Case 1: Clitoromegaly, Oligomenorrhea, and Hirsutism in a 17-year-old Transgender Male

Presented here are three patients who have a common chief complaint. All three cases have discussions on presentation, the differential diagnosis, and management that collectively serve as a Review article. Following the three cases, an expert weighs in in a short commentary with 5 questions for CME credit.A 17-year-old transgender male (assigned female at birth) with a history of gender dysphoria and obesity presents with his mother for evaluation of clitoromegaly. He began identifying as male at age 11 years and began using he/him pronouns at age 13 years; however, his parents have not accepted his gender identity, and medical attempts to treat his identity are self-initiated. He first noticed hair above his upper lip several years ago; new hair on his chin, neck, and abdomen during the past year; and his voice starting to deepen approximately 6 months ago. He started using over-the-counter topical minoxidil to induce hair growth on his face several months ago. His last menstrual cycle was 2 weeks before this visit. Puberty was uneventful and menarche was at age 11 years. He has experienced oligomenorrhea for the past couple of years. The longest he had gone without a menstrual cycle was 8 months in the year prior. He feels dysphoric when he has a menstrual cycle. He is happy with these new physical changes that had developed but is nervous about discussing his clitoromegaly with anyone, so he did not disclose his missed menstrual cycles or clitoromegaly to his parents or medical providers. His mother had inadvertently noticed his clitoromegaly while the patient was changing clothes at home and subsequently brought the patient in for evaluation. He denies acne, vision changes, nipple discharge, abdominal and pelvic pain, and headaches.The patient reports no significant medical problems at birth or in childhood. He has not begun gender-affirming hormone treatment (GAHT) due to conflict with his parents regarding his gender identity. His parents do not consent to him beginning GAHT at this time. His family is not accepting of his gender identity and does not use his affirmed name and pronouns. He is currently followed by a psychiatrist and therapist for a history of major depressive disorder and attention-deficit/hyperactivity disorder. He is prescribed quetiapine and methylphenidate by his psychiatrist. He has a history of multiple inpatient psychiatric hospitalizations for suicide attempts in the past 3 years. He denies drug or alcohol use and denies previous or current sexual activity.The patient’s body mass index is 32.6 (97th percentile for age). His height is 63.4 in (161 cm) (36th percentile for age) and weight is 186.3 lb (84.5 kg) (96th percentile for age). His blood pressure is 122/76 mm Hg and heart rate is 102 beats/min. On physical examination the patient is obese, anxious, but in no acute distress. His pupils are equal, round, and reactive to light with normal extraocular movements. His breathing is unlabored and his lungs are clear to auscultation. He is mildly tachycardic with normal heart sounds without murmur, rubs, or gallops. His abdomen is soft, nontender, and nondistended, without masses or organomegaly. His skin examination reveals moderate hirsutism on the upper lip, chin, upper neck, and abdomen, as well as numerous well-healed linear scars on his arms bilaterally. The patient is Tanner stage 5 for breasts and pubic hair. Pelvic examination with a speculum reveals the presence of a normal cervix and vagina with grade II clitoromegaly using the Prader classification system. The speculum was able to pass without issue. Bimanual examination did not reveal any palpable pelvic masses.Initial fasting laboratory testing reveals elevated total (89 ng/dL [3.09 nmol/L]) and free (21.6 pg/mL [74.9 nmol/L]) testosterone levels, elevated androstenedione level (361 ng/dL [12.6 nmol/L]), elevated 17-hydroxyprogesterone (17-OHP) level (258 ng/dL) with a normal dehydroepiandrosterone sulfate (DHEAS) level (201 μg/dL [5.43 µmol/L]), normal luteinizing hormone (13 mIU/mL [13 IU/L]) and follicle-stimulating hormone (3.4 mIU/mL [3.4 IU/L]) levels, and a normal estradiol level for Tanner stage 5 individuals assigned female at birth (92 pg/mL [337.73 pmol/L]) (Table). Comprehensive metabolic panel, hemoglobin A1c level, lipid panel, prolactin level, and thyrotropin level are all within normal limits, and a pregnancy test is negative. Pelvic ultrasonography reveals the presence of ovaries and a uterus of normal size and appearance, without masses.Pediatric endocrinology is consulted after initial laboratory testing was completed due to concern for a disorder of adrenal steroidogenesis based on the elevated total and free testosterone, androstenedione, and 17-OHP levels. They recommend adding renal bladder ultrasonography, which reveals normal kidneys and bladders without any masses or signs of adrenal hyperplasia. A 24-hour urine cortisol level is obtained and is normal. Despite the 17-OHP level at the initial visit being within the laboratory reference range for Tanner (or pubertal) stage 5 patients assigned female at birth, given the patient’s physical findings, this level is concerning because early-morning levels of 200 to 1,500 ng/dL may be indicative of nonclassical congenital adrenal hyperplasia (NC-CAH). Pediatric endocrinology recommends performing a corticotropin (ACTH) stimulation test to evaluate adrenal function and for NC-CAH. Approximately 2 months after initial presentation, the ACTH stimulation test is performed by pediatric endocrinology. The cortisol level appropriately rose from 9.3 μg/dL (256.57 nmol/L) at 0 minutes to 23.9 μg/dL (659.35 nmol/L) 30 minutes after administration of cosyntropin (synthetic derivative of ACTH). A CAH-6 panel is collected at minutes 0 and 60 after cosyntropin administration. This panel is used to aid in the diagnosis and management of the most common forms of CAH. It is drawn concurrently with the ACTH stimulation test and includes testing for 17-hydroxypregnenolone, 11-deoxycorticosterone, androstenedione, cortisol, dehydroepiandrosterone, testosterone, 17-OHP, progesterone, and 11-deoxycortisol. In this panel, the 17-OHP level is 115 and 205 ng/dL at minutes 0 and 60, respectively, which is within normal limits based on the patient’s Tanner staging. The CAH-6 panel results at minutes 0 and 60 are otherwise within normal limits. Total and free testosterone levels are 52 ng/dL (1.80 nmol/L) and 11.1 pg/mL (38.49 pmol/L), respectively, and DHEAS level is 189 μg/dL (5.10 µmol/L).The differential diagnosis for clitoromegaly, oligomenorrhea, and hirsutism in an individual assigned female at birth includes virilizing tumors, disorders of sex development including NC-CAH, polycystic ovarian syndrome (PCOS), and exogenous androgen use.Virilizing tumors typically present with rapid onset of hirsutism, including hair growth in a distribution typically seen in adult men, voice deepening, or frontal balding. Total testosterone level greater than 200 ng/dL (>6.94 nmol/L) (1) would be concerning for an ovarian tumor, and a DHEAS level greater than 700 μg/dL (>18.90 µmol/L) (2) would be concerning for an adrenal tumor. Pelvic ultrasonography would be indicated to assess for an ovarian androgen-secreting tumor. (2) With an elevated DHEAS level and normal findings on pelvic ultrasonography, an adrenal computed tomographic scan would be indicated to evaluate for an androgen-secreting tumor of adrenal origin. (1)Disorders of sex development can present as a spectrum including normal or ambiguous genitalia with clitoromegaly, cryptorchidism, underdeveloped vagina, or absence of Mullerian structures. (3) Presentation can vary in timing from infancy to adolescence depending on the cause of the disorder of sex development.NC-CAH typically presents with acne, hirsutism, and irregular menstrual cycles in adolescent and young adult women. NC-CAH is due to reduced activity of the enzyme 21-hydroxylase, leading to increased androgen production. 17-OHP levels drawn at approximately 8 am that are greater than 200 ng/dL is concerning for NC-CAH, with 92% to 98% sensitivity and specificity. (4)(5)(6) An exaggerated 17-OHP response to an ACTH stimulation test (>1,500 ng/dL) is used to diagnose NC-CAH. (7) One-fifth of patients with PCOS have elevated baseline 17-OHP levels, making it difficult to distinguish between the 2 diagnoses. (8)Signs and symptoms concerning for PCOS in patients include hirsutism, acne, irregular menses, acanthosis nigricans, and central obesity. When making a diagnosis of PCOS in adolescents, gynecologic age needs to be considered because menstrual cycles are commonly irregular in the first 1 to 2 years after menarche. International recommendations state that PCOS in adolescents can be diagnosed by the presence of an abnormal menstrual pattern for at least 2 years (or 1 year with additional clinical evidence for PCOS) and clinical and/or biochemical evidence of hyperandrogenism, which includes hirsutism or elevated total or free testosterone levels. (9)(10)(11) If an adolescent demonstrates signs of PCOS in the first 1 to 2 years after menarche, then only a provisional diagnosis of PCOS can be made. (12) Clitoromegaly is not typical in PCOS.Another diagnosis to consider in this adolescent transgender male is exogenous androgen use, specifically testosterone, for gender affirmation. Testosterone is most commonly administered either topically or intramuscularly for this indication. The goal testosterone range for GAHT is 400 to 700 ng/dL (13.88–24.29 nmol/L) when checked either 2 to 6 hours after application of testosterone gel or halfway between intramuscular testosterone doses. (13) When testosterone levels reach this therapeutic range, menstrual cycles ideally should be suppressed. Anticipated effects of testosterone use include increase in lean muscle mass, decrease in subcutaneous fat, male pattern hair growth, menstrual suppression, breast tissue atrophy, clitoromegaly, and voice deepening. In addition, adverse effects of testosterone use include acne, polycythemia, dyslipidemia, elevated transaminase levels, weight gain, hypertension, and mood lability.An adrenal adenoma secreting ACTH can cause Cushing disease, with increased production of cortisol and androgens leading to hirsutism or menstrual irregularity. Other causes of hirsutism or menstrual irregularity include hypothyroidism and hyperprolactinemia.The patient’s laboratory results indicate that his biochemical hyperandrogenism had resolved by the time the pediatric endocrinology appointment had occurred. His ACTH stimulation test demonstrates an adequate cortisol response. His DHEAS level is not elevated, and pelvic ultrasonography did not show any masses, making an adrenal or ovarian virilizing tumor less likely. Because the patient’s DHEAS level was well below the recommended threshold for obtaining a computed tomographic scan of the adrenal glands at both the initial visit and the subsequent pediatric endocrinology visit 2 months later, further imaging is not obtained. The CAH panel at the pediatric endocrinology appointment, which includes a 17-OHP level, is within normal limits, making NC-CAH and other adrenal steroidogenesis defects less likely.The patient’s mother is called to review the laboratory results drawn at the pediatric endocrinology appointment and she reveals that she is concerned that the patient is obtaining testosterone through an acquaintance not prescribed by a physician for his own use for gender affirmation based on text messages she reviewed on the patient’s phone.The patient’s initial presentation of oligomenorrhea for several years before presentation and clinical and biochemical signs of hyperandrogenism (which includes his elevated testosterone and androstenedione levels) indicate that the patient may meet the criteria for PCOS based on the Rotterdam criteria; however, this diagnosis is clouded by the patient’s use of over-the-counter topical minoxidil for facial hair growth and resolved biochemical hyperandrogenism. (14) Given the mother’s concerns and resolved biochemical hyperandrogenism, it is also presumed that the cause of the patient’s transient biochemical hyperandrogenism, clitoromegaly, hirsutism, and oligomenorrhea may also be secondary to exogenous nonprescription testosterone use for gender affirmation.The patient meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria for gender dysphoria; however, the patient’s parents were not amenable to starting GAHT before age 18 years. This case highlights ethical considerations for this patient, such as beneficence and nonmaleficence and supporting patient autonomy. (15) Depending on the state they reside in, minors in the United States can consent to treatment for certain infectious, sexual, reproductive, and psychiatric health conditions without parental consent. There are, however, still limitations on minors consenting to GAHT without parental consent in the United States.Further education at subsequent follow-up appointments was provided to the parents on the strong importance of parental support and creation of a welcoming home and social environment that affirms the patient’s gender to support his social transition, regardless of whether he starts GAHT. (16) In addition, they were advised that initiation of GAHT in gender-diverse adolescents can improve future mental health outcomes, such as decreased suicidality, psychological distress, and substance use in adulthood. (17) They were also provided information on local support groups for LGBTQIA+ youth and their families. He has close follow-up scheduled with both his psychiatrist and therapist.The patient was also reminded of the importance of receiving GAHT from a physician with expertise in this field. The patient denied use of exogenous testosterone. Use of testosterone for GAHT is not without risk, and patients receiving this treatment need to be closely monitored under the care of a physician.The patient should be off any type of hormonal therapy for 6 months before we can reevaluate for a true PCOS diagnosis. The patient was given information on local community-based clinics that provide GAHT to young adults. Due to lack of parental support, the patient desired to seek further care after his 18th birthday, when he is able to legally consent to treatment himself.Exogenous testosterone use in individuals assigned female at birth can cause hirsutism, clitoromegaly, menstrual suppression, and voice deepening.Polycystic ovarian syndrome can clinically and biochemically present similarly to nonclassical congenital adrenal hyperplasia. Thorough laboratory and radiologic investigation may need to take place to rule out more severe and life-threatening causes of hirsutism.Gender-affirming care improves mental health outcomes in gender-diverse adolescents. It is important for both clinicians and families to create gender-affirming environments both in the medical setting and at home.Patients who identify as transgender males should be counseled on appropriate and safe use of exogenous testosterone as a part of a masculinizing hormone therapy regimen.Thank you to the fellows and teaching faculty of the Adolescent Medicine Fellowship at Brooke Army Medical Center for their assistance in the care of this patient.