Introduction
Androgen excess in females can manifest clinically as hirsutism, severe acne, male-pattern balding, deepening of the voice, and enlargement of the clitoris. Biochemical correlates may include elevated levels of androgenic steroids stemming either from the ovaries or adrenals. The degree of association between clinical features of androgen excess and biochemical hyperandrogenism varies greatly between individuals and depends on the sensitivity of the pilosebaceous unit. When hirsutism does not correlate with androgenic steroid levels, it is deemed idiopathic. The most common etiology for mild to moderate androgen excess in adults and adolescents is PCOS. Late-onset congenital adrenal hyperplasia (CAH) and severe insulin resistance syndromes are other conditions that may present with symptoms of androgen excess during adolescence. Virilizing features such as clitoral enlargement, voice deepening, and rapidly worsening hirsutism should be evaluated for androgen-producing tumors.
Clinical features of androgen excess
Hirsutism is defined as the presence of excessive coarse terminal hair in areas of the body that are responsive to the effect of androgens. A commonly used clinical tool for assessing hirsutism is the modified Ferriman-Gallwey (F-G), a pictogram that allows for visual grading in nine body areas (upper lip, chin, chest, lower and upper abdomen, lower and upper back, upper arms, and thighs). Each area is scored separately from 0 (absent) to 4 (extensive) hair growth. 
In adults, a summation score of ≥4 to 6 has been suggested to indicate clinically relevant hirsutism by the 2023 International PCOS Guidelines ( Fig. 19.1 ). Clinically, these cut-off scores also guide the assessment of hirsutism in adolescents.
Although the F-G scoring system can help quantify clinical features of hair in androgen-sensitive areas, scoring remains observer dependent and may be inaccurate if cosmetic hair removal has occurred in these areas.
Hirsutism must be differentiated from hypertrichosis, which denotes hair growth in androgen-independent body areas such as the forearms and lower legs. Hypertrichosis is not associated with hyperandrogenism, and hair is usually vellus and noncoarse. Hypertrichosis may be hereditary among teens of Middle Eastern or Mediterranean descent. Hypertrichosis can be observed in states of malnutrition, but can also be medication induced (e.g., diazoxide or phenytoin).
Acne may indicate androgen excess in adults, but in adolescents is a common manifestation of puberty. Androgen excess contributes to acne through stimulating sebum production, but other factors such as bacterial colonization also play a role, explaining the poor correspondence between severity of acne and androgen levels. Still, severe, cystic acne should prompt a search for biochemical correlates in adolescence.
Hidradenitis suppurativa refers to inflamed painful nodules and abscesses involving the pilosebaceous units of the axillae, groin, perineum, and breast region and should prompt further consideration of androgen excess.
Androgenic alopecia is diffuse thinning of crown hair with the frontal hairline preserved. It is uncommon in adolescents, yet when present should be evaluated for biochemical hyperandrogenism.
PCOS
PCOS is a heterogeneous condition where the severity of clinical expression is compounded by environmental, nutritional, lifestyle, and transgenerational factors. PCOS in terms of nomenclature originated as an acronym standing for Polycystic Ovary Syndrome. However, ovarian cysts are not part of the PCOS diagnosis and therefore the origins of the acronym are misleading. PCOS more accurately affects ovarian function and morphology, manifesting in a tendency toward ovulation dysregulation and hormonal imbalance that favors ovarian testosterone production. Minor upregulation of adrenal androgens can also be seen, but modest elevations in dehydroepiandrosterone sulfate or androstenedione provide limited additional information in the diagnosis of PCOS. Prominent elevation of adrenal hormones should direct the clinician toward considering adrenal pathologies instead of PCOS.
Short- and long-term consequences of menstrual dysfunction and hormonal imbalance may include hirsutism and treatment-resistant/cystic acne, hidradenitis suppurativa, insulin resistance, weight gain, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), endometrial hyperplasia, subfertility, depression/anxiety, and in adults disordered eating ( Table 19.1 ).
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In adolescents, the diagnosis can be challenging because key clinical features of PCOS such as irregular menstrual cycles are also physiologically present in this age group.
Diagnosis
Currently, the international PCOS guidelines endorse application of the Rotterdam Criteria for diagnosing PCOS in adults and 
recommend the National Institutes of Health Criteria (menstrual irregularity and hyperandrogenism) for adolescents. , Both sets of criteria overlap in the diagnostic features of menstrual dysregulation and clinical and/or biochemical hyperandrogenism. However, the Rotterdam Criteria allow for sonographic evidence of polycystic ovarian morphology (not the same as ovarian cysts) to substitute for either menstrual dysregulation or hyperandrogenism. In adults this has led to the diagnosability of a broader clinical spectrum, which also includes an ovulatory and nonandrogenic PCOS phenotype. In support of phenotypic distinctions, the recent 2023 update of the international PCOS guidelines has furthermore endorses Anti-Muellerian Hormone level in the diagnostic consideration of adult PCOS. Genome-wide association studies validate the expression of similar genetic underpinnings for classical and nonclassical phenotypes of PCOS, further supporting the variability in expression of the condition.
In adolescents, although some ovarian sonographic features may reflect the severity of the reproductive disturbance in PCOS, , current adult sonographic diagnostic criteria may not sufficiently differentiate PCOS from normal adolescent ovarian morphology. Therefore until normative ovarian features and specific PCOS distinguishing features have been examined in adolescents, the application of adult ultrasound criteria for diagnosing PCOS is not recommended until 8 years post menarche. Therefore in adolescents only the classical B phenotype can be diagnosed ( Table 19.2 ). If adolescents only meet one of the diagnostic criteria, they may be considered “at risk” for PCOS and should be followed and offered symptom-based management.
| Phenotypes | CLINICAL MANIFESTATIONS | ||
|---|---|---|---|
| Menstrual Dysfunction | Clinical or Biochemical Hyperandrogenism | Sonographic Ovarian Features of PCOS | |
| A: complete | x | x | x |
| B: classical a | x | x | |
| C: ovulatory | x | x | |
| D: nonandrogenic | x | x | |
a Only phenotype B can be diagnosed in adolescents and is based on National Institutes of Health criteria.
It is important to note that PCOS in adults and adolescents is a diagnosis of exclusion and therefore other conditions presenting with similar symptoms must first be ruled out. Such conditions include adrenal disorders (i.e., nonclassical CAH), thyroid disorders, primary or secondary ovarian insufficiency, hyperprolactinemia, androgen-producing tumors ( Table 19.3 ).
| Etiologies | Clinical Findings | Evaluation |
|---|---|---|
| Hypothyroidism | Menstrual irregularity, possible hypertrichosis, possible weight gain | Elevated TSH |
| Disordered eating (anorexia/bulimia) | Menstrual irregularity, hypertrichosis | Low/prepubertal LH, FSH, low estradiol |
| Hyperprolactinemia | Menstrual irregularity, possible acne, mild hirsutism (prolactin stimulates adrenal androgens), galactorrhea | Fasting elevated prolactin; differential: pituitary mass or drug induced: antipsychotic, SSRI, methyl-dopa; other cause: prominent elevation of TSH, renal disease |
| Type 1 diabetes | Secondary PCOS, menstrual irregularity, hirsutism, acne | Elevated total and/or free testosterone in the setting of T1DM |
| Nonclassical CAH | Irregular menstrual cycles, acne, hirsutism | Morning 17-hydroxyprogesterone >200 ng/dL (>6.05 nmol/L) |
| Androgen-producing tumors | Signs of virilization: voice deepening/clitoromegaly, acute onset, rapidly progressing hirsutism |
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Ovarian or adrenal tumors must be considered when the presentation is acute and/or with virilizing features such as clitoromegaly and voice deepening. Biochemically, tumors of the ovaries are more likely if testosterone is elevated beyond 200 ng/dL. When examining for tumors of the adrenal glands, concern should arise if dehydroepiandrosterone-sulfate rises above 700 μg/dL. When there is concern for either adrenal or ovarian tumors, imaging studies should be pursued. Although transabdominal ultrasound would be the first step in imaging evaluation, if negative, magnetic resonance imaging (MRI) should be considered. Nonclassical CAH is differentiated from PCOS by a morning 17-hydroxyprogesterone value of >200 ng/dL.
In general, any chronic illness or form of malnutrition may also lead to irregular menstrual cycles. Under this premise, irregular menstrual cycles in type 1 diabetes have long been attributed to chronic disease and poor metabolic control. However, in recent years the notion of “secondary” PCOS has emerged, attributed to the effect of intensive insulin therapy on the ovaries, leading to anovulation with a rise in testosterone.
Pathophysiology
PCOS pathophysiology does not have a definable origin, but rather follows a circular pattern that snowballs into a self-perpetuating vicious cycle. The cycle is fed by environmental, metabolic, genetic, epigenetic, and neuroendocrine factors.
Independent of obesity but exaggerated by the degree of adiposity, insulin resistance is a central finding in adults and adolescents with PCOS. However, despite whole-body insulin resistance, steroidogenic organs like the ovaries remain insulin-sensitive, allowing for high circulating insulin levels to exert their effect. Insulin directly promotes testosterone production from ovarian theca cells and acts as a co-gonadotropin by enhancing luteinizing hormone (LH) effect on the ovaries. Even without the effect of insulin, there is intrinsic upregulation of ovarian testosterone production in PCOS. The elevated testosterone, in a circular fashion, further augments insulin resistance and perpetuates the ovarian effect of hyperinsulinemia. Insulin resistance itself also lowers hepatic sex hormone–binding globulin (SHBG) production, which leaves more testosterone in the unbound and free/biochemically active form.
In addition to the effects of insulin, there is dysregulation of the hypothalamic-pituitary-ovarian axis with enhanced LH drive, which promotes testosterone production. Further perpetuating the LH drive is a reduced sensitivity of LH to negative feedback from estrogen and progesterone. It has been suggested that elevated testosterone levels enhance LH resistance to feedback inhibition by progesterone and estrogen. ,
Genome-wide association studies seem to further support the circular premise, with genetic PCOS loci found in areas of gonadotropin signaling, ovarian cellular signaling, and regions associated with energy metabolism/insulin resistance and type 2 diabetes mellitus ( Fig. 19.2 ).
Assessment
Ovulatory dysfunction
Pathologic ovulatory dysregulation can be difficult to determine in adolescents, as cycles are commonly irregular the first 2 to 3 years post menarche, until the hypothalamic-pituitary-ovarian axis has physiologically matured. Given that normal cycle intervals vary from year to year post menarche, irregularity is defined differently from the first to the fourth year post menarche ( Table 19.4 ).
| First Year Post Menarche | Second Year Post Menarche | Third Year Post Menarche | Fourth Year Post Menarche | |
|---|---|---|---|---|
| Menstrual pattern | Any menstrual pattern, including stretches of amenorrhea, are considered normal during the first year post menarche. | Irregular cycles and skipping of cycles are still considered normal. | Cycles should now be more regular (every 21–45 days) between menstrual periods. | Adult menstrual cycle with intervals of 21–35 days (at least eight cycles a year) should be established. |
| Interpretation | PCOS cannot be considered. | If periods are >90 days apart, the adolescent should be evaluated for PCOS. | If periods are >45 days apart or <21 days, the adolescent should be evaluated for PCOS. | If periods are >35 days apart or <21 days, the adolescent should be evaluated for PCOS. |
Biochemical hyperandrogenism
Although adrenal androgens can be upregulated in PCOS, most androgen production stems from the ovaries in the form of testosterone. Therefore the diagnosis of PCOS relies on total and/or free testosterone elevation. Because of the low SHBG in PCOS, the most sensitive determinant of hyperandrogenism is free testosterone, most accurately measured by equilibrium dialysis. Alternatively, the free androgen index can be calculated from measures of SHBG and total testosterone and can serve as a substitute assessment of free testosterone. Total testosterone should be measured using tandem mass spectrometry. Because of diurnal hormone variability, it is recommended to not rule in or rule out PCOS based on a one-time measure. Peak testosterone levels occur in the morning, which is the best time to measure levels. Before testing for hyperandrogenism a 3-month washout period from any hormone treatment, such as oral contraceptive pills, is advised ( Box 19.1 ).
Total and free testosterone
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More sensitive than other androgens
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High-quality assays such as liquid chromatography-tandem mass spectrometry
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No actual cut-offs recommended – should be based on lab reference range and normal values derived from well-characterized populations
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Total Testosterone > 40-50 ng/dL
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Free Testosterone > 1.4-1.7 nmol/L
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More important than a one-time value is persistent elevation
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Diurnal/menstrual cycle variability
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If a patient was on hormone therapy (i.e., combined oral contraceptive pills), a 3-month washout period is recommended before testing
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Other androgen elevations provide limited additional information in diagnosing PCOS but may be of use in ruling out other conditions
Comorbidities
Prediabetes and type 2 diabetes
Even though insulin resistance does not factor into defining and diagnosing PCOS, insulin resistance is tightly linked to the pathophysiology and perpetuation of the clinical phenotype, leading to a higher incidence and earlier onset of prediabetes and type 2 diabetes in mostly obese adults and adolescents with PCOS. , Data on prediabetes and type 2 diabetes in lean adolescents with PCOS are difficult to extrapolate because of the common comorbidity of obesity. Still, prediabetes as assessed by an oral glucose tolerance test may be present across the body mass index (BMI) spectrum. ,
Metabolic dysfunction-asssociated steatotic liver disease: MASLD
MASLD, previously knows as NAFLD (non-alcoholic fatty liver disease) is closely tied to insulin resistance and deteriorating glucose metabolism and more commonly occurs in the male sex. In adults with PCOS, NAFLD risk is independently associated with high serum androgens. In adolescents and adults with PCOS, NAFLD may occur across all BMI categories. Therefore screening liver functions should be obtained at the time of PCOS diagnosis, independently of BMI, and if persistently elevated greater than two times the upper limit, a referral to hepatology for further diagnostics and management is indicated.
Obesity/metabolic syndrome
General and central obesity are greatly increased in adults with PCOS and may start in childhood. The degree of obesity is strongly tied to metabolic syndrome in adolescents of both sexes and in adolescents with PCOS. Metabolic syndrome is a constellation of metabolic disturbances that are known to enhance cardiovascular risk in adults. The most common definition requires any three of the following five criteria to be present: impaired glucose metabolism, central obesity, hypertension, and dyslipidemia related to either high-density lipoprotein (HDL) or triglycerides ( Box 19.2 ). In adults with PCOS, the hyperandrogenic phenotype has the highest risk prevalence of dyslipidemia and an overall higher prevalence of metabolic syndrome. In adolescents with PCOS, the risk of metabolic syndrome is 2.5-fold higher than for those without PCOS and more common in the classical (hyperandrogenic) phenotype.
