Polycystic Ovary Syndrome in Adolescents
Case Study
Initial Presentation
A 16-year-old female patient presents to the PCOS clinic for evaluation of obesity and amenorrhea.
History
The patient, who is otherwise healthy, began gaining weight at age 7. During this period, her weight increased from the 15th to (currently) the 90th percentile; her height remained constant (75th percentile). Menarche was at 12 years of age. Menstrual periods have been irregular since the onset of menarche and she has had no periods for the past 5 months. She noticed excessive hair growth on her face, chin, and neck soon after the onset of menarche. She has been shaving her facial hair once every 2–3 days.
The patient’s detailed diet history included eating 3 meals daily and snacks in-between meals. The patient was consuming sweet beverages regularly. There was minimal intake fruits and vegetables. The portion sizes for each meal were large. The patient had minimal physical activity and screen time was more than 2 hours daily.
Family history is significant for obesity and type 2 diabetes in her mother and maternal grandmother and is negative for PCOS.
Physical Examination
Vital signs were within normal limits. She was 5 ft 6 in tall and weighed 242 lb, with a body mass index (BMI) of 40 (99th percentile; Z-score 2.41). Physical examination showed coarse hair extending from the sideburns to the chin as well as from pubis symphysis to navel with evidence of hair removal. She had acanthosis nigricans on her neck, mild acne, and evidence of central obesity with pink striae marks on the abdomen. She was Tanner stage 5 for breast and pubic hair and there was no evidence of virilization (clitoral hypertrophy, deepening of the voice, severe hirsutism, male pattern baldness, and masculine habitus). Other physical examination findings were within normal limits.
What physical findings in this patient are suggestive of clinical hyperandrogenemia?
Physiologic irregular menstruation is a well known phenomenon in adolescent girls and is generally due to anovulatory cycles [9–12]. Menstrual cycles shorter than 19 days or longer than 90 days at any stage after menarche are considered abnormal. The menstrual irregularity that is commonly seen within the first 2–3 years after the first menarche can last up to 5 years [5]. However, the majority of girls establish 20- to 45-day cycles within the first 2 years [13].
Androgen excess, defined by the presence of clinical and/or biochemical hyperandrogenemia, should be considered in any adolescent girl who is 2 to 3 years’ post-menarche and presenting with irregular menstrual periods, coarse terminal hair in a male distribution pattern (hirsutism), or moderate to severe inflammatory acne. Hirsutism is androgen dependent [14–16] and must be distinguished from hypertrichosis, which is generalized excessive vellus hair growth present all over the body. Clinical hyperandrogenemia, which includes hirsutism, acne vulgaris, as well as androgenetic alopecia, is well correlated with elevated androgen levels; however, the severity of hirsutism does not correlate well with circulating androgen levels [17,18]. Mild hirsutism is often not associated with hyperandrogenemia in otherwise asymptomatic individuals,but it may be a sign of hyperandrogenemia in adolescents when associated with other features of PCOS, ie, menstrual irregularity [14–16, 19–22]. Defining hirsutism in early adolescence may be difficult since the sexual hair may still be developing, and laboratory evaluation should be considered (see below), especially in an overweight/obese adolescent girl presenting with oligomenorrhea. Ethnic variation due to decreased skin sensitivity to androgens can result in minimal hirsutism despite elevated plasma androgen levels and must be considered among certain Asian women. Women with PCOS from China, Japan, Thailand, and East and Southeast Asian countries tend to have low scores on hirsutism rating scales even with elevated plasma androgens levels [16,23].
Although having acne during puberty is not considered as a marker for hyperandrogenemia, patients with moderate to severe inflammatory acne that is poorly responsive to topical treatment should be evaluated for underlying hyperandrogenemia [19,24,25].
What laboratory tests should be obtained to when there is clinical suspicion of hyperandrogenemia?
Case Continued
The patient underwent laboratory assessment that included total and free testosterone levels, lipid panel, thyroid studies, prolactin level, comprehensive metabolic panel (CMP) and hemoglobin A1c (HbA1c). Due to lack of virilization, she was not tested for PCOS-like syndromes. Her total and free testosterone were 90 ng/dL (normal, < 41) and 24.7 pg/mL (normal, 0.5–3.9) respectively. Thyroid-stimulating hormone and prolactin levels were normal. She had normal lipid levels and CMP but HbA1c was 5.9% (pre-diabetic range). The results of a 2-hour oral glucose tolerance test revealed a level of 160 mg/dL, indicative of impaired glucose tolerance.
What is the pathophysiology and diagnostic criteria for PCOS in adolescents?
PCOS has diverse etiology and has been linked to both genetic and environmental factors affecting ovarian steroidogenesis [13,30]. While the familial clustering strongly supports the role of genetic factors, variability in phenotypic features within the same or different families indicates the importance of environmental contribution [31–34].
The exact underlying mechanism leading to disruption of ovulation is still unclear; however, hyperinsulinemia augmenting ovarian androgen production has been well recognized [35–37]. Insulin resistance is a characteristic finding in PCOS and occurs both in obese and lean patients [38,39]. Obesity further exacerbates the insulin resistance state in PCOS patients. Therefore, obese patients with PCOS have more severe hyperandrogenemia and consequences from it (hirsutism, menstrual abnormalities, and metabolic derangements) than normal-weight PCOS patients [40,41]. Similar to LH, insulin can stimulate ovarian theca cells directly and cause increased production of androgens [42]. Elevated androgen levels cause the irregular menstrual periods as well as clinical signs of hyperandrogenemia, such as hirsutism and acne.
Altered gonadotropin dynamics is another possible etiological factor that is linked with PCOS. Hyperinsulinemia affects the regulation of gonadotropin-releasing hormone (GnRH) pulse generator, causing hypersecretion of LH [43]. Obese peripubertal girls have been identified having altered LH secretion [44,45]. This results in increased LH levels relative to FSH. Normal FSH is required to stimulate ovarian folliculognensis; insufficient FSH levels cause anovulation and menstrual irregularities. Abnormal LH secretion and fasting insulin levels have been identified the independent predictors for hyperandrogenemia in some peripubertal obese girls [46].
In 2010 Carmina et al published new criteria to diagnose PCOS in adolescents [27].They recommended that in diagnosing PCOS in adolescents, all 3 previously mentioned criteria should be present: hyperandrogenemia, chronic anovulation, and polycystic ovaries. With the exception of worsening hirsutism, the new recommendations greatly emphasized biochemical hyperandrogenemia (elevated free testosterone levels using sensitive assays). Chronic anovulation was defined as persistence of menstrual irregularities 2 years post-menarche and pelvic ultrasound (USG) showing increased ovarian size (> 10 cm3). Normal physiological variations unrelated to hyperandrogenemia are common in adolescent ovaries and limits the usefulness of pelvic USG as a diagnostic criterion for PCOS [13,47,48]. Also, the prevalence of increased ovarian size in hyperandrogenemic adolescent patients was reported to be low, and its utility as a criterion for diagnosis needs to be further explored [49]. In our current practice we do not rely on pelvic USG findings to make a PCOS diagnosis.
Due to longstanding controversies and lack of consensus surrounding the accurate diagnostic criteria, a recent guideline was developed by experts in pediatric endocrinology and adolescent medicine invited by the Pediatric Endocrine Society to address these issues [13].The guideline committee assessed the literature in order to define which criteria have sufficient evidence to be used for diagnosis of PCOS in adolescents. They recommend that PCOS should be considered in an adolescent girl presenting with unexplained menstrual irregularities, moderate to severe hirsutism or acne, and elevated levels of serum androgens (total and free testosterone) using reliable assay with well-defined ranges. Although intrinsic insulin resistance unique to PCOS is well known, none of the current guidelines either for adolescent and adult women include it as part of the diagnostic criteria. Since longitudinal studies focusing on the natural history of PCOS in this age-group are lacking, the current recommendations focus on timely screening and treatment in symptomatic adolescent girls suspected of having PCOS.
When there are PCOS features but menstrual irregularity has not been present for at least 2 years, one can defer the diagnostic label and instead use the term at-risk for PCOS. Such patients should have frequent longitudinal re-evaluations and should be offered treatment for their symptoms [13].
