history, physical exam information, anthropometrics, Ferriman–Gallwey (FG) hirsutism score, hormone measures, metabolic measures, and other medical diagnoses. Patients who self-reported as male, nonbinary, or gender-fluid at any single appointment were considered under the umbrella term “gender diverse (GD).” In our practice, gender identity was assessed via open-ended questions by our board-certified adolescent medicine specialists with subsequent documentation in the EMR. This was done as part of a complete psychosocial assessment while following best practices in adolescent medicine. No formal questionnaires were employed. Mental health diagnoses were obtained from previous chart diagnosis or by clinician assessment through interview with adolescent medicine.

Study data were managed using the REDCap electronic data capture tools hosted at Children’s Mercy Hospital, Kansas City, MO. REDCap is a secure, web-based software platform designed to support data capture for research studies [13, 14]. The study was approved by the hospital’s institutional review board.

Patient population and inclusion and exclusion criteria

Cases included natal female patients aged 11.9–21.4 years old who were evaluated for PCOS at MAPP. In this 5 year period, 528 patients were evaluated in MAPP clinic for possible PCOS. Patients were excluded for the following reasons: menstrual irregularity secondary to hyperprolactinemia, hypothyroidism, anorexia nervosa, insulin receptor mutation, pregnancy, adrenal disorder, or prior gonadotropin releasing hormone agonist use (n=12); incomplete data sufficient to make a diagnosis (n=3); gynecological age <1 year (n=22).

After these exclusions, 247 met NIH criteria for PCOS and 243 patients did not. Among patients with PCOS, 157 adolescents had gender identity recorded. Of patients evaluated in MAPP that did not meet the NIH criteria for PCOS, 165 had gender identity recorded. Of note, the Rotterdam criteria for PCOS would not be applicable in this patient population since the 2018 international evidence-based PCOS guideline recommends against using ultrasound to examine for polycystic ovary morphology until at least 8 years post menarche [2].

A comparison group of 334 patients was obtained from natal female patients aged 12.5–21.3 years old evaluated in the ASC. After excluding those who carried a physician or chart diagnosis of PCOS, were referred to or evaluated through MAPP, had a gynecological age <1 year or typical laboratory evaluation for PCOS such as androgen profiles, the comparison group consisted of 77 adolescents. Of these, 68 of them had gender identity recorded and were seen during the same period.

PCOS criteria

For the present study, PCOS was defined as menstrual dysregulation at >1 year post-menarche or primary amenorrhea (≥15 years old or >3 years post thelarche without menarche) and clinical or biochemical hyperandrogenism. Menstrual dysregulation was based on self-report assessed via open-ended questions by our adolescent medicine specialists with subsequent documentation in the EMR. Clinical hyperandrogenism was defined as an FG hirsutism score >4 [2] assessed via physical examination with subsequent documentation in the EMR. Acne can be used as a marker of hyperandrogenism; however, its use has been controversial as it is difficult to quantify severity and therefore the presence of acne was not used in the diagnostic evaluation of subjects. Biochemical hyperandrogenism was defined as a total testosterone ≥40 ng/dL or elevated free testosterone, which was based on reference ranges provided for the different assays used. Those who received care in the MAPP based on a prior diagnosis of PCOS by outside clinicians were also included if their diagnosis could be confirmed by applying NIH criteria to the prior assessments or by confirming with repeat labs. Patients with PCOS using oral contraceptive pills (OCPs) were included if a PCOS diagnosis was established prior to OCPs start date (n=46).

Biochemical assays

Total testosterone was analyzed either at Mayo Clinic Laboratories (376/528 of total patients evaluated) or our hospital laboratory. Both laboratories utilized the same method, liquid chromatography-tandem mass spectrometry. Given the diurnal variability of testosterone, our clinic routinely obtains blood work in the morning. However, the specific time was not noted on our database. Since free testosterone levels were not measured using a standard, common method, free testosterone data was not used in this analysis. Dehydroepiandrosterone sulfate (DHEAS) was measured by immunoassay using Immulite^R.

Analysis

Participants were divided into three groups: those evaluated by the MAPP and diagnosed with PCOS, those evaluated by the MAPP and not diagnosed with PCOS, and those patients evaluated solely by the ASC for conditions other than PCOS. Groups were compared using chi-square or Fisher’s exact tests for categorical variables and t-tests or Wilcoxon rank sum tests for continuous variables, depending on the distribution of the data. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC). Data are presented as mean (standard deviation) or median (inter-quartile range) for continuous variables and number (percentage) for categorical data. A significant p-value was defined as p<0.05 for all analyses.

Results

Participant demographics are listed in Table 1. On average, participants with PCOS had a higher BMI and were of a later gynecological age vs. both non-PCOS counterparts (Table 1). Of those seen at the MAPP, participants with PCOS had significantly higher total testosterone concentrations compared to the non-PCOS group (p<0.01). Median testosterone levels were 54 ng/dL (IQR: 46–67) in the PCOS group and 28 ng/dL (IQR: 21–35) in the non-PCOS group.

Table 1:

Demographics.

Mean (SD) or percentage	PCOS (MAPP) n=157	No PCOS (MAPP) n=165	No PCOS (ASC) n=68
Age at presentation, years	16.16 (1.58)	15.89 (1.47)	15.78 (1.46)
Caucasian	42.31%	53.05%	62.69%
Hispanic	18.59%	21.95%	11.94%
Black	26.28%	14.02%	17.91%
Asian	3.21%	3.05%	0%
Multiracial or other	9.62%	7.93%	7.46%
Age at menarche	11.97 (1.34)	12.17 (1.37)	12.31 (1.45)
Gyn age, years	4.20 (1.80)	3.73 (1.73)a	3.44 (1.63)a
BMI, kg/m2	34.10 (7.87)	32.28 (8.72)a	24.55 (5.37)a

Age, PCOS vs. no PCOS MAPP; p=0.12; PCOS vs. no PCOS ASC p=0.09; age at menarche, PCOS vs. no PCOS MAPP p=0.20; PCOS vs. no PCOS ASC p=0.10; Gyn age, PCOS vs. no PCOS MAPP p=0.02; PCOS vs. no PCOS ASC p<0.01; BMI, PCOS vs. no PCOS MAPP p=0.05, PCOS vs. no PCOS ASC p<0.01.

Of the patients evaluated in the MAPP, a higher prevalence of patients with PCOS self-identified as GD; 7.6% (n=12) vs. 1.8% (n=3) of those who did not meet NIH criteria for PCOS (p=0.01; Figure 1). However, when compared to the prevalence of adolescents without PCOS seen at ASC, there was no statistical difference in the prevalence of GD-identifying adolescents (PCOS, 7.6%; n=12 vs. ASC patients, 4.4%; n=3; p=0.56).

Figure 1:

Gender identity among comparison groups.

Among patients with PCOS, we evaluated whether differences in gender identity were associated with clinical and/or biochemical hyperandrogenism. Those already on contraception or metformin at the time of evaluation were excluded since both can improve hyperandrogenism. Adolescents who identified as GD had higher FG scores than cisgender patients (Table 2). No differences in biochemical measures of hyperandrogenism, namely DHEA-S and total testosterone, were detected between GD and cisgender patients (p>0.05, Table 2).

Table 2:

Androgen assessment comparison between cisgender and GD patients.

Median (IQR)	n	Cisgender n (PCOS)	n	GD (PCOS)	p-Value
FG score	116	6 (4–9)	10	15 (11–16)	<0.01
DHEA-S	113	235 (167–314)	9	259 (160–297)	0.83
Total testosterone, ng/dL	118	55 (46–68)	10	56 (51–63)	0.84

Associations between gender identity and mental health among patients with PCOS seen in MAPP are reported in Table 3. A higher proportion of GD compared to cisgender teens with PCOS experienced depression (100% vs. 37.6%, p<0.01) and anxiety (77.8% vs. 35.8%, p=0.03). A trend toward an increased prevalence of history of suicidality in GD PCOS teens compared to cisgender PCOS teens was also observed: 36.4% vs. 14.4% (p=0.08).

Table 3:

Depression and anxiety in cisgender compared to GD.

n/total n (%)	Cisgender (PCOS)	GD (PCOS)	p-Value
Depression	50/133 (37.6)	11/11 (100)	<0.01
History of suicidality	18/125 (14.4)	4/11 (36.4)	0.08
Anxiety	44/123 (35.8)	7/9 (77.8)	0.03

Discussion

In our setting of an adolescent PCOS clinic, a significantly higher percentage of those who met the diagnostic criteria for PCOS self-identified as GD compared to those who did not meet adolescent PCOS diagnostic criteria. Of those identifying as GD, participants were more hirsute and reported a greater prevalence of depression and anxiety vs. cisgender participants with PCOS. Collectively, our findings suggest that consideration of gender identity may be an important clinical standard in the evaluation and management of PCOS and its related comorbidities.

The increased prevalence of adolescents with PCOS identifying as GD of 7.6% is, to our knowledge, a novel finding and higher than the reported national average among U.S. adolescents, which estimates the percentage of transgender and gender non-conforming individuals to be 3.6% in natal females [8]. However, a potential contributing factor in this discrepancy may be how gender identity is assessed given that our study utilized open ended questions by experienced clinicians whereas national averages are collected by surveys. For our non-PCOS adolescent comparison groups, we acknowledge that both groups may not represent an externally valid cross-section. The MAPP is a referral clinic for adolescents with suspected PCOS while the ASC, by nature of the clinic, may inherently capture a referral bias for teens with psychosocial concerns who may harbor underlying struggles with gender identity. Still, we noted an increased prevalence of teens that self-identified as GD within the PCOS group in the MAPP referral population. When compared to non-PCOS teens from the ASC referral clinic, the difference, while still nearly double, was no longer statistically different (7.6%vs. 4.4%, p=0.56). Ultimately, our retrospective data suggest that adolescents with PCOS may be more likely to self-report differences in gender identity, and future systematic prospective assessments of gender identity included in routine clinical care may fully capture the divergence in gender identity among adolescents with and without PCOS.

A few studies in adults have looked at transgender identity in relationship to PCOS, mostly surveying the prevalence of PCOS in transmasculine adults. One study examined 128 treatment naïve adults seeking transmasculine care in Japan. All had hormone lab testing and ovarian ultrasound performed. 17% of the cohort met diagnostic criteria for PCOS based on stringent NIH criteria and 32% met PCOS criteria based on the more inclusive Rotterdam criteria [9], suggesting a higher prevalence of PCOS in this population. A similar study, examining 61 adults seeking female to male (FTM) care found a prevalence of PCOS in 11.5% based on NIH criteria and 14.8% based on Rotterdam criteria and therefore concluded that PCOS was as common in their transgender clinic as in their unselected controls [10]. One study examined hormone levels in transmasculine adolescents (n=49, mean age 18.6 (SD 2.84)) attending a transgender clinic. Testosterone levels were noted as generally appropriate for natal sex, albeit a wide range of levels (7 to 288 ng/dL) with one subject diagnosed with a virilizing condition. While four participants (8%) carried a preexisting diagnosis of PCOS, neither menstrual cycle regularity nor hirsutism score were assessed at baseline and therefore the prevalence of PCOS was not established [15].

Our findings contrast a recent report noting that the prevalence of GD identity does not differ based on PCOS status [16]. In this Swedish national registry examination using ICD diagnostic codes from 1990 to 2013, the authors reported that those with a PCOS diagnosis had an overall 50% increased odds of also carrying a psychiatric diagnosis, supporting previous understandings of psychiatric comorbidities in PCOS [17]. The authors additionally examined whether gender identity disorder/transsexualism recorded as ICD codes were more common in PCOS. Although the documentation of transgender ICD codes was very low (<0.1%), gender identity disorder was twice as common in PCOS vs. non-PCOS (0.06% vs. 0.03% with a significant unadjusted odds ratio of 2.02). Given the strong association of gender-identity disorder with mood disorder, the findings were no longer significant when the authors adjusted for comorbid psychiatric disorders. However, adjusting for comorbid psychiatric disorders may have led to an unsuitable leveling of this statistical difference, since mood disorders, while associated with gender dysphoria do not predispose to GD identity. Furthermore, registry studies dating back 20 years may not be ideal for capturing sensitive diagnoses that may not have been routinely documented.

Gender diversity was associated with higher FG hirsutism scores but not biochemical hyperandrogenism in participants with PCOS, which is a noteworthy finding. Hirsutism does not always correlate with higher androgen levels, given varying inter-individual sensitivity of hair follicles to hormone levels [18]. In adolescents, hirsutism scores are generally thought to be lower, as it may take a few years to manifest more pronounced hair growth [19]. We propose two plausible interpretations to our findings. First, adolescents who identified as GD may have embraced hirsutism manifestation of PCOS, choosing to forgo common cosmetic procedures such as bleaching, tweezing, waxing, or shaving. In contrast, FG scoring in cisgender youth may have been limited by undisclosed self-treatment due to discomfort with the manifestation of excessive hair growth. Both stances toward a common manifestation of PCOS may have led to our observed difference.

We did not find an association between GD youth and biochemical hyperandrogenism. Observations in individuals with genetic conditions affecting androgen metabolism or androgen receptors have allowed for some insight into the complex interconnectivity between gender identity and androgens. For example, in complete androgen insensitivity syndrome, a condition where genetic males lack all androgen receptors and are raised as female, only 1.7% express a sense of gender incongruence [20]. However, in partial androgen insensitivity syndrome, where there is still some androgen receptor activity, prevalence of gender identity disorder was much higher at 12% for those raised as female [20]. Other conditions, such as congenital adrenal hyperplasia (CAH), that do not affect sex steroid receptors but raise androgen levels in utero, suggest a potential relationship between the intra-uterine hormone milieu and gender identity. In a study reviewing 250 individuals with congenital adrenal hyperplasia (CAH) across multiple case reports and small studies, 13 (5.2%) of those raised as female experienced gender dysphoria [21]. Given that PCOS is highly heritable [22], further exploration of maternal history and presentation of PCOS may be an intriguing next examination in GD youth with PCOS.

Among GD youth with PCOS we also noted an increased prevalence of anxiety and depression and a trend towards an increase in history of suicidality. Recent literature on mental health in GD youth showed that female to male adolescents have higher rates of suicide behaviors (50.9%) compared to all other gender identity groups [23]. Nonbinary adolescents had the next highest rate at 41.8%. In our study, 36.4% of GD teens with PCOS had a history of suicidality compared to 14.4% of cisgender youth which is consistent with recently published estimates of adolescent suicidality [23]. PCOS itself also predisposes to anxiety and depression with similar evidence emerging for adolescents with PCOS [2, 24]. Our findings suggest that differences in gender identity place additional emotional strain on teens, exceeding the general risk associated with PCOS.

Treatment goals in GD patients may not align with general PCOS treatment recommendations which traditionally aim to regularize menstrual cycles, a potential amplifier of gender dysphoria. Additionally, some patients may embrace their hirsutism and not desire hormone treatment that reduces growth. In the clinical setting, unawareness of a patient’s gender identity by the clinician may lead to unsuitable or insufficient treatment recommendations resulting in poor treatment adherence. Therefore, we recommend routine assessment of gender identity in all patients presenting in a multi-specialty PCOS care setting.

Our study had several strengths. We were able to assess a large number of adolescents in a multi-specialty setting that offered a consistent approach to reproductive, metabolic, and psychological evaluations for PCOS. Furthermore, our PCOS diagnosis was based on the NIH criteria which allows for examination of a single phenotype rather than adults’ studies which often reflected up to four phenotypes [25]. Our study had noteworthy limitations. Gender identity was not initially charted on all patients in the MAPP, though over time, this practice had become routine for all patients being evaluated. Additionally, a standardized tool was not utilized to collect gender identity. The lack of standardized discussion of gender-identity in the beginning of our study might have contributed to the high percentage of GD patients in those that were assessed. However, it is notable that both PCOS and non-PCOS groups each had gender identity recorded in about 2/3 of cases and therefore any difference between the groups was less likely related to assessment bias. We furthermore did not specifically ask if undocumented gender affirming treatment had been sought out by those identifying as GD. Given the lack in difference of biochemical hyperandrogenism between GD and cisgender adolescents with PCOS, testosterone supplementation in the GD youth appears unlikely.

All patients seen in the MAPP were referred for concern of possible PCOS, so those who did not receive a diagnosis of PCOS may be at higher risk for developing PCOS in the future compared to the general population. However, while we acknowledge this selection bias, it would likely decrease differences between the groups as opposed to magnifying them. Additionally, the ASC comparison group was small secondary to elimination of attendees with natal male sex, attendees with any symptoms of PCOS, or any laboratory evaluation of sex hormones. Lastly, while we acknowledge a potential for divergence in hirsutism reporting amongst our participants, inter-observer variability can be a concern among practitioners. To that end, the MAPP clinicians were well trained in using the FG system and highly experienced in assessing hirsutism.

In summary, we report that gender identity and mental health assessments are important in the clinical evaluation of PCOS in adolescents. Our findings suggest routine screening of gender identity should be considered in practice recommendations for comprehensive adolescent PCOS programs. In the setting of multidisciplinary care, we recommend involving the subspecialty of Adolescent Medicine for their expertise in the psychosocial interview. This may additionally identify risk for gender dysphoria and uncover unmet needs prompting referrals to other specialists such as mental health experts or social workers. Unawareness of personal comfort with PCOS features such as infrequent menses and hirsutism may inadvertently subject the patient to cis-normative treatment, potentially worsening psychological distress. We endorse routine assessment of gender identity in the care of adolescents with PCOS as it offers a unique opportunity to individualize treatment and to address healthcare disparities often seen in GD youth.