INTRODUCTION — Polycystic ovary syndrome (PCOS) is the most common cause of infertility in women [1], frequently becomes manifest during adolescence, and is primarily characterized by ovulatory dysfunction and hyperandrogenism. The syndrome is heterogeneous clinically and biochemically. It encompasses a spectrum of variably associated clinical features:
●Cutaneous signs of hyperandrogenism (eg, hirsutism, moderate-severe acne)
●Menstrual irregularity (eg, oligo- or amenorrhea, or irregular bleeding)
●Polycystic ovaries (one or both)
●Obesity and insulin resistance
Because of this clinical heterogeneity, most cases will not have all of these features, so it is sometimes challenging to diagnose PCOS. The diagnosis of PCOS has lifelong implications with increased risk for metabolic syndrome, type 2 diabetes mellitus, and, possibly, cardiovascular disease and endometrial carcinoma [2-4]. PCOS should be considered in any adolescent female with a chief complaint of hirsutism, treatment-resistant acne, menstrual irregularity, or obesity. (See 'Clinical features' below.)
The cause of PCOS is unknown. Considerable evidence suggests that it arises as a complex trait with contributions from both heritable and nonheritable intrauterine and extrauterine factors [5]. Functional ovarian hyperandrogenism is usually the major source of the androgen excess and can account for the major features of the syndrome (ie, hirsutism, anovulation, and polycystic ovaries) [5]. This ovarian dysfunction is unique: It appears to be intrinsic and is characterized by abnormal ovarian steroidogenesis and folliculogenesis that are manifested clinically by androgen excess and anovulation. It is important to appreciate that PCOS is a syndrome, not a disease, reflecting multiple potential etiologies. (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents".)
The definition, clinical manifestations, and differential diagnosis of PCOS in adolescents are presented here. Other aspects of PCOS in adolescents are reviewed separately:
●(See "Diagnostic evaluation of polycystic ovary syndrome in adolescents".)
●(See "Treatment of polycystic ovary syndrome in adolescents".)
●(See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents".)
DEFINITION AND DIAGNOSTIC CRITERIA FOR POLYCYSTIC OVARY SYNDROME
Adults — Over the past 25 years, internationally accepted diagnostic criteria have been developed for adults based on various combinations of otherwise unexplained hyperandrogenism, anovulation, and a polycystic ovary, which are all encompassed by the Rotterdam consensus criteria [6-10]. These criteria generate four phenotypes, as displayed in the table (table 1), in order of decreasing clinical severity (severity of hyperandrogenism, insulin resistance, obesity, and luteinizing hormone [LH] excess), which corresponds to decreasing specificity of the milder phenotypes [5]. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'Phenotypes of PCOS'.)
Adolescents — Diagnostic criteria for PCOS in adults have been problematic when applied to mid- to late pubertal girls, for several reasons: First, anovulatory cycles and associated menstrual irregularity are frequent in normal adolescents. Second, the common signs of hyperandrogenism in adults are less reliable when applied to adolescents because hirsutism is in a developmental phase and acne vulgaris is common. Third, measurement of testosterone concentrations in adolescents is problematic because serum concentrations rise during anovulatory cycles, there is a paucity of reliable norms for androgen levels in adolescent females, and the extent to which adolescent hyperandrogenism predicts adult hyperandrogenism is unclear. Fourth, polycystic ovary morphology by adult standards is common in normal adolescents.
Three international expert conferences, representing all relevant subspecialties, have published recommendations for the diagnosis of adolescent PCOS [11-13]. These documents agree about the essential criteria: otherwise unexplained persistent evidence of ovulatory dysfunction (as indicated by a menstrual abnormality, based on chronologic and gynecologic age-appropriate standards) and clinical and/or biochemical evidence of androgen excess (hyperandrogenism), as summarized in the table (table 2) [14].
However, these recommendations differ in some clinical details regarding suitable evidence to satisfy these criteria [14]. They differ in whether a menstrual abnormality should persist for one or two years in order to differentiate PCOS from the normal immaturity of the menstrual cycle ("physiologic adolescent anovulation"). They differ in the extent to which hirsutism or acne can be considered evidence of hyperandrogenism on a par with accurate biochemical evidence of hyperandrogenemia. They agree, however, that adolescents with evidence of PCOS within one to two years after menarche should be assigned a provisional diagnosis of "at risk for PCOS" and treated symptomatically.
Whether a PCOS phenotype exists in which obesity is accompanied by intrinsic ovarian hyperandrogenism in the absence of hirsutism or acne and anovulatory symptoms remains to be determined.
CLINICAL FEATURES — The chief complaint in adolescents with PCOS may be hirsutism, topical treatment-resistant acne, menstrual irregularities, acanthosis nigricans, and/or obesity. PCOS in adolescents is usually recognized because of the symptoms of hyperandrogenic anovulation, but one-third of cases come to medical attention because of hirsutism or obesity-associated acanthosis nigricans before menstrual abnormalities become apparent [15]. While obesity and insulin resistance are commonly associated with the syndrome, they are not essential to the diagnosis; indeed, approximately one-half of patients are nonobese. (See 'Associated metabolic features' below.)
An abnormal menstrual pattern may be of little concern to the patient. Some patients have an abnormal degree of inflammatory acne instead of hirsutism, but cutaneous symptoms of hyperandrogenism are not necessarily present or of primary concern to the patient. Elucidating their presence is critical to the diagnosis in adolescents.
Cutaneous manifestations of hyperandrogenism
Hirsutism — Hirsutism is defined clinically as an abnormal amount of sexual hair that appears in a male pattern [16]. It is commonly scored according to the Ferriman-Gallwey system, which quantitates the extent of hair growth in the most androgen-sensitive areas of adults (figure 1). Sexual hair growth normally matures throughout puberty to achieve adult scores by two years after menarche, at approximately 15 years of age, based on sparse normative data [17,18]. Hirsutism is defined as a score of 8 or more in the general United States adult female population [16]. The normal score varies with ethnicity: Hirsutism is defined in Asian populations like Han Chinese as a score ≥2 to 3 and in Mediterranean populations as a score ≥9 to 10 [19].
Not all "patient-important hirsutism" is abnormal. Localized excessive sexual hair growth ("focal hirsutism") with a normal hirsutism score is a common cosmetic complaint ("even a single hair casts a shadow") [20].
Hirsutism must also be distinguished from hypertrichosis, the generalized excessive growth of vellus hair that sometimes occurs on a hereditary basis or in patients taking glucocorticoids, phenytoin, diazoxide, or cyclosporine. Hypertrichosis is distributed in a nonsexual pattern (eg, generalized distribution or more prominent distribution on the forehead or shoulders) and is not caused by excess androgen, although it may be aggravated by excess androgen.
Hirsutism is a variably expressed manifestation of hyperandrogenemia. Approximately one-half of hyperandrogenemic females have hirsutism or an alternative pilosebaceous unit response to androgen (sometimes called a "hirsutism equivalent"), including acne (see 'Acne' below and 'Other' below). In the remaining one-half of hyperandrogenemic females, hirsutism does not develop, seemingly because their pilosebaceous unit is relatively insensitive to androgens.
Conversely, hirsutism may occur without elevated circulating levels of androgen or menstrual abnormality; this is defined as "idiopathic hirsutism" by adult hirsutism guidelines [16]. Idiopathic hirsutism accounts for approximately one-half of cases of mild hirsutism (Ferriman-Gallwey score 8 to 15) and one-sixth of cases of moderate or severe hirsutism (score >15) (see "Evaluation of premenopausal women with hirsutism"). These individuals should be followed clinically. If hirsutism or acne progress or a menstrual disorder develops, the patient should be reevaluated for hyperandrogenemia. If infertility becomes an issue in adulthood, the patient may be further evaluated for the possibility of ovulatory PCOS by ultrasonography to detect polycystic ovary morphology.
Because one-half of the cases of mild hirsutism are due to idiopathic hirsutism, adolescent PCOS guidelines from 2015 and 2017 consider only moderate to severe hirsutism to constitute clinical evidence of hyperandrogenism and also consider even this to be less reliable evidence of hyperandrogenism than persistent testosterone elevation determined by a reliable reference assay.
Acne — Excessive acne vulgaris is an important, but variably expressed, cutaneous manifestation of hyperandrogenemia [21]. Although acne is a common symptom among adolescents, meta-analysis indicates that 60 percent of adolescents with PCOS experience acne, a prevalence that is 2.8-fold higher than in adolescents without PCOS [22]. There is no uniformly accepted system for scoring acne severity, but a simple scoring system is graded on the basis of lesion counts (table 3) [23]. While comedonal acne is common in adolescents, the presence of moderate (>10 facial lesions) or severe inflammatory acne through the perimenarcheal years suggests hyperandrogenemia [12,24]. Such patients are often prescribed hormonal therapy for their acne [25], which suppresses androgen levels. In a group of young women with moderate acne without hirsutism, 25 percent had an elevated plasma free testosterone level [26]. Thus, moderate to severe inflammatory acne vulgaris that is persistent and poorly responsive to topical or oral antibiotic treatment is an indication to test for hyperandrogenemia [11,14].
Other — Alopecia is an unusual manifestation of hyperandrogenemia in adolescents. When it occurs, it may be either male pattern (affecting the fronto-temporo-occipital scalp) or female pattern (affecting the crown, typically manifesting early as a midline part widened in a "Christmas tree" pattern) [21,27]. Alternate cutaneous manifestations of hyperandrogenemia ("hirsutism equivalents"), like hirsutism and acne, are also variably expressed. They include seborrhea, hyperhidrosis, and hidradenitis suppurativa [21,28,29]. Hidradenitis suppurativa is characterized by painful inflammatory nodules in intertriginous areas, particularly the axillae. (See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis".)
Frank virilization (eg, rapid onset or progression of hirsutism, temporal hair recession, increased muscle bulk, voice deepening, and onset of clitoromegaly) is unusual in PCOS and should raise concerns for another cause of hyperandrogenemia. (See 'Differential diagnosis' below.)
Ovarian findings
Anovulation — In adolescents, the distinction between abnormal and physiologic anovulation is often delayed because patients, families, and clinicians alike often are unsure about the normal range of menstrual cycle variation. Normal adolescent menstrual cyclicity differs only slightly from that of reproductive-age adults. Cycles shorter than 19 days or longer than 90 days are abnormal at any stage; 75 percent of menstrual cycles range from 21 to 45 days during the first postmenarcheal (gynecologic) year, and 95 percent of females achieve 21- to 38-day adult menstrual cyclicity by their fourth gynecologic year [13,23,30,31].
Physiologic adolescent anovulation presents a paradox: The proportion of cycles that occur at regular intervals is substantially greater than the proportion that are mature ovulatory cycles [32]. Most "adolescent anovulation" is asymptomatic, with most menstrual bleeding occurring at 21- to 45-day cyclic intervals, even in the first postmenarcheal year (figure 2) [23]. This paradox arises because immature cyclic ovarian function is common during these intervals [33]. Most regular adolescent menstrual cycles that are not ovulatory by adult criteria have hormonal evidence of cyclic but immature follicular function that results in varying degrees of attenuated ovulation and, subsequently, attenuated luteal function (figure 2). Serum hormonal changes during such menstrual cycles of normal adolescents show that substantial but immature cyclic follicular development is occurring and that corpus luteum formation is inadequate to produce serum progesterone levels sufficient to support implantation and pregnancy [32,33].
The following menstrual dysfunctions suggest an abnormal extent of anovulation in adolescents (table 4) [14].
●Primary amenorrhea – Defined as lack of menarche by 15 years of age (or by 15 years bone age, if puberty onset was early) or more than three years after the onset of breast development.
●Secondary amenorrhea – Defined as >90 days without a menstrual period, after previously menstruating.
●Oligomenorrhea – During the first five postmenarcheal years, oligomenorrhea is defined as:
•Year 0 to <1 postmenarche: Fewer than six periods in the year (average cycle length >60 days between menstrual periods).
•Year 1 to <3 postmenarche: Fewer than eight periods per year, ie, missing more than four periods per year (average cycle length >45 days).
•Year 3 to perimenopause: Fewer than nine periods per year, ie, missing more than three periods per year (average cycle length >38 days). This is the adult criterion.
●Excessive abnormal uterine bleeding [31] – Excessive uterine bleeding (traditionally termed dysfunctional uterine bleeding) is defined as uterine bleeding that is excessively frequent, prolonged, or heavy:
•Excessive frequency is defined as bleeding more frequently than every 21 days in adolescents [30] (19 days in postmenarcheal year 1 [34]) or every 24 days in adults [31].
•Prolonged bleeding is defined as that lasting more than seven days in an adolescent [30] and more than eight days in an adult [31].
•Heavy uterine bleeding is usually associated with menses but may be intermenstrual [35]. It is defined by the International Federation of Gynecology and Obstetrics [31] as soaking pads or tampons sufficiently to interfere with physical, social, emotional, or material quality of life. Clues that heavy uterine bleeding is causing significant blood loss include the sensation of flooding or gushing, soaking through sanitary products more frequently than every two hours, or the passage of >1-cm clots [36]. An acute episode of heavy abnormal uterine bleeding may require immediate intervention to minimize or prevent further blood loss [31].
Excessive uterine bleeding may be functional (coagulopathy, ovulatory dysfunction, etc) or structural (polyps, etc) [31]. PCOS and coagulopathy are the most common causes of hospital admission for adolescents with excessive uterine bleeding [37,38]. Excessive uterine bleeding in anovulatory disorders results from shedding of a hyperplastic endometrium exposed to estrogen with insufficient progesterone. It usually arises from a normal proliferative endometrium that results from increased estrogen exposure during the prolonged follicular phase of immature or anovulatory cycles [39]. Endometrial biopsy in the broad population of patients with excessive nonstructural bleeding demonstrates that very few are completely acyclic and often shows evidence of diverse types of ovulatory dysfunction, including secretory changes consistent with luteal insufficiency and, sometimes, cystic glandular hyperplasia [40,41], which is a direct effect of androgen excess [42]. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis".)
An abnormal menstrual bleeding pattern ("symptomatic adolescent anovulation") is almost always the result of anovulatory cycles and is cause for concern if persistent. Symptomatic adolescent anovulation has an overall long-term persistence rate of approximately one-third (figure 3) [23,43]. In a study of adolescents with diverse menstrual irregularities of unknown etiology, as irregularity persisted for one to two years, actuarial risk for ongoing menstrual abnormality rose from 54 percent to 62 percent [43]. In a school population-based study, 51 percent of girls who became oligomenorrheic at 15 years of age after initially menstruating regularly remained oligomenorrheic at 18 years; no data exist for intervening intervals [44]. Studies of healthy school-aged females have shown that menstrual irregularity [44,45] and above-average androgen levels [45,46] are significant risk factors for PCOS or infertility in adulthood.
The risk for ongoing anovulation is greater for hyperandrogenic anovulatory adolescents than for nonhyperandrogenic ones. Among patients evaluated for abnormal menstrual bleeding who lack clinical signs of hyperandrogenism, approximately one-half have elevated androgen levels [47,48]. Reevaluation of such patients has shown that hyperandrogenemia resolves in approximately one-half; these individuals have physiologic adolescent anovulation. Among the other one-half, PCOS is the single most common cause of a residual ongoing hyperandrogenic menstrual disorder (figure 4) [44,49-51]. Furthermore, in the presence of clinical evidence of hyperandrogenism (eg, moderately severe hirsutism), hyperandrogenic oligo-anovulation (ie, PCOS) persisted for ≥3 years in more than 80 percent [15,44]. Indeed, in a small series of adolescents with elevated free testosterone and documented functional ovarian hyperandrogenism of the PCOS type, follow-up showed that all still had PCOS as young adults [15]. Thus, the actuarial curve describing the prognosis for symptomatic anovulation seems to be comprised of two components: one for hyperandrogenemic cases, one-half of which persist, and another for nonhyperandrogenemic cases, few of which persist (figure 3) [23]. The transient cases are due to physiologic anovulation. The persistent hyperandrogenemic cases are mostly PCOS, and the persistent nonhyperandrogenic cases have some form of hypogonadism.
In summary, uterine bleeding at intervals more frequent than every 19 days or less frequent than every 90 days is abnormal even in the first postmenarcheal year, and most cycles occur at 21- to 45-day intervals from the onset of menses (table 4). In the absence of clinical evidence of an endocrine disorder, a menstrual abnormality that goes on for one year has approximately a 50 percent probability of persisting and approximately one-half of such ongoing cases will have PCOS (figure 3). Lengthier persistence progressively increases the likelihood of an underlying anovulatory disorder. Clinical evidence of hyperandrogenism such as hirsutism increases the risk of PCOS.
The international guidelines and recommendations have urged caution before labeling hyperandrogenic adolescents as having PCOS if the menstrual abnormality has not persisted for one to two years [11-13]. Prior to that point in time, they recommend that such patients be assigned the provisional diagnosis of "at-risk for PCOS" to avoid misdiagnosing physiologic pubertal changes as PCOS. This recommendation has been coupled with one for longitudinal reevaluation [11,14]. These recommendations place a higher value on the accuracy of diagnosis than on early diagnosis.
However, earlier initiation of diagnostic testing is advisable if a combined oral contraceptive or other medical treatment is indicated to regulate menstrual cyclicity or to treat comorbidities suggestive of PCOS (eg, development of hirsutism, moderate inflammatory acne resistant to topical therapy, and acanthosis nigricans). This is because androgen-suppressive treatment will delay diagnosis, which also delays control of symptoms and increases the risk of developing endometrial hyperplasia and carcinoma (see "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'). Occasionally, excessive uterine bleeding may mandate emergency evaluation early in the course. Primary amenorrhea should be evaluated when recognized.
In adolescents in whom a provisional diagnosis of PCOS has been made, the recommendation for longitudinal reevaluation requires withdrawing the combined oral contraceptive for approximately three months when the patient is gynecologically mature (eg, upon graduation from high school) to determine persistence of hyperandrogenic anovulation; this maneuver should be coupled with contraceptive counseling because the infertility of PCOS is not absolute (ie, these girls may ovulate unpredictably).
While PCOS often begins during adolescence, it sometimes cannot be definitively diagnosed, because the menstrual abnormality may not become apparent until three or more years after the onset of menarche [23,52,53].
Polycystic ovaries — Polycystic ovaries themselves have little, if any, clinical manifestation other than their relationship to anovulation, which is a weak association, as discussed in a separate topic review. (See "Diagnostic evaluation of polycystic ovary syndrome in adolescents", section on 'Ultrasonography'.)
Associated metabolic features — Obesity and clinical manifestations of insulin resistance are strongly associated with PCOS, particularly among African-American women and Hispanic White women [54], but are not diagnostic criteria. The clinical manifestations of insulin resistance include acanthosis nigricans, metabolic syndrome, sleep-disordered breathing (SDB), and hepatic steatosis as an early reversible type of nonalcoholic fatty liver disease (NAFLD; sometimes called metabolic syndrome-associated fatty liver disease [MAFLD]). Insulin resistance is an important factor in the pathogenesis of PCOS because it participates in dysregulated steroidogenesis and excessive androgen production. (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents", section on 'Insulin-resistant hyperinsulinism'.)
Obesity — Obesity is present in approximately one-half of patients with PCOS (the reported prevalence varies from 30 to 75 percent) [55]. In a chart review of female adolescents referred to a pediatric endocrinology general weight management clinic, 18 percent were found to have PCOS [56]. In a pediatric endocrinology clinic PCOS study based in Chicago, obesity was the chief complaint in 20 percent of cases [57] and was frequently associated with another PCOS symptom (ie, hirsutism, menstrual abnormality, or acanthosis nigricans) [15]. On rare occasions, Cushingoid obesity due to severe insulin resistance precedes the development of PCOS [58]. PCOS is the most common obesity-related endocrine syndrome in females. Although the possibility exists that the relationship of PCOS to obesity is partly due to referral bias [59], most evidence indicates that body fat content is excessive for body mass index in women with PCOS [60-64]. Central (android) obesity is common and is defined by a waist circumference ≥88 cm in adolescents as well as adult women [65]. Whether the insulin resistance of PCOS is more fundamentally related to central obesity than global adiposity is controversial [62,63]. (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents", section on 'Obesity'.)
Manifestations of insulin resistance — Insulin resistance in PCOS is significant independently of obesity [5]. The metabolic features of insulin resistance are common in adolescents with PCOS and are aggravated by obesity [66,67]. Insulin resistance, as determined by gold-standard euglycemic clamp methodology, is present in approximately 16 percent of nonobese adolescents with PCOS [68] and in 50 to 75 percent of obese adolescents with PCOS, among whom approximately 60 percent have metabolic syndrome [69,70].
Insulin resistance in individuals with PCOS seems to be established during adolescence, judging from a similar prevalence of abnormal indices of insulin resistance in adolescent and adult PCOS in our case series of patients in the University of Chicago PCOS study (45 percent overall, unpublished data) [71]. Adolescents with PCOS are at increased risk for glucose intolerance and thus have significant pancreatic beta cell dysfunction similar to that seen in type 2 diabetes [72]. Glucose tolerance deteriorates over time [73]; approximately 10 percent of women with PCOS will have type 2 diabetes mellitus by 40 years of age [73-75]. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'IGT/type 2 diabetes'.)
The clinical manifestations of insulin resistance include acanthosis nigricans, metabolic syndrome, SDB, and hepatic steatosis:
●Acanthosis nigricans – Acanthosis nigricans is an indicator of insulin resistance and may be the presenting complaint of patients with PCOS [76]. It is usually but not necessarily accompanied by obesity and may precede the onset of classical PCOS symptoms [15,76]. Acrochordons (fibroepithelial skin tags) may be present within or around affected areas, particularly in adults [77,78]. (See "Acanthosis nigricans".)
●Metabolic syndrome – The metabolic syndrome results from the interaction of insulin resistance with obesity and age. It refers to the co-occurrence of metabolic risk factors for type 2 diabetes and cardiovascular disease, including abdominal obesity, hyperglycemia, elevated triglycerides, low high-density lipoprotein cholesterol, and hypertension. Three or more of these findings confer a high risk of cardiovascular disease in adults [79,80]. There is not yet consensus about the critical levels necessary for the diagnosis in adolescents. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)
Approximately 25 percent of adolescents with PCOS have metabolic syndrome. Ethnicity plays a role: Adult women from India and Norway have a higher prevalence of metabolic syndrome without obesity compared with White women in the United States; this may reflect both genetic and environmental factors [81]. Studies suggest that the prevalence of metabolic syndrome in adolescents with PCOS is related to obesity [82] and is approximately three times more common than expected for age, ethnicity, or body mass index in the general population [65,83,84]. The prevalence of dyslipidemia is generally low but is related to the degree of obesity, insulin resistance, and hyperandrogenism [70,82,85,86].
●Diabetes mellitus – The combination of insulin resistance and a failing pancreatic beta cell insulin response results in type 2 diabetes. In a study of 493 overweight and obese women with PCOS aged 11 to 21 years, type 2 diabetes developed in 23, with the diagnosis of diabetes made, on average, 1.8 years after that of PCOS [87]. Compared with published rates of type 2 diabetes in youth without PCOS, those with PCOS and obesity have an 18-fold increased risk of developing diabetes. In a smaller case series (n = 36) in which all the adolescents with PCOS had an oral glucose tolerance test, 8.6 percent were found to have type 2 diabetes [65].
●SDB – SDB is independently associated with hyperandrogenism (male sex or PCOS), obesity, and insulin resistance in adults [5]. Obstructive sleep apnea as determined by polysomnography was associated with metabolic syndrome in two of three studies of obese adolescents with PCOS (n = 14 to 28 subjects) [84,88,89]. However, all of these studies showed some evidence of SDB (eg, reduced sleep efficiency) in association with metabolic syndrome. Severity of the SDB was correlated with the number of features of metabolic syndrome present [89]. While insulin resistance/metabolic syndrome is a risk factor for PCOS, SDB is in turn a risk factor for insulin resistance/metabolic syndrome; thus, there appears to be a bidirectional causal link between insulin resistance and SDB [5].
●Hepatic steatosis – Hepatic steatosis was identified by magnetic resonance imaging in 49 percent of obese adolescents with PCOS versus 14 percent of obese controls [90]. It is related to excess deposition of visceral fat [90] and, in women, to hyperandrogenism [91]. Hepatic steatosis (an early and reversible form of NAFLD) is defined by over 5 percent hepatic fat in the absence of excessive alcohol intake [91]. Hepatic steatosis is associated with changes in the gut microbiome in obese girls with PCOS [92]. (See "Overview of the health consequences of obesity in children and adolescents", section on 'Nonalcoholic fatty liver disease' and "Nonalcoholic fatty liver disease in children and adolescents".)
●Pseudo-Cushing syndrome and pseudo-acromegaly – Uncommon clinical manifestations of severe insulin resistance that are occasionally associated with PCOS in children include pseudo-Cushing syndrome and pseudo-acromegaly [58]. These may begin prepubertally and precede the development of PCOS. (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents", section on 'Insulin-resistant hyperinsulinism'.)
Psychological issues — PCOS in adolescents is associated with depressive symptoms and other psychological issues. This was shown in a case series of 28 adolescents with PCOS who had a significantly higher prevalence of major depressive symptoms than 31 controls (21 versus 3 percent) [93]. Cohort-, community-, and population-based studies have demonstrated that women with PCOS have an approximately 17 to 50 percent increased prevalence of depressive symptoms and anxiety versus controls [94-98]. Distress with body appearance may contribute to these symptoms [96]. Some reports suggest that women with PCOS have an increased prevalence of disordered eating [95] and autism spectrum disorders [99] and that their offspring also have an increased prevalence of autism spectrum disorders [99] along with attention deficit hyperactivity disorder [94,100].
PCOS subjects may be at risk for gender dysphoria, as suggested by three series of untreated female-to-male transgender adults, two-thirds of whom had significantly increased testosterone levels and associations with diverse PCOS criteria [101-103]. However, these conclusions are suspect because occult testosterone use was not consistently ruled out and the studies used suboptimal testosterone assay methodology.
DIFFERENTIAL DIAGNOSIS — Although PCOS accounts for over 80 percent of cases of androgen excess in postmenarcheal females, there are a number of conditions other than PCOS that present with hyperandrogenism [5]. Often, these disorders have similar clinical findings and are difficult to distinguish from PCOS or one another. The evaluation for hyperandrogenism utilizes pelvic ultrasonography and specific endocrine tests to differentiate among the many causes of hyperandrogenism, as reviewed next. This diagnostic work-up is discussed in a separate topic review. (See "Diagnostic evaluation of polycystic ovary syndrome in adolescents", section on 'Screening tests to exclude common non-PCOS causes of hyperandrogenemia'.)
The following conditions share many presenting features with PCOS (table 5):
●Physiologic adolescent anovulation – Physiologic adolescent anovulation is the most common cause of adolescent menstrual irregularity. It may present in approximately one-quarter of cases with hyperandrogenemia without clinical evidence of androgen excess, but the hyperandrogenemia and anovulation do not persist. (See 'Anovulation' above.)
●Virilizing congenital adrenal hyperplasia (CAH) – CAH is a term historically applied to disorders that arise from an autosomal recessive deficiency in the activity of an adrenocortical enzyme step necessary for corticosteroid biosynthesis.
Nonclassic ("late-onset") CAH is the second most common cause of androgen excess that presents in adolescence: It accounts for 4.2 percent of hyperandrogenic women worldwide, the prevalence varying from 0.1 to 2 percent in the general United States population, to 4 percent in Ashkenazi Jews, to 10 percent in countries in the Mediterranean region and Middle East [104]. Nonclassic CAH usually results from a mild deficiency of 21-hydroxylase, is only mildly hyperandrogenic, and lacks the genital ambiguity of classic CAH. Affected patients may present with premature pubarche (appearance of sexual hair), adolescent- or adult-onset hirsutism, and/or symptoms of anovulation. Affected females may have polycystic ovaries and elevated serum luteinizing hormone (LH) levels. The diagnosis is strongly suggested by elevated levels of serum 17-hydroxyprogesterone. CAH is treated with glucocorticoid replacement therapy [105]. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Classic CAH due to 21-hydroxylase deficiency is the most well-known form of CAH. It is almost always diagnosed during infancy, presenting with genital ambiguity due to congenital virilization of affected females, and may be associated with a salt-losing crisis. Affected individuals may develop signs and symptoms resembling PCOS during adolescence, especially if their disorder is poorly controlled by glucocorticoid therapy. Symptoms may include menstrual irregularity, hirsutism, and clitoromegaly. Polycystic ovaries can result from the direct effects of virilizing extraovarian androgen excess in CAH [105] and other conditions (eg, transgender individuals who take testosterone) [42]. Rarely, CAH can be complicated by virilizing adrenal rests of the ovaries [105-107]. Adrenal progesterone excess in CAH may be sufficient in the absence of androgen excess to cause ovarian dysfunction by inhibiting LH pulsatility [108,109]. (See "Genetics and clinical presentation of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)
Even in patients who are well controlled on glucocorticoid therapy, classic CAH and, to a smaller extent, nonclassic CAH are associated with a PCOS-type of functional ovarian hyperandrogenism that is responsible for persistent menstrual irregularity [105,110]. This secondary PCOS appears to result from epigenetic programming by in utero hyperandrogenism. (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents".)
Other forms of CAH associated that may resemble PCOS include:
•Deficiency of 3ß-HSD (HSD3B2) in genetic females usually presents in infancy with mild genital ambiguity accompanied by symptoms of cortisol and aldosterone deficiency. The disorder is not captured by newborn screens for CAH, so mildly affected patients may not be identified as newborns. Occasionally, undiagnosed patients come to attention during adolescence, with signs of androgen excess that resemble PCOS, including premature pubarche, acne, and hirsutism with menstrual disturbances. The diagnosis of nonclassic 3ß-HSD deficiency should be suspected when the dehydroepiandrosterone sulfate (DHEAS) level is very elevated [108,111]. The diagnosis is made based upon 17-hydroxypregnenolone elevation >10 standard deviations above the normal mean (ie, >4500 ng/dL or 150 nmol/L) after adrenocorticotropic hormone (ACTH) stimulation and confirmed by molecular testing [112,113] (see "Uncommon congenital adrenal hyperplasias", section on '3-beta-hydroxysteroid dehydrogenase type 2 deficiency'). Lesser elevations of DHEAS and 17-hydroxypregnenolone usually are due to the primary functional adrenal hyperandrogenism of PCOS (table 5), which the older literature confused with 3ß-HSD deficiency. (See "Diagnostic evaluation of polycystic ovary syndrome in adolescents" and "Etiology and pathophysiology of polycystic ovary syndrome in adolescents".)
•Deficiency of 11β-hydroxylase (CYP11B1) classically presents with ambiguous genital appearance due to congenital virilization accompanied by hypertension. Rarely, in <1 percent of hyperandrogenic women, it presents in adolescence in its nonclassic form with mild hyperandrogenism; hypertension and hypokalemia are not necessarily present [114,115]. Only an 11-deoxycortisol response to ACTH >5 times greater than the upper limit of normal (>4000 ng/dL [116 nmol/L]) has been shown to be specific for mutation detection [115]. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency'.)
●Related congenital disorders of adrenal steroid metabolism or action – Glucocorticoid resistance is caused by defects in glucocorticoid receptor signaling. It is a rare congenital form of ACTH-dependent adrenal hyperandrogenism that results from inadequate negative feedback by cortisol, with consequent excessive ACTH release [116]. (See "Causes of primary adrenal insufficiency in children", section on 'End-organ unresponsiveness'.)
Cortisone reductase deficiency is a rare autosomal recessive disorder in which there is a defect in the peripheral metabolism of cortisol [117]. Increased ACTH production is necessary to compensate for the excessively rapid cortisol turnover resulting from failure to regenerate cortisol from cortisone in peripheral tissues. This disorder is caused either by deficiency of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which is functionally the major cortisone reductase [118], or, more commonly, by deficiency of hexose-6-phosphate dehydrogenase (H6PDH), which is a cofactor for cortisone reductase (this form is known as "apparent" cortisone reductase deficiency) [119]. (See "Uncommon congenital adrenal hyperplasias", section on 'Hexose-6-phosphate-dehydrogenase deficiency (apparent cortisone reductase deficiency)'.)
Apparent DHEA sulfotransferase deficiency is due to a genetic defect in DHEA metabolism that does not affect corticosteroid secretion [120,121]. Inactivating mutation of the sulfate donor to SULT2A1 (3'- phosphoadenosine-5'-phosphosulfate synthase 2 [PAPSS2]) prevents sulfation of DHEA and causes high DHEA yet undetectable to low DHEAS levels. In affected females, premature pubarche preceded hyperandrogenic anovulation and a skeletal growth defect was usually present (see "Uncommon congenital adrenal hyperplasias", section on 'PAPSS2 deficiency (apparent DHEA sulfotransferase deficiency)'). A similar pattern of impaired hepatic DHEA sulfation can be caused by portosystemic shunting, as described under "other causes" below.
●Cushing syndrome – Diverse forms of Cushing syndrome due to adrenal hyperplasia are, on rare occasions, associated with hyperandrogenic anovulation [122,123]. Although not main features, polycystic ovaries can sometimes occur [122]. (See 'Manifestations of insulin resistance' above and "Epidemiology and clinical manifestations of Cushing's syndrome".)
●Virilizing tumors – Virilizing tumors of the adrenals or ovaries are rare causes of hyperandrogenism [124,125]. However, they are serious as more than one-half are malignant [16] (see "Li-Fraumeni syndrome"). In most cases, these tumors cause rapid onset of virilizing symptoms, including hirsutism, temporal hair recession, increased muscle bulk, voice deepening, and onset of clitoromegaly without genital ambiguity. Other tumor manifestations may include Cushingoid changes and abdominal or pelvic masses. A substantial minority of these tumors are mildly hyperandrogenic, indolent in onset, and mimic PCOS in their presentation. Virilization during pregnancy may occur because of androgen hypersecretion by chorionic gonadotropin-dependent ovarian cysts (either luteoma or hyperreactio luteinalis) [126]. Acanthosis nigricans may occur with virilizing tumors, though it is an uncommon feature and is more suggestive of PCOS [127]. (See "Adrenal hyperandrogenism", section on 'Adrenal tumors'.)
●Ovarian steroidogenic blocks – Steroidogenic blocks in ovarian steroid synthetic pathways, such as those caused by 3ß-HSD [128], the adrenal manifestations of which were noted above, or aromatase deficiency [129], can cause hyperandrogenism in association with grossly polycystic ovaries and elevated LH levels. Ovarian 17-ketosteroid reductase deficiency has been reported to be responsible for a PCOS-like picture in two families, but there has been no molecular confirmation of an underlying mutation [130,131].
●Hyperprolactinemia – Serum prolactin values more than 25 ng/mL usually have an identifiable cause other than PCOS [132]. Most common are pituitary adenoma and treatment with dopamine antagonists. Hyperandrogenism occurs in approximately 40 percent of hyperprolactinemic women, and approximately 85 percent of those with hyperandrogenism have galactorrhea [133]. The combination of hirsutism, galactorrhea, and amenorrhea has been termed the Forbes-Albright syndrome [133]. Some patients also have polycystic ovaries on ultrasound [134]. Hyperprolactinemia is less prevalent than CAH [71]. The hyperandrogenism results from multiple effects of prolactin excess on adrenal androgen production and androgen metabolism [133]. The meager available evidence suggests that the hyperandrogenemia is dexamethasone-suppressible [133] and that dopaminergic agonist treatment normalizes the androgenic abnormalities [135]. (See "Clinical manifestations and evaluation of hyperprolactinemia".)
●Insulin-resistance disorders – All extreme states of insulin-resistant hyperinsulinemia, such as congenital diabetes mellitus caused by insulin-receptor mutations (eg, Donohue syndrome or leprechaunism) or lipodystrophy, are accompanied by PCOS [136,137]. Less extreme, but nevertheless severe, insulin resistance is also associated with PCOS in the setting of pseudo-Cushing syndrome and pseudo-acromegalic gigantism, disorders that mimic glucocorticoid excess and childhood growth hormone excess clinically, without excess production of these hormones. In these disorders, the symptoms of insulin resistance often precede the PCOS [58] (see "Establishing the diagnosis of Cushing's syndrome", section on 'Exclude physiologic hypercortisolism'). In addition, modest forms of insulin resistance also are associated with PCOS, including type 1 [138,139] and type 2 diabetes mellitus [140,141]. Elevated insulin levels seem to promote PCOS by increasing the activity of steroidogenic enzymes in the ovaries and adrenal glands, similarly to insulin-like growth factor 1 (IGF-1). (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents".)
●Acromegaly – Acromegaly, which is caused by pituitary growth hormone oversecretion, is associated with PCOS, and its presentation is usually insidious [142]. The growth hormone excess causes elevated levels of IGF-1, which probably cause PCOS by increasing the activity of multiple steroidogenic enzymes in the ovaries and adrenal glands. Acromegaly must be distinguished from pseudo-acromegaly, a more insulin-resistant state that likewise is associated with PCOS [58]. (See "Causes and clinical manifestations of acromegaly" and "Etiology and pathophysiology of polycystic ovary syndrome in adolescents", section on 'Secondary functional ovarian hyperandrogenism'.)
●Thyroid dysfunction – Thyroid dysfunction interferes with sex hormone metabolism and causes menstrual irregularity. Hypothyroidism also causes multicystic ovarian changes and low serum levels of sex hormone-binding globulin. It may cause confusion with hyperandrogenism by causing coarsening of hair, which can be mistaken for hirsutism [23]. An increased prevalence of autoimmune thyroiditis has been suspected in PCOS [9]. (See "Acquired hypothyroidism in childhood and adolescence".)
●Drugs – Anabolic steroids cause virilization in women and may present with features similar to those of virilizing tumors. Virilizing amounts of endogenous androgens [105] or exogenous androgens [42,143] cause polycystic ovaries. Valproic acid directly augments the transcription of the steroidogenic gene CYP17 that encodes cytochrome P450c17 and can cause elevated serum testosterone (figure 5) [144,145]. Epilepsy may be associated with PCOS independently of drug treatment [146]. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'High-risk groups'.)
●Other causes – Other rare conditions that are included in the differential diagnosis of PCOS include:
•Differences/disorders of sex development – Rarely, phenotypic females have mixed ovarian and testicular tissue (either ovotestis, or ovary and testis). The development of the internal and external genitalia in these individuals can be quite variable. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
•Portosystemic shunting – The PCOS phenotype can occur as a complication of portal hypertension complicated by portosystemic shunting [147,148]. The hyperandrogenism of this condition has been attributed to a combination of impaired hepatic DHEA sulfation, which results in an increase in DHEA available for testosterone formation, and hyperinsulinemia, which results in postprandial hypoglycemia and ovarian hyperandrogenism [149].
●Idiopathic hyperandrogenism – Approximately 8 percent of hyperandrogenic patients have no identifiable ovarian or adrenal source of androgen despite thorough testing. Those who present with hirsutism and normal menses, but lack a polycystic ovary, are traditionally given this diagnosis.
Obesity may account for most cases of idiopathic hyperandrogenism. However, obesity can sometimes cause hyperandrogenic anovulation ("the atypical PCOS of obesity") [150], and symptoms can be expected to correct with weight loss [151]. In our series of PCOS patients in Chicago who met National Institutes of Health diagnostic criteria, the subset of patients with no demonstrable ovarian or adrenal dysfunction was obese [150]. We postulated that their excess adipose tissue was both the cause of the testosterone excess (since adipocyte 17β-hydroxysteroid dehydrogenase type 5 has the capacity to convert circulating androstenedione to testosterone in response to insulin) and the cause of the ovulatory dysfunction (since obesity suppresses LH levels). These patients were characterized by mild hyperandrogenemia, and most had normal-size ovaries and normal LH, DHEAS, and anti-müllerian hormone levels. (See "Etiology and pathophysiology of polycystic ovary syndrome in adolescents", section on 'Primary functional ovarian hyperandrogenism'.)
It is possible that some cases of idiopathic hyperandrogenism are caused by hereditary defects in peripheral metabolism of steroids (a theoretical example being decreased hepatic DHEA sulfation).
OTHER RESOURCES — The following online resources are available to patients with PCOS and their families:
●PCOS Resources for a Healthier You – From the Center for Young Women's Health of Boston Children's Hospital [152]
●Polycystic Ovary Syndrome: A Guide for Families – From the Pediatric Endocrine Society and the American Academy of Pediatrics [153]
●PCOS Challenge – A patient support and advocacy organization [154]
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Polycystic ovary syndrome" and "Society guideline links: Hirsutism".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Polycystic ovary syndrome (The Basics)")
●Beyond the Basics topic (see "Patient education: Polycystic ovary syndrome (PCOS) (Beyond the Basics)")
SUMMARY
●Consequences of polycystic ovary syndrome (PCOS) – Recognizing and treating PCOS in adolescents is important for management of the symptoms of hyperandrogenism and abnormal menses (ovulatory dysfunction). In addition, these patients are at increased risk of developing endometrial hyperplasia and carcinoma, type 2 diabetes mellitus, metabolic syndrome, and, possibly, cardiovascular disease.
●Diagnostic criteria – Diagnostic criteria for adolescent PCOS have been developed by international consensus (table 2). These are the diagnostic criteria developed by the National Institutes of Health for adults, adapted for gynecologic age (see 'Adolescents' above):
•Evidence of hyperandrogenism (eg, hirsutism, persistent acne, pattern alopecia), particularly if confirmed by a persistently elevated serum testosterone, and
•A menstrual pattern that is abnormal for gynecologic age (eg, menstrual irregularity, oligo- or amenorrhea, excessive bleeding) (table 4) and that persists for one to two years
●Clinical features – Adolescent females with PCOS may present with hirsutism, treatment-resistant acne, menstrual irregularities, acanthosis nigricans, and/or obesity. Any one of these findings may initially be the sole feature of the syndrome, although one feature is not sufficient to establish the diagnosis. Some patients have other cutaneous symptoms of hyperandrogenism, including an abnormal degree of inflammatory acne. (See 'Clinical features' above.)
•Hirsutism – Hirsutism is defined clinically as an abnormal amount of sexual hair that appears in a male pattern. It is a variably expressed manifestation of hyperandrogenemia. Approximately two-thirds of hyperandrogenemic females have hirsutism. Conversely, hirsutism may occur without elevated circulating levels of androgen ("idiopathic hirsutism"). (See 'Hirsutism' above.)
•Acne – An abnormal degree of acne is suggested by moderate or more comedonal acne (>10 facial lesions) in early puberty, moderate or more inflammatory acne through the perimenarcheal years, or acne that is persistent and poorly responsive to topical dermatologic therapy (table 3). (See 'Acne' above.)
•Menstrual dysfunction – Menstrual dysfunctions that suggest abnormal degrees of anovulation in adolescence include fewer than six periods per year during postmenarcheal year 2, fewer than nine periods per year during or after postmenarcheal year 5, or excessive menstrual bleeding (table 4). (See 'Anovulation' above.)
●Differential diagnosis – Although PCOS accounts for approximately 85 percent of androgen excess in adolescent females, there are a number of conditions other than PCOS that present with hyperandrogenism (table 5). The evaluation for a patient with hyperandrogenism utilizes pelvic ultrasonography and specific endocrine tests to exclude these disorders and establish the diagnosis of PCOS. (See 'Differential diagnosis' above and "Diagnostic evaluation of polycystic ovary syndrome in adolescents".)
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