Diagnosis and treatment of PCOS in adolescents: a summary of guidelines and systematic reviews for practitioners.

Controversy continues about the underlying etiopathogenesis, diagnostic criteria, and recommendations for polycystic ovary syndrome (PCOS) in adolescents. Recent literature has recognized these deficiencies and evidence based expert recommendations have become more available. The purpose of this chapter is to offer primary care providers a practical understanding and approach to the diagnosis and treatment of PCOS in adolescents. Although the presence of polycystic ovary morphology (PCOM) is included as a key diagnostic criterion of PCOS in adults, it is currently not recommended for the diagnosis in adolescents. As such, the diagnosis of PCOS in adolescents currently hinges on evidence of ovulatory dysfunction and androgen excess. Recommended evidence of ovulatory dysfunction includes: consecutive menstrual intervals >90 days even in the first year after menstrual onset; menstrual intervals persistently <21 or >45 days 2 or more years after menarche; and lack of menses by 15 years or 2-3 years after breast budding. Recommended evidence of androgen excess include: moderate to severe hirsutism; persistent acne unresponsive to topical therapy; and persistent elevation of serum total and/or free testosterone level. Importantly, a definitive diagnosis of PCOS is not needed to initiate treatment. Treatment may decrease risk of future comorbidity even in the absence of a definitive diagnosis. Deferring diagnosis, while providing symptom treatment and regular/ frequent follow-up of symptomology, is a recommended option. The treatment options for PCOS should be individualized to the presentation, needs, and preferences of each patient. Goals of treatment are to improve quality of life and long-term health outcomes. Lifestyle modifications remain first-line management of overweight and obese adolescents with PCOS. Combined oral contraceptives (COC) are first line pharmacotherapy for management of menstrual irregularity and acne, and metformin is superior to COCs for weight reduction and improved dysglycemia. COCs and metformin have similar effects on hirsutism, but often need to be paired with other treatment modalities to achieve further improvement of cutaneous symptoms. Clinicians should be cognizant that PCOS is associated with significant metabolic and psychological comorbidity and screen for these issues appropriately.

Тhe diagnosis of polycystic ovary syndrome (PCOS) in adolescence still raises many questions. The problem is that the characteristics of normal puberty often coincide with the symptoms of PCOS. The article presents the criteria of a normal menstrual cycle, clinical and laboratory hyperandrogenism. In the diagnosis of the latter, the most informative indicators are the determination of the index of free testosterone and androstenedione, and the assessment of free and total testosterone are relatively low sensitivity. Clinical hyperandrogenism in adolescents includes only severe acne and hirsutism. The level of antimullerian hormone has no independent significance. Irregular menstrual cycles during the first year after menarche represent a normal period of puberty. At the second and third year after menarche , menstrual cycles of less than 21 days and more than 45 days are considered irregular, and from the fourth year – less than 21 days and more than 35 days. From the second year after menarche, menstrual irregularities are considered to be more than 90 days for any cycle. Primary amenorrhea is indicated by the absence of menarche at 15 years, or 3 years after telarche. Ultrasound is not used as a criterion for PCOS in the first 8 years after menarche due to the high frequency of ovarian multifollicularity in adolescence. Therefore, adolescent girls in the presence of menstrual disorders and hyperandrogenism may be diagnosed with «PCOS. Phenotype B» (ultrasound signs are not taken into account). Adolescents who have signs of PCOS but do not meet the diagnostic criteria are at risk for PCOS. The most important stage of PCOS therapy is lifestyle modification, normalization of body weight and metabolic processes. Combined oral contraceptives in adolescents are more often prescribed not for direct purposes (contraception), but as off-label therapy not only at diagnosis, but also in the «risk group», which involves the treatment of irregular menstrual cycles and / or clinical hyperandrogenism. In the absence of the effect of lifestyle changes, proper nutrition to correct metabolic disorders in addition to combined oral contraceptives may be prescribed metformin, inositol and etc.

36. Primary Care Provider Behaviors, Attitudes and Beliefs In the Diagnosis and Management of Polycystic Ovary Syndrome in Adolescents

Although the diagnostic criteria for polycystic ovary syndrome (PCOS) have become less stringent over the years, determination of the minimum diagnostic features in adolescents is still an area of controversy. Of particular concern is that many of the features considered to be diagnostic for PCOS may evolve over time and change during the first few years after menarche. Nonetheless, attempts to define young women who may be at risk for development of PCOS is pertinent since associated morbidity such as obesity, insulin resistance, and dyslipidemia may benefit from early intervention. The relative utility of diagnostic tools such as persistence of anovulatory cycles, hyperandrogenemia, hyperandrogenism (hirsutism, acne, or alopecia), or ovarian findings on ultrasound is not established in adolescents. Some suggest that even using the strictest criteria, the diagnosis of PCOS may not valid in adolescents younger than 18 years. In addition, evidence does not necessarily support that lack of treatment of PCOS in younger adolescents will result in untoward outcomes since features consistent with PCOS often resolve with time. The presented data will help determine if it is possible to establish firm criteria which may be used to reliably diagnose PCOS in adolescents.

Objective (1) To investigate anti-Mullerian-hormone (AMH) in adolescents with polycystic ovary syndrome (PCOS) compared to age-matched girls without PCOS; (2) to determine whether AMH is a valuable marker for diagnosing PCOS and to explore the best cutoff value in adolescents; (3) using a multivariate predictive model for the diagnosis of PCOS. Methods Ninety girls (aged 10–20 years) recruited during two years for the PCOS-group (n = 45) or control-group (n = 45). PCOS diagnostic criteria according guidelines of the Endocrinology Expert Group, Obstetrics/Gynecology Branch of the Chinese Medical Association. Serum AMH and other sex hormones were measured. Logistic regression analysis to estimate the odds ratio of AMH and other variables for the diagnosis of PCOS. Receiver operator characteristics (ROC) curve analysis was performed to reveal the diagnostic potential. Results (A) AMH was significantly higher in PCOS patients than in controls (10.21 ± 5.85 ng/ml vs. 4.31 ± 2.84 ng/ml, p < .001). In PCOS-group, total testosterone (TT), free testosterone (FT) and biologically active testosterone (BioT) were significantly higher than in controls (p < .001). (B) Logistic regression suggests that AMH and TT are correlated with the diagnosis of PCOS (p < .05). (C) ROC curve analyses demonstrated that the optimal value of AMH for predicting PCOS was 6.32 ng/mL, with 69.8% sensitivity and 80.5% specificity. Furthermore, AMH combined with TT can provide 83.7% sensitivity and 80.5% specificity for diagnosing PCOS in adolescents. Conclusions AMH may be a useful biomarker for the diagnosis of PCOS in Chinese adolescent girls. A cutoff value of 6.32 ng/mL best discriminated between PCOS patients and controls. Besides AMH a multivariate predictive model should include TT.

Background. Scientific debate continues on the diagnostic criteria for polycystic ovary syndrome in adolescents (PCOS). In adolescents these criteria cause special diagnostic problems due to the fact that the characteristics of normal puberty often coincide with the signs and symptoms of PCOS. There is a need to develop diagnostic criteria for PCOS in adolescents, which could be used in addition to those proposed. A possible additional diagnostic criterion may be the level of anti-Mullerian hormone (AMH). The purpose of the study is to assess the levels of anti-Mullerian hormone in the blood of adolescent girls with polycystic ovary syndrome. Materials and methods. A clinical-anamnestic and laboratory study of 27 adolescent girls (12–18 years) with PCOS was conducted. The comparison group consisted of 25 girls of the same age without gynecological disorders. Determination of AMG was performed in venous serum (Gen II ELISA, Beckman Coulter). Results. The anamnesis of adolescent girls with PCOS was analyzed: intrauterine hypoxia occurred in almost half of adolescents, pathological course of the postnatal period was observed in 25.9%, infectious index was 4.6, hypertensive-hydrocephalic syndrome was found in 23.8%, minimal cerebral dysfunction 28.5%, autonomic disorders— in 47.6%, most of the surveyed girls had average body weight and height, inverted puberty and disharmonious sexual development. The most common symptoms of PCOS in girls were: hypomenstrual syndrome (86.9%), dermopathy (82.6%) and hirsutism (60.8%). The mean AMG in girls with PCOS and in the comparison group was 3.67±1.0 ng/ml (in girls with PCOS 4.8±0.9 and in girls in the comparison group 3.1±0.7 ng/ml, p&lt;0.05). Adolescent girls with form A PCOS had the highest hormone levels— 6.4 [4.8; 6.9] pg/ml, p&lt;0.01, which may indicate a probable diagnostic value of AMG concentration. Conclusions. Adolescent girls with suspected polycystic ovary syndrome should have a complete set of tests to determine the level of anti-Mullerian hormone as an additional marker, especially in the absence of clinical manifestations of hyperandrogenemia.

Variation in metabolic and cardiovascular risk in women with different polycystic ovary syndrome phenotypes

This study aimed to [1] confirm that nonobese adolescents with polycystic ovary syndrome (PCOS) have higher anti-Mullerian hormone (AMH) than controls; [2] examine the relationship of AMH with PCOS features and hormonal profile; and [3] approximate an AMH value that discriminates between adolescents with PCOS and controls. Case-control study. Subspecialty ambulatory clinic. Thirty-one nonobese adolescent girls (age 13-21 years), 15 with PCOS diagnosed using the National Institutes of Health (NIH) criteria and 16 healthy control subjects. Subjects and controls were comparable for body mass index z-score, age and ethnicity. AMH in PCOS subjects and control groups, correlation of AMH with hormonal parameters. AMH was higher in PCOS subjects (4.4±3.4 ng/mL) than in controls (2.4±1.3 ng/mL), when adjusted for menstrual age. In the entire group (PCOS and controls), AMH correlated with androgens, ovarian size and the presence of polycystic ovary (PCO) appearance. There was no difference in average ovarian size between PCOS (7.1±2.6 cm³) and controls (6.7±1.8 cm³). PCOS subjects were 1.49 times more likely to have AMH >3.4 ng/mL (confidence interval 0.98-2.26 ng/mL). Our data suggest that AMH may be a useful adjunct in the diagnosis of PCOS in adolescents.

ContextDespite the importance of timely diagnosis and treatment of polycystic ovary syndrome (PCOS) among adolescent females, considering the paucity of data focusing on this group and controversies documented on its recognition and management, the purpose of this review was to summarize challenges and recommendations of diagnosis and treatment for adolescents with PCOS.Evidence AcquisitionThis review summarizes papers documented on PCOS among adolescent females. PubMed, Scopus, Web of Science, and Google Scholar databases were searched for retrieving studies conducted on PCOS among adolescent females up to March, 2019. The final selection of papers was made based on their relevancy with the fields of diagnosis and treatment of PCOS in this age group.ResultsOligo-anovulation in adolescents, if persistent, is a matter for concern. Hirsutism and moderate to severe acne in adolescent females should be considered as clinical manifestations of hyperandrogenism (HA). Diagnosis of biochemical HA in adolescents with PCOS requires reliable tests using well-defined normal ranges. In adolescent females, an elevated androgen level (hyperandrogenemia) alone is not enough to detect HA, unless it is persistent and associated with anovulation. Metabolic disorders should not be used as diagnostic criteria of PCOS among adolescent females. Re-assessment of all adolescent females with probable PCOS, using reliable diagnostic criteria, is needed to avoid over diagnosis and unnecessary treatment in healthy normal females without HA. In adolescent females with PCOS, the main clinical problem is the control of menstrual irregularity and hirsutism; treatment approaches for these patients are primarily directed at the major clinical manifestations and complaints. Lifestyle modifications are baseline interventions, which can be added to special treatments, such as Oral Contraceptives (OCs), metformin, or antiandrogens for most adolescents with PCOS, particularly those with overweight or obesity.ConclusionsThis review emphasizes the use of standard diagnostic criteria for PCOS, developed for adolescents. Although early recognition and management of PCOS in adolescents can prevent long-term complications associated with this syndrome, clinicians should re-evaluate all such patients with features very similar to PCOS to avoid over/incorrect diagnosis using precise criteria, suggested for this age group.

Consensus has recently been reached by international pediatric subspecialty societies that otherwise unexplained persistent hyperandrogenic anovulation using age- and stage-appropriate standards are appropriate diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescents. The purpose of this review is to summarize these recommendations and discuss their basis and implications. Anovulation is indicated by abnormal uterine bleeding, which exists when menstrual cycle length is outside the normal range or bleeding is excessive: cycles outside 19 to 90 days are always abnormal, and most are 21 to 45 days even during the first postmenarcheal year. Continued menstrual abnormality in a hyperandrogenic adolescent for 1 year prognosticates at least 50% risk of persistence. Hyperandrogenism is best indicated by persistent elevation of serum testosterone above adult norms as determined in a reliable reference laboratory. Because hyperandrogenemia documentation can be problematic, moderate-severe hirsutism constitutes clinical evidence of hyperandrogenism. Moderate-severe inflammatory acne vulgaris unresponsive to topical treatment is an indication to test for hyperandrogenemia. Treatment of PCOS is symptom-directed. Cyclic estrogen-progestin oral contraceptives are ordinarily the preferred first-line medical treatment because they reliably improve both the menstrual abnormality and hyperandrogenism. First-line treatment of the comorbidities of obesity and insulin resistance is lifestyle modification with calorie restriction and increased exercise. Metformin in conjunction with behavior modification is indicated for glucose intolerance. Although persistence of hyperandrogenic anovulation for ≥2 years ensures the distinction of PCOS from physiologic anovulation, early workup is advisable to make a provisional diagnosis so that combined oral contraceptive treatment, which will mask diagnosis by suppressing hyperandrogenemia, is not unnecessarily delayed.

Polycystic ovary syndrome (PCOS) is often difficult to diagnose in adolescents. Recent recommendations and concepts regarding the diagnosis and treatment of PCOS in the adolescent girl are considered. The diagnosis of PCOS in adolescents should be primarily based on clinical and biochemical signs of hyperandrogenism and presentation with irregular menses. Because of the similarity of normal pubertal development and features of PCOS, the diagnosis should be deferred until at least 2 years following menarche. For girls who do not fulfill the diagnostic criteria, the focus should be on treatment of symptoms. PCOS is a complex, multifaceted disorder, and should be diagnosed and treated in adolescents after taking into consideration the patient's full diagnostic picture, metabolic risks, and individual concerns, to both avoid overdiagnosis but yet be able to provide early and meaningful interventions.

Study question Can novel biomarkers be identified to distinguish between PCOS-positive cases and healthy PCOS-negative controls in women as early as adolescence? Summary answer Meteorin-like protein (METRNL), fibroblast growth factor binding protein-1 (FGFBP1) and leukotriene A4 hydrolase (LTA4H) identified PCOS as early as adolescence, independent of PCOS phenotype. What is known already International evidence-based guidelines recommend use of the Rotterdam criteria for PCOS diagnosis. Despite this guidance, diagnosing PCOS can be extremely challenging due to the heterogeneity of clinical presentation, and further complicated in adolescence and young adulthood due to overlap between signs of physiologic changes during puberty and common symptoms of PCOS (e.g., menstrual irregularity, excess male hormones/androgens, multiple follicles in ovaries). Timely diagnosis of PCOS allowing for appropriate monitoring, follow up and early intervention may reduce the risk of associated comorbidities. An unmet need exists for biomarkers/alternative tools to support earlier diagnosis of PCOS in adolescents/adult women of reproductive age. Study design, size, duration This was a retrospective study (October 2020–June 2023) using banked samples from women with PCOS (confirmed per Rotterdam criteria) and healthy controls who had participated in previous studies sponsored by/in collaboration with Roche Diagnostics. Candidate biomarkers identified by exploratory proteomics analysis (Olink Proximity Extension Assay) were verified by ELISA and receiver operating characteristic-area under the curve (ROC-AUC) analysis for their ability to discriminate PCOS cases and controls in women aged 15-45 years. Participants/materials, setting, methods Top-performing biomarkers from Olink discovery (n = 51 PCOS phenotype A; n = 37 controls) were selected for further validation based on AUC &amp;gt;0.970, biological relevance for PCOS and commercial ELISA availability. Serum biomarker concentrations/biomarker ratios were determined and ROC-AUC analysis conducted in two validation cohorts (Cohort 1: n = 90 cases [phenotype A, n = 30; B, n = 20; C, n = 20; D, n = 20]; n = 47 controls; Cohort 2: n = 240 cases [15-19 years, n = 70; 20-24 years, n = 99; 25-40 years, n = 71]; n = 48 controls, median 26.0 years). Main results and the role of chance Serum METRNL concentrations were numerically lower, and FGFBP1 and LTA4H concentrations numerically higher, in PCOS cases compared with controls. All three biomarkers distinguished PCOS cases and controls, regardless of PCOS phenotype A-D (Cohort 1: AUCs 0.91-0.99 [METRNL], 0.84-0.88 [FGFBP1] and 0.76-0.90 [LTA4H]), and across different age groups in women of reproductive age (Cohort 2: 15-19, 20-24 and 25-40 years; AUCs 0.88, 0.91 and 0.96 [METRNL], respectively; 0.90, 0.88 and 0.91 [FGFBP1], respectively; 0.74, 0.70 and 0.78 [LTA4H], respectively). Compared with results for the individual biomarkers, combining FGFBP1 with METRNL, and LTA4H with METRNL, as biomarker ratios further improved the ability to distinguish PCOS cases and controls, independent of PCOS phenotype A-D (Cohort 1: AUCs 0.95-1.00 [FGFBP1:METRNL] and 0.97-0.99 [LTA4H:METRNL]) and across age groups (Cohort 2: 15-19, 20-24 and 25-40 years; AUCs 0.91, 0.96 and 0.98 [FGFBP1:METRNL], respectively, and 0.91, 0.91 and 0.97 [LTA4H:METRNL], respectively). Findings were not impacted by adjustment for baseline body mass index. METRNL, FGFBP1 and LTA4H are linked to biological mechanisms associated with clinical manifestations and underlying characteristics of PCOS, i.e., metabolic pathways, inflammation and ovarian function. While METRNL has been described previously in adult PCOS, FGFBP1 and LTA4H findings are novel in this context. Limitations, reasons for caution These findings in retrospective samples warrant validation in additional independent prospective cohorts, particularly in adolescents and young adult women. Wider implications of the findings Reliable diagnosis of PCOS in adolescents and young adult women represents an unmet medical need. METRNL, FGFBP1 and LTA4H have potential use as biomarkers to support the detection of PCOS in adolescents and adult women, potentially shortening time to diagnosis and allowing for earlier and targeted intervention. Trial registration number not applicable

Not all women diagnosed with PCOS share the same cardiovascular risk profiles

Menstrual irregularities and cutaneous signs of androgen excess are commonly encountered when caring for adolescent girls. Polycystic ovary syndrome (PCOS) is the most common cause of these symptoms in adult women, and it can be diagnosed in adolescents as well. Diagnostic criteria used to diagnose adult women are not applicable in adolescents, as some diagnostic criteria overlap with the normal physiology of a maturing reproductive system. Thus, application of adult criteria will overdiagnose adolescents with PCOS. Two recent guidelines on the diagnosis and treatment of PCOS in adolescence were created to provide clarity in the diagnosis of PCOS in adolescent girls and to guide best practices in treatment. This review summarizes the recommendations and gives practical advice on the application of these recommendations to everyday pediatric practice. [Pediatr Ann. 2019;48(8):e304-e310.].

Source: Cioana M, Deng J, Nadarajah A, et al. Prevalence of polycystic ovary syndrome in patients with pediatric type 2 diabetes a systematic review and meta-analysis. JAMA Netw Open. 2022;5(2):e2147454. doi:10.1001/jamanetworkopen.2021.47454Investigators from multiple institutions conducted a meta-analysis to estimate the prevalence of polycystic ovary syndrome (PCOS) in girls with type 2 diabetes (T2D). For the meta-analysis, systematic search procedures were used to identify studies in which the prevalence of PCOS in girls diagnosed with T2D when they were ≤18 years old was estimated. Studies included could have cross-sectional, retrospective, or prospective cohort designs, if they had a minimum sample of 10 patients. No specific criteria for the diagnosis of PCOS were required. The prevalence of PCOS in each included study was determined, and a pooled prevalence was calculated. A secondary analysis that included studies in which specific criteria were required for the diagnosis of PCOS also was conducted. For studies with the available data, the prevalence of PCOS among girls with T2D from different racial groups was calculated.The authors screened 722 articles to identify 6 studies that met the inclusion criteria; 5 of these were retrospective cohort studies. Data on 470 girls were included in the meta-analysis. The mean age at diagnosis of T2D among participants in the included studies ranged from 12.9 years to 16.1 years. Overall, the pooled prevalence of PCOS among adolescent females with T2D was 19.58% (95% CI, 12.02%, 27.14%). Three studies required a history of persistent oligomenorrhea and clinical and/or biochemical hyperandrogenism for a diagnosis of PCOS. Among 87 girls with T2D included in these studies, the pooled prevalence of PCOS was 24.04% (95% CI, 15.07%, 33.01%). There were 2 studies in which the prevalence of PCOS by race was reported; reported prevalence was 17% among 36 white females, 23.10% in Indian adolescent females (N = 195), and 2.0% in indigenous females in Canada (N = 64).The authors conclude that approximately 1 in 5 girls with T2D had PCOS.Dr. Fechner has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.It is not surprising that 1 in 5 girls with T2D have PCOS, as insulin resistance with hyperinsulinemia increases androgen production by the ovary, leading to PCOS.1 While the diagnosis of PCOS in adult women requires 2 of 3 criteria: androgen excess, oligo/anovulation or polycystic ovaries,2 the presence of polycystic ovaries on ultrasound and anovulatory symptoms may be normal in the early post-menarchal years. Thus, a history of anovulation and an ultrasound with polycystic ovaries may be normal during the period after menarche. A consensus statement on the pathophysiology, diagnosis, and treatment of PCOS in adolescence in 2017 suggested the diagnostic criteria of clinical and/or biochemical hyperandrogenism with irregular menses/oligomenorrhea at least 2 years post-menarche.3As in adults, it is important to exclude other etiologies such as non-classic congenital adrenal hyperplasia, hyperprolactinemia, and thyroid disease. PCOS has many of the same co-morbidities as T2D. In addition, there is increased infertility and increased risk of endometrial cancer as well as possible increased androgen exposure to the female fetus leading to ambiguous genitalia in the fetus.2 Treatment of PCOS overlaps T2D treatment, with lifestyle management to lose weight as a primary intervention. Adolescents with PCOS may also benefit from the use of an oral contraceptive to decrease androgens and improve acne, hirsutism, anovulatory symptoms, and to prevent pregnancy. Metformin for those unsuccessful with lifestyle management may also benefit both PCOS and T2D management.3It is important to gather menstrual history and look for signs of hyperandrogenism in females with T2D as PCOS appears to be a relatively common morbidity in girls with T2D.