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Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents

Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents
Authors:
Natalie Shaw, MD, MMSc
Robert L Rosenfield, MD
Section Editors:
Amy B Middleman, MD, MPH, MS Ed
Mitchell E Geffner, MD
Deputy Editor:
Diane Blake, MD
Literature review current through: Mar 2023. | This topic last updated: Jan 26, 2022.

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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  88. de Sousa G, Schlüter B, Menke T, et al. A comparison of polysomnographic variables between adolescents with polycystic ovarian syndrome with and without the metabolic syndrome. Metab Syndr Relat Disord 2011; 9:191.
  89. Simon S, Rahat H, Carreau AM, et al. Poor Sleep Is Related to Metabolic Syndrome Severity in Adolescents With PCOS and Obesity. J Clin Endocrinol Metab 2020; 105.
  90. Cree-Green M, Bergman BC, Coe GV, et al. Hepatic Steatosis is Common in Adolescents with Obesity and PCOS and Relates to De Novo Lipogenesis but not Insulin Resistance. Obesity (Silver Spring) 2016; 24:2399.
  91. Grossmann M, Wierman ME, Angus P, Handelsman DJ. Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease. Endocr Rev 2019; 40:417.
  92. Jobira B, Frank DN, Silveira LJ, et al. Hepatic steatosis relates to gastrointestinal microbiota changes in obese girls with polycystic ovary syndrome. PLoS One 2021; 16:e0245219.
  93. Çoban ÖG, Tulacı ÖD, Adanır AS, Önder A. Psychiatric Disorders, Self-Esteem, and Quality of Life in Adolescents with Polycystic Ovary Syndrome. J Pediatr Adolesc Gynecol 2019; 32:600.
  94. Berni TR, Morgan CL, Berni ER, Rees DA. Polycystic Ovary Syndrome Is Associated With Adverse Mental Health and Neurodevelopmental Outcomes. J Clin Endocrinol Metab 2018; 103:2116.
  95. Tay CT, Teede HJ, Hill B, et al. Increased prevalence of eating disorders, low self-esteem, and psychological distress in women with polycystic ovary syndrome: a community-based cohort study. Fertil Steril 2019; 112:353.
  96. Alur-Gupta S, Chemerinski A, Liu C, et al. Body-image distress is increased in women with polycystic ovary syndrome and mediates depression and anxiety. Fertil Steril 2019; 112:930.
  97. Dokras A, Stener-Victorin E, Yildiz BO, et al. Androgen Excess- Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome. Fertil Steril 2018; 109:888.
  98. Greenwood EA, Yaffe K, Wellons MF, et al. Depression Over the Lifespan in a Population-Based Cohort of Women With Polycystic Ovary Syndrome: Longitudinal Analysis. J Clin Endocrinol Metab 2019; 104:2809.
  99. Katsigianni M, Karageorgiou V, Lambrinoudaki I, Siristatidis C. Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry 2019; 24:1787.
  100. Cesta CE, Öberg AS, Ibrahimson A, et al. Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding? Psychol Med 2020; 50:616.
  101. Baba T, Endo T, Ikeda K, et al. Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan. J Sex Med 2011; 8:1686.
  102. Becerra-Fernández A, Pérez-López G, Román MM, et al. Prevalence of hyperandrogenism and polycystic ovary syndrome in female to male transsexuals. Endocrinol Nutr 2014; 61:351.
  103. Mueller A, Gooren LJ, Naton-Schötz S, et al. Prevalence of polycystic ovary syndrome and hyperandrogenemia in female-to-male transsexuals. J Clin Endocrinol Metab 2008; 93:1408.
  104. Carmina E, Dewailly D, Escobar-Morreale HF, et al. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Hum Reprod Update 2017; 23:580.
  105. Barnes RB, Rosenfield RL, Ehrmann DA, et al. Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab 1994; 79:1328.
  106. Zaarour MG, Atallah DM, Trak-Smayra VE, Halaby GH. Bilateral ovary adrenal rest tumor in a congenital adrenal hyperplasia following adrenalectomy. Endocr Pract 2014; 20:e69.
  107. Chen HD, Huang LE, Zhong ZH, et al. Ovarian Adrenal Rest Tumors Undetected by Imaging Studies and Identified at Surgery in Three Females with Congenital Adrenal Hyperplasia Unresponsive to Increased Hormone Therapy Dosage. Endocr Pathol 2017; 28:146.
  108. Rosenfield RL, Rich BH, Wolfsdorf JI, et al. Pubertal presentation of congenital delta 5-3 beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 1980; 51:345.
  109. Bachelot A, Chakhtoura Z, Plu-Bureau G, et al. Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia. Eur J Endocrinol 2012; 167:499.
  110. Ghizzoni L, Virdis R, Vottero A, et al. Pituitary-ovarian responses to leuprolide acetate testing in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 1996; 81:601.
  111. Sanchez R, Rhéaume E, Laflamme N, et al. Detection and functional characterization of the novel missense mutation Y254D in type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene of a female patient with nonsalt-losing 3 beta HSD deficiency. J Clin Endocrinol Metab 1994; 78:561.
  112. Lutfallah C, Wang W, Mason JI, et al. Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2002; 87:2611.
  113. Mermejo LM, Elias LL, Marui S, et al. Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. J Clin Endocrinol Metab 2005; 90:1287.
  114. Zachmann M, Tassinari D, Prader A. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients. J Clin Endocrinol Metab 1983; 56:222.
  115. Joehrer K, Geley S, Strasser-Wozak EM, et al. CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Hum Mol Genet 1997; 6:1829.
  116. Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder. J Clin Endocrinol Metab 2008; 93:1563.
  117. Qin K, Rosenfield RL. Mutations of the hexose-6-phosphate dehydrogenase gene rarely cause hyperandrogenemic polycystic ovary syndrome. Steroids 2011; 76:135.
  118. Lawson AJ, Walker EA, Lavery GG, et al. Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1. Proc Natl Acad Sci U S A 2011; 108:4111.
  119. Lavery GG, Walker EA, Tiganescu A, et al. Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. J Clin Endocrinol Metab 2008; 93:3827.
  120. Noordam C, Dhir V, McNelis JC, et al. Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 2009; 360:2310.
  121. Oostdijk W, Idkowiak J, Mueller JW, et al. PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations. J Clin Endocrinol Metab 2015; 100:E672.
  122. Kaltsas GA, Korbonits M, Isidori AM, et al. How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing's syndrome? Clin Endocrinol (Oxf) 2000; 53:493.
  123. Fegan PG, Sandeman DD, Krone N, et al. Cushing's syndrome in women with polycystic ovaries and hyperandrogenism. Nat Clin Pract Endocrinol Metab 2007; 3:778.
  124. Azziz R, Sanchez LA, Knochenhauer ES, et al. Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 2004; 89:453.
  125. Carmina E, Rosato F, Jannì A, et al. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab 2006; 91:2.
  126. Hensleigh PA, Woodruff JD. Differential maternal-fetal response to androgenizing luteoma or hyperreactio luteinalis. Obstet Gynecol Surv 1978; 33:262.
  127. Givens JR, Kerber IJ, Wiser WL, et al. Remission of acanthosis nigricans associated with polycystic ovarian disease and a stromal luteoma. J Clin Endocrinol Metab 1974; 38:347.
  128. Barnes RB, Rosenfield RL, Burstein S, Ehrmann DA. Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med 1989; 320:559.
  129. Conte FA, Grumbach MM, Ito Y, et al. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 1994; 78:1287.
  130. Pang SY, Softness B, Sweeney WJ 3rd, New MI. Hirsutism, polycystic ovarian disease, and ovarian 17-ketosteroid reductase deficiency. N Engl J Med 1987; 316:1295.
  131. Toscano V, Balducci R, Bianchi P, et al. Ovarian 17-ketosteroid reductase deficiency as a possible cause of polycystic ovarian disease. J Clin Endocrinol Metab 1990; 71:288.
  132. Filho RB, Domingues L, Naves L, et al. Polycystic ovary syndrome and hyperprolactinemia are distinct entities. Gynecol Endocrinol 2007; 23:267.
  133. Glickman SP, Rosenfield RL, Bergenstal RM, Helke J. Multiple androgenic abnormalities, including elevated free testosterone, in hyperprolactinemic women. J Clin Endocrinol Metab 1982; 55:251.
  134. Futterweit W, Krieger DT. Pituitary tumors associated with hyperprolactinemia and polycystic ovarian disease. Fertil Steril 1979; 31:608.
  135. Vermeulen A, Andó S, Verdonck L. Prolactinomas, testosterone-binding globulin, and androgen metabolism. J Clin Endocrinol Metab 1982; 54:409.
  136. Ehrmann DA, Barnes RB, Rosenfield RL. Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 1995; 16:322.
  137. Lungu AO, Zadeh ES, Goodling A, et al. Insulin resistance is a sufficient basis for hyperandrogenism in lipodystrophic women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2012; 97:563.
  138. Codner E, Escobar-Morreale HF. Clinical review: Hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus. J Clin Endocrinol Metab 2007; 92:1209.
  139. Codner E, Iñíguez G, Villarroel C, et al. Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus. J Clin Endocrinol Metab 2007; 92:4742.
  140. Conn JJ, Jacobs HS, Conway GS. The prevalence of polycystic ovaries in women with type 2 diabetes mellitus. Clin Endocrinol (Oxf) 2000; 52:81.
  141. Peppard HR, Marfori J, Iuorno MJ, Nestler JE. Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care 2001; 24:1050.
  142. Kaltsas GA, Mukherjee JJ, Jenkins PJ, et al. Menstrual irregularity in women with acromegaly. J Clin Endocrinol Metab 1999; 84:2731.
  143. Pache TD, Chadha S, Gooren LJ, et al. Ovarian morphology in long-term androgen-treated female to male transsexuals. A human model for the study of polycystic ovarian syndrome? Histopathology 1991; 19:445.
  144. Nelson-DeGrave VL, Wickenheisser JK, Cockrell JE, et al. Valproate potentiates androgen biosynthesis in human ovarian theca cells. Endocrinology 2004; 145:799.
  145. Isojärvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms. Seizure 2008; 17:111.
  146. Herzog AG. Menstrual disorders in women with epilepsy. Neurology 2006; 66:S23.
  147. Speiser PW, Susin M, Sasano H, et al. Ovarian hyperthecosis in the setting of portal hypertension. J Clin Endocrinol Metab 2000; 85:873.
  148. Satoh M, Yokoya S, Hachiya Y, et al. Two hyperandrogenic adolescent girls with congenital portosystemic shunt. Eur J Pediatr 2001; 160:307.
  149. Bas S, Guran T, Atay Z, et al. Premature pubarche, hyperinsulinemia and hypothyroxinemia: novel manifestations of congenital portosystemic shunts (Abernethy malformation) in children. Horm Res Paediatr 2015; 83:282.
  150. Rosenfield RL, Mortensen M, Wroblewski K, et al. Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test. Hum Reprod 2011; 26:3138.
  151. Escobar-Morreale HF, Santacruz E, Luque-Ramírez M, Botella Carretero JI. Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update 2017; 23:390.
  152. Center for Young Women's Health. PCOS (polycystic ovary syndrome). Available at: https://youngwomenshealth.org/2014/02/25/polycystic-ovary-syndrome/ (Accessed on March 15, 2018).
  153. Pediatric Endocrine Society and the American Academy of Pediatrics: Polycystic Ovary Syndrome: A guide for Patients and Parents. Available at: https://www.pedsendo.org/assets/patients_families/Educational_Materials/PolycysticOvarySyndrome.pdf (Accessed on March 15, 2018).
  154. National Polycystic Ovary Syndrome Association. PCOS Challenge. Available at: https://pcoschallenge.org/ (Accessed on January 18, 2022).
Topic 5852 Version 47.0

References

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2 : Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis.

3 : Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood.

4 : Is There Really Increased Cardiovascular Morbidity in Women with Polycystic Ovary Syndrome?

5 : The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.

6 : Amenorrhea associated with bilateral polycystic ovaries

7 : Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.

8 : Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.

9 : The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report.

10 : The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report.

11 : The Diagnosis of Polycystic Ovary Syndrome during Adolescence.

12 : An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

13 : Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.

14 : Perspectives on the International Recommendations for the Diagnosis and Treatment of Polycystic Ovary Syndrome in Adolescence.

15 : Adolescent polycystic ovary syndrome due to functional ovarian hyperandrogenism persists into adulthood.

16 : Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline.

17 : Clinical assessment of body hair growth in women.

18 : The prevalence of upper lip hair in black and white girls during puberty: a new standard.

19 : Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society.

20 : Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society.

21 : Role of hormones in pilosebaceous unit development.

22 : Prevalence of acne vulgaris among women with polycystic ovary syndrome: a systemic review and meta-analysis.

23 : The Diagnosis of Polycystic Ovary Syndrome in Adolescents.

24 : Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study.

25 : Evidence-based recommendations for the diagnosis and treatment of pediatric acne.

26 : Plasma androgens in women with acne vulgaris.

27 : Female Pattern Hair Loss and Androgen Excess: A Report From the Multidisciplinary Androgen Excess and PCOS Committee.

28 : Polycystic ovary syndrome in adolescence.

29 : Hidradenitis suppurativa/Acne inversa: an endocrine skin disorder?

30 : ACOG Committee Opinion No. 651: Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign.

31 : The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions.

32 : Clinical review: Adolescent anovulation: maturational mechanisms and implications.

33 : Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity.

34 : Variation of the human menstrual cycle through reproductive life.

35 : The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding.

36 : Evaluation and management of heavy menstrual bleeding in adolescents: the role of the hematologist.

37 : Polycystic Ovary Syndrome: An Under-recognized Cause of Abnormal Uterine Bleeding in Adolescents Admitted to a Children's Hospital.

38 : Adolescents Presenting to the Emergency Department with Heavy Menstrual Bleeding.

39 : Impaired estrogen-induced luteinizing hormone release in young women with anovulatory dysfunctional uterine bleeding.

40 : Dysfunctional uterine bleeding. A classification.

41 : Histological and histochemical study of endometrium in dysfunctional uterine haemorrhage.

42 : Histopathological effects of exogenously administered testosterone in 19 female to male transsexuals.

43 : The prognosis for adolescents with menstrual abnormalities.

44 : Predictive value of menstrual cycle pattern, body mass index, hormone levels and polycystic ovaries at age 15 years for oligo-amenorrhoea at age 18 years.

45 : Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: Northern Finland Birth Cohort 1986 study.

46 : Endocrine determinants of fertility: serum androgen concentrations during follow-up of adolescents into the third decade of life.

47 : Menstrual irregularities in adolescents: hormonal pattern and ovarian morphology.

48 : Circadian variations of luteinizing hormone can have two different profiles in adolescent anovulation.

49 : Longitudinal evaluation of the different gonadotropin pulsatile patterns in anovulatory cycles of young girls.

50 : Longitudinal change of sonographic ovarian aspects and endocrine parameters in irregular cycles of adolescence.

51 : Prospective follow-up of menstrual disorders in adolescence and prognostic factors.

52 : Anovulation after precocious pubarche: early markers and time course in adolescence.

53 : Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.

54 : Racial and ethnic differences in the metabolic response of polycystic ovary syndrome.

55 : Polycystic ovary syndrome.

56 : Polycystic Ovary Syndrome among Obese Adolescents.

57 : Diagnosis of the polycystic ovary syndrome in adolescence: comparison of adolescent and adult hyperandrogenism.

58 : Intractable early childhood obesity as the initial sign of insulin resistant hyperinsulinism and precursor of polycystic ovary syndrome.

59 : Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome.

60 : Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome.

61 : Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS).

62 : Global adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndrome.

63 : Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance.

64 : PCOS is associated with increased CD11c expression and crown-like structures in adipose tissue and increased central abdominal fat depots independent of obesity.

65 : Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome.

66 : Metabolic features of polycystic ovary syndrome are found in adolescent girls with hyperandrogenism.

67 : Metabolic effect of obesity on polycystic ovary syndrome in adolescents: a meta-analysis.

68 : Insulin Resistance, Hyperinsulinemia, and Mitochondria Dysfunction in Nonobese Girls With Polycystic Ovarian Syndrome.

69 : Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome.

70 : Distinguishing characteristics of metabolically healthy versus metabolically unhealthy obese adolescent girls with polycystic ovary syndrome.

71 : Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population.

72 : Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome.

73 : Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.

74 : Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women.

75 : Clinical review 135: The importance of beta-cell failure in the development and progression of type 2 diabetes.

76 : Acanthosis Nigricans, insulin action, and hyperandrogenism: clinical, histological, and biochemical findings.

77 : Cutaneous Manifestations of Polycystic Ovary Syndrome: A Cross-Sectional Clinical Study.

78 : Skin Manifestations of Insulin Resistance: From a Biochemical Stance to a Clinical Diagnosis and Management.

79 : Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition.

80 : Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.

81 : Racial and ethnic differences in the prevalence of metabolic syndrome and its components of metabolic syndrome in women with polycystic ovary syndrome: a regional cross-sectional study.

82 : Extent of metabolic risk in adolescent girls with features of polycystic ovary syndrome.

83 : Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance.

84 : Screening for sleep-disordered breathing and excessive daytime sleepiness in adolescent girls with polycystic ovarian syndrome.

85 : Lipoprotein Particles in Adolescents and Young Women With PCOS Provide Insights Into Their Cardiovascular Risk.

86 : Impaired ApoB-Lipoprotein and Triglyceride Metabolism in Obese Adolescents With Polycystic Ovary Syndrome.

87 : Development of type 2 diabetes in adolescent girls with polycystic ovary syndrome and obesity.

88 : A comparison of polysomnographic variables between adolescents with polycystic ovarian syndrome with and without the metabolic syndrome.

89 : Poor Sleep Is Related to Metabolic Syndrome Severity in Adolescents With PCOS and Obesity.

90 : Hepatic Steatosis is Common in Adolescents with Obesity and PCOS and Relates to De Novo Lipogenesis but not Insulin Resistance.

91 : Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease.

92 : Hepatic steatosis relates to gastrointestinal microbiota changes in obese girls with polycystic ovary syndrome.

93 : Psychiatric Disorders, Self-Esteem, and Quality of Life in Adolescents with Polycystic Ovary Syndrome.

94 : Polycystic Ovary Syndrome Is Associated With Adverse Mental Health and Neurodevelopmental Outcomes.

95 : Increased prevalence of eating disorders, low self-esteem, and psychological distress in women with polycystic ovary syndrome: a community-based cohort study.

96 : Body-image distress is increased in women with polycystic ovary syndrome and mediates depression and anxiety.

97 : Androgen Excess- Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome.

98 : Depression Over the Lifespan in a Population-Based Cohort of Women With Polycystic Ovary Syndrome: Longitudinal Analysis.

99 : Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis.

100 : Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding?

101 : Distinctive features of female-to-male transsexualism and prevalence of gender identity disorder in Japan.

102 : Prevalence of hyperandrogenism and polycystic ovary syndrome in female to male transsexuals.

103 : Prevalence of polycystic ovary syndrome and hyperandrogenemia in female-to-male transsexuals.

104 : Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women.

105 : Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women.

106 : Bilateral ovary adrenal rest tumor in a congenital adrenal hyperplasia following adrenalectomy.

107 : Ovarian Adrenal Rest Tumors Undetected by Imaging Studies and Identified at Surgery in Three Females with Congenital Adrenal Hyperplasia Unresponsive to Increased Hormone Therapy Dosage.

108 : Pubertal presentation of congenital delta 5-3 beta-hydroxysteroid dehydrogenase deficiency.

109 : Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia.

110 : Pituitary-ovarian responses to leuprolide acetate testing in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

111 : Detection and functional characterization of the novel missense mutation Y254D in type II 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) gene of a female patient with nonsalt-losing 3 beta HSD deficiency.

112 : Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency.

113 : Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping.

114 : Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients.

115 : CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

116 : Generalized glucocorticoid resistance: clinical aspects, molecular mechanisms, and implications of a rare genetic disorder.

117 : Mutations of the hexose-6-phosphate dehydrogenase gene rarely cause hyperandrogenemic polycystic ovary syndrome.

118 : Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1.

119 : Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency.

120 : Inactivating PAPSS2 mutations in a patient with premature pubarche.

121 : PAPSS2 deficiency causes androgen excess via impaired DHEA sulfation--in vitro and in vivo studies in a family harboring two novel PAPSS2 mutations.

122 : How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing's syndrome?

123 : Cushing's syndrome in women with polycystic ovaries and hyperandrogenism.

124 : Androgen excess in women: experience with over 1000 consecutive patients.

125 : Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism.

126 : Differential maternal-fetal response to androgenizing luteoma or hyperreactio luteinalis.

127 : Remission of acanthosis nigricans associated with polycystic ovarian disease and a stromal luteoma.

128 : Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome.

129 : A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom).

130 : Hirsutism, polycystic ovarian disease, and ovarian 17-ketosteroid reductase deficiency.

131 : Ovarian 17-ketosteroid reductase deficiency as a possible cause of polycystic ovarian disease.

132 : Polycystic ovary syndrome and hyperprolactinemia are distinct entities.

133 : Multiple androgenic abnormalities, including elevated free testosterone, in hyperprolactinemic women.

134 : Pituitary tumors associated with hyperprolactinemia and polycystic ovarian disease.

135 : Prolactinomas, testosterone-binding globulin, and androgen metabolism.

136 : Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion.

137 : Insulin resistance is a sufficient basis for hyperandrogenism in lipodystrophic women with polycystic ovarian syndrome.

138 : Clinical review: Hyperandrogenism and polycystic ovary syndrome in women with type 1 diabetes mellitus.

139 : Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus.

140 : The prevalence of polycystic ovaries in women with type 2 diabetes mellitus.

141 : Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes.

142 : Menstrual irregularity in women with acromegaly.

143 : Ovarian morphology in long-term androgen-treated female to male transsexuals. A human model for the study of polycystic ovarian syndrome?

144 : Valproate potentiates androgen biosynthesis in human ovarian theca cells.

145 : Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms.

146 : Menstrual disorders in women with epilepsy.

147 : Ovarian hyperthecosis in the setting of portal hypertension.

148 : Two hyperandrogenic adolescent girls with congenital portosystemic shunt.

149 : Premature pubarche, hyperinsulinemia and hypothyroxinemia: novel manifestations of congenital portosystemic shunts (Abernethy malformation) in children.

150 : Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test.

151 : Prevalence of 'obesity-associated gonadal dysfunction' in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis.

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