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Cited by 653Ovarian function and disordersEndometriosis Research and TreatmentAcne and Rosacea Treatments and Effects

Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls

Open access
Witchel, Selma Feldman, Oberfield, Sharon E, Peña, Alexia S·2019·Journal of the Endocrine Society
DOI 10.1210/js.2019-00078PMC PMC6676075
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Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. Depending on diagnostic criteria, 6% to 20% of reproductive aged women are affected. Symptoms of PCOS arise during the early pubertal years. Both normal female pubertal development and PCOS are characterized by irregular menstrual cycles, anovulation, and acne. Owing to the complicated interwoven pathophysiology, discerning the inciting causes is challenging. Most available clinical data communicate findings and outcomes in adult women. Whereas the Rotterdam criteria are accepted for adult women, different diagnostic criteria for PCOS in adolescent girls have been delineated. Diagnostic features for adolescent girls are menstrual irregularity, clinical hyperandrogenism, and/or hyperandrogenemia. Pelvic ultrasound findings are not needed for the diagnosis of PCOS in adolescent girls. Even before definitive diagnosis of PCOS, adolescents with clinical signs of androgen excess and oligomenorrhea/amenorrhea, features of PCOS, can be regarded as being “at risk for PCOS.” Management of both those at risk for PCOS and those with a confirmed PCOS diagnosis includes education, healthy lifestyle interventions, and therapeutic interventions targeting their symptoms. Interventions can include metformin, combined oral contraceptive pills, spironolactone, and local treatments for hirsutism and acne. In addition to ascertaining for associated comorbidities, management should also include regular follow-up visits and planned transition to adult care providers. Comprehensive knowledge regarding the pathogenesis of PCOS will enable earlier identification of girls with high propensity to develop PCOS. Timely implementation of individualized therapeutic interventions will improve overall management of PCOS during adolescence, prevent associated comorbidities, and improve quality of life.

AI snapshot

Written from the paper’s full text.

TL;DR

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of hyperandrogenism and chronic anovulation affecting ∼6% to 20% of reproductive-aged women, with features often emerging in early puberty. This narrative review emphasizes adolescent-specific diagnosis and management, including lifestyle, metformin, combined oral contraceptives, antiandrogens, and local hirsutism/acne treatments.

Key findings

  • PCOS affects ∼6% to 20% of reproductive-aged women depending on diagnostic criteria; it is characterized by hyperandrogenism and chronic anovulation, with symptoms arising during the early pubertal years.
  • For adolescent girls, diagnostic features are menstrual irregularity, clinical hyperandrogenism, and/or hyperandrogenemia; pelvic ultrasound findings are not needed for diagnosis, and girls with features but without persistent oligomenorrhea can be considered “at risk for PCOS.”
  • Management includes education, healthy lifestyle interventions, metformin, combined oral contraceptive pills (COCPs), spironolactone, and local treatments for hirsutism and acne; metformin doses ranged from 1000 to 2000 mg daily, and the lowest effective COCP estrogen dose (20 to 30 µg ethinylestradiol) should be considered.
  • Weight loss strategies up to 7% of body weight improved menstrual irregularity and testosterone levels; heritability is ∼70%, and GWASs have identified at least 16 susceptibility loci for PCOS.

Methods

  • Narrative review synthesizing clinical, experimental, and genetic data, with emphasis on adolescent girls; it is not a systematic review or meta-analysis.
  • Evidence includes adult clinical studies, preclinical animal and in vitro models, GWASs, and international guidelines; the paper notes that most relevant clinical data come from adult women and referral-based severe phenotypes.
  • Main analysis is qualitative synthesis of pathophysiology, diagnosis, and treatment, citing meta-analyses and randomized controlled trials where available.

Limitations

  • The paper states that most clinical data communicate findings in adult women, referral bias focuses on more severe phenotypes, adolescent-specific data are limited, and some cited studies have small sample sizes; no microbiome data for adolescents are available.
  • The paper states that diagnosing PCOS in adolescent girls is problematic because irregular menses, acne, mild hyperandrogenism, and multifollicular ovarian morphology overlap with normal puberty, and pelvic ultrasound is unnecessary/inconsistent in adolescents.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy or formal quality appraisal, and many treatment recommendations are extrapolated from adult women or small/short adolescent trials (e.g., metformin RCTs mostly 6 months, only one 24 months, with no longer-term studies).

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/js.2019-00078

Cites

225 of 225 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 173 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The concentrations of 11-oxygenated steroids are higher in women with PCOS than among healthy premenopausal women.

    “The concentrations of these 11-oxygenated steroids were reported to be higher in women with PCOS than among healthy premenopausal women [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] O’Reilly, 2017, 11-Oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Premisecitation

    Symptoms of PCOS arise during the early pubertal years.

    “Symptoms of PCOS arise during the early pubertal years.”
    • Also stated in: § 1. Pathophysiology · plain
      “PCOS develops during the early pubertal years [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Apter, 1994, Accelerated 24-hour luteinizing hormone pulsatile activity in adolescent girls with ovarian hyperandrogenism: relevance to the developmental phase of polycystic ovarian syndrome, J Clin Endocrinol Metab

      Not checked in the free run.

  • Premisecitation

    Available data document constitutively increased androgen production and CYP17A1 expression in cultured theca cells isolated from PCOS ovaries.

    “Available data document constitutively increased androgen production and CYP17A1 expression in cultured theca cells isolated from PCOS ovaries [24–26].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Gilling-Smith, 1994, Hypersecretion of androstenedione by isolated thecal cells from polycystic ovaries, J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [25] Gilling-Smith, 1997, Evidence for a primary abnormality of thecal cell steroidogenesis in the polycystic ovary syndrome, Clin Endocrinol (Oxf) source

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    • cites [26] Nelson, 1999, Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries, Mol Endocrinol source

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  • Premisecitation

    Aberrant development during the earliest stages of follicular growth likely contributes to the ovarian aspects of PCOS.

    “Aberrant development during these earliest stages of follicular growth likely contributes to the ovarian aspects of PCOS [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Franks, 2018, Androgen action in the ovary, Front Endocrinol (Lausanne) source

      Not checked in the free run.

  • Premisecitation

    Most relevant information on PCOS has been accrued through clinical studies involving adult women in which referral bias focuses on investigation of the more severe phenotypes.

    “However, most relevant information has been accrued through clinical studies involving adult women in which referral bias focuses on investigation of the more severe phenotypes [7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Lizneva, 2016, Phenotypes and body mass in women with polycystic ovary syndrome identified in referral versus unselected populations: systematic review and meta-analysis, Fertil Steril source

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    Interpretationcitation

    AMH appears to have a dual role: whereas AMH promotes preantral follicle survival, it negatively impacts later stages of antral follicle maturation.

    “Hence, AMH appears to have a dual role: whereas AMH promotes preantral follicle survival, it negatively impacts later stages of antral follicle maturation [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Xu, 2016, Anti-Müllerian hormone promotes pre-antral follicle growth, but inhibits antral follicle maturation and dominant follicle selection in primates, Hum Reprod source

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    Premisecitation

    Androgens synthesized in preantral follicle theca cells promote growth of preantral and antral follicles and induce granulosa cell FSH receptor (FSHR) expression in early antral follicles.

    “Despite prior assumptions that androgens negatively impact follicles, androgens synthesized in preantral follicle theca cells promote growth of preantral and antral follicles and induce granulosa cell FSH receptor (FSHR) expression in early antral follicles [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Weil, 1998, Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations, J Clin Endocrinol Metab source

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    Interpretationcitation

    Excessive prenatal AMH exposure could promote the aberrant neuroendocrine function typical of PCOS and AMH can modulate GnRH neuron function.

    “These data suggest that excessive prenatal AMH exposure could promote the aberrant neuroendocrine function typical of PCOS and that AMH can modulate GnRH neuron function [37, 38].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Cimino, 2016, Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion, Nat Commun source

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    • cites [38] Tata, 2018, Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood, Nat Med source

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    Premisecitation

    The classic ovarian phenotype of enlarged ovaries with string-of-pearl morphology and theca interstitial hyperplasia reflects androgen exposure; this morphology has also been observed in women with congenital adrenal hyperplasia (CAH) and female-to-male transgender individuals.

    “The classic ovarian phenotype of enlarged ovaries with string-of-pearl morphology and theca interstitial hyperplasia reflects androgen exposure; this morphology has also been observed in women with congenital adrenal hyperplasia (CAH) and female-to-male transgender individuals [8].”
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    • cites [8] Pache, 1993, Polycystic ovaries in female-to-male transsexuals, Clin Endocrinol (Oxf)

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    Premisecitation

    AMH appears to promote growth of preantral follicles to the antral stage in nonhuman primate ovaries, in contrast to mice where AMH inhibits preantral follicle growth and antral follicle maturation.

    “In contrast to mice where AMH inhibits preantral follicle growth and antral follicle maturation, AMH appears to promote growth of preantral follicles to the antral stage in nonhuman primate (NHP) ovaries [11, 12].”
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    • cites [11] Carlsson, 2006, Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro, Hum Reprod source

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    • cites [12] Xu, 2016, Anti-Müllerian hormone promotes pre-antral follicle growth, but inhibits antral follicle maturation and dominant follicle selection in primates, Hum Reprod source

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    Premisecitation

    Prepubertal ovaries contain a high proportion of abnormal nongrowing follicles, which are not found in pubertal ovaries.

    “Specifically, prepubertal ovaries contain a high proportion of abnormal nongrowing follicles, which are not found in pubertal ovaries [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Anderson, 2014, The immature human ovary shows loss of abnormal follicles and increasing follicle developmental competence through childhood and adolescence, Hum Reprod source

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    Premisecitation

    Persistent hyperandrogenism is associated with impaired hypothalamic-pituitary feedback, LH hypersecretion, premature granulosa cell luteinization, aberrant oocyte maturation, and premature arrest of activated primary follicles.

    “The persistent hyperandrogenism is associated with impaired hypothalamic–pituitary feedback, LH hypersecretion, premature granulosa cell luteinization, aberrant oocyte maturation, and premature arrest of activated primary follicles [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Palomba, 2017, Oocyte competence in women with polycystic ovary syndrome, Trends Endocrinol Metab source

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    Premisecitation

    Normal-weight adolescent girls with PCOS have peripheral insulin resistance, increased liver fat, and muscle mitochondrial dysfunction compared with normal-weight girls.

    “Normal-weight adolescent girls with PCOS have peripheral IR, increased liver fat, and muscle mitochondrial dysfunction compared with normal-weight girls [70].”
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    • cites [70] Cree-Green, 2017, Insulin resistance, hyperinsulinemia, and mitochondria dysfunction in nonobese girls with polycystic ovarian syndrome, J Endocr Soc source

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    Premisecitation

    In PCOS, liver, skeletal muscle, and adipose tissue exhibit insulin resistance, whereas steroid-producing tissues and the pituitary retain insulin sensitivity.

    “This leads to the paradox of insulin signaling in PCOS; liver, skeletal muscle, and adipose tissue exhibit IR, whereas steroid-producing tissues and the pituitary retain insulin sensitivity [71, 72].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Geffner, 1988, Selective insulin action on skin, ovary, and heart in insulin-resistant states, Diabetes Care source

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    • cites [72] Wu, 2012, Reproductive tissues maintain insulin sensitivity in diet-induced obesity, Diabetes source

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    Premisecitation

    A longitudinal study found that the median age at menarche for American girls was 12.25 years, with lower menarcheal ages in black and Hispanic girls compared with white and Asian girls.

    “A longitudinal study found that the median age at menarche for American girls was 12.25 years, with lower menarcheal ages in black and Hispanic girls compared with white and Asian girls [130].”
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    • cites [130] Biro, 2018, Age of menarche in a longitudinal US cohort, J Pediatr Adolesc Gynecol source

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    Premisecitation

    Consequences of ectopic fat deposition may include impaired tissue hypoxia, inflammation, and insulin resistance.

    “Among prenatally androgenized NHPs, when the capacity of subcutaneous adipocytes to store fat is exceeded, excess free fatty acids may be deposited in ectopic locations such a liver and muscle; consequences of ectopic fat deposition may include impaired tissue hypoxia, inflammation, and IR [106].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] True, 2017, Sex differences in androgen regulation of metabolism in nonhuman primates, Adv Exp Med Biol source

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    Interpretationcitation

    A mismatch between prenatal weight and postnatal weight gain is associated with increased risk for PCOS, ectopic fat storage, and hepatic steatosis.

    “These findings are consistent with the concept that a mismatch between prenatal weight and postnatal weight gain is associated with increased risk for PCOS, ectopic fat storage, and hepatic steatosis [92–94].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] Ibáñez, 2014, Hyperinsulinaemic androgen excess in adolescent girls [published correction appears in Nat Rev Endocrinol. 2014;10:578], Nat Rev Endocrinol source

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    • cites [93] de Zegher, 2018, Central obesity, faster maturation, and “PCOS” in girls, Trends Endocrinol Metab source

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    • cites [94] de Zegher, 2017, Reduced prenatal weight gain and/or augmented postnatal weight gain precedes polycystic ovary syndrome in adolescent girls, Obesity (Silver Spring) source

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    Premisecitation

    Early pubertal nonhuman primates treated with testosterone and a "Western style diet" with increased fat content showed increased larger visceral adipocytes, greater insulin resistance, and ectopic fat storage.

    “Early pubertal NHP treated with testosterone and a “Western style diet” with increased fat content showed increased larger visceral adipocytes, greater IR, and ectopic fat storage [106].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] True, 2017, Sex differences in androgen regulation of metabolism in nonhuman primates, Adv Exp Med Biol source

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    Premisecitation

    Girls with obesity and PCOS compared with girls with obesity without PCOS demonstrated decreased lipid mobilization, diminished fat oxidation, and impaired ability to switch from lipid to carbohydrate oxidation during insulin stimulation (metabolic inflexibility).

    “Girls with obesity with PCOS compared with those without PCOS demonstrated decreased lipid mobilization, diminished fat oxidation, and impaired ability to switch from lipid to carbohydrate oxidation during insulin stimulation (metabolic inflexibility) [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Kim, 2018, Impaired lipolysis, diminished fat oxidation, and metabolic inflexibility in obese girls with polycystic ovary syndrome, J Clin Endocrinol Metab source

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    Premisecitation

    Epigenetic variants have been reported for adipose tissue and muscle.

    “Epigenetic variants have been reported for adipose tissue and muscle [120, 121].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [120] Kokosar, 2016, Epigenetic and transcriptional alterations in human adipose tissue of polycystic ovary syndrome [published correction appears in Sci Rep. 2016;6:25321], Sci Rep source

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    • cites [121] Nilsson, 2018, Transcriptional and epigenetic changes influencing skeletal muscle metabolism in women with polycystic ovary syndrome, J Clin Endocrinol Metab source

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    Premisecitation

    Several genetic variants are similar in both Han Chinese and European populations, implying that PCOS is an ancient disease.

    “Several genetic variants are similar in both Han Chinese and European populations, implying that PCOS is an ancient disease [117].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Fessler, 2016, Evolutionary determinants of polycystic ovary syndrome: part 2, Fertil Steril source

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    Premisecitation

    Activation of androgen precursors appears to regulate adipocyte proliferation and differentiation, insulin sensitivity, adipokine signaling, and lipid metabolism.

    “Activation appears to regulate adipocyte proliferation and differentiation, insulin sensitivity, adipokine signaling, and lipid metabolism [96].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] O’Reilly, 2014, Understanding androgen action in adipose tissue, J Steroid Biochem Mol Biol source

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    Premisecitation

    By age 15 years, 98% of girls will have experienced menarche.

    “By age 15 years, 98% of girls will have experienced menarche [131].”
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    • cites [131] Chumlea, 2003, Age at menarche and racial comparisons in US girls, Pediatrics source

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    Premisecitation

    Both low-glycemic load and low-fat diets during 6 months improved weight with no difference between diets.

    “Similarly, both low–glycemic load and low-fat diets during 6 months improved weight with no difference between diets [168].”
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    • cites [168] Wong, 2016, A randomized pilot study of dietary treatments for polycystic ovary syndrome in adolescents, Pediatr Obes source

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    Premisecitation

    The cut point of a basal 17-hydroxyprogesterone >200 ng/dL has been suggested as the threshold for performing ACTH stimulation tests.

    “The cut point of a basal 17-hydroxyprogesterone >200 ng/dL has been suggested as the threshold for performing ACTH stimulation tests [148].”
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    • cites [148] Armengaud, 2009, Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche, J Clin Endocrinol Metab source

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    Premisecitation

    In 22 studies involving more than 2000 adolescents, frequent menstrual bleeding (<21 days) occurred in 23% and prolonged menstrual bleeding (>30 to 45 days) occurred in at least 33%.

    “In 22 studies involving >2000 adolescents, frequent menstrual bleeding (<21 days) occurred in 23% and prolonged menstrual bleeding (>30 to 45 days) occurred in at least 33% [135].”
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    • cites [135] Gunn, 2018, Menstrual patterns in the first gynecological year: a systematic review, J Pediatr Adolesc Gynecol source

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    Premisecitation

    AMH concentrations reflect ovarian reserve and are correlated with the number of growing follicles.

    “AMH concentrations reflect ovarian reserve and are correlated with the number of growing follicles [149].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Pigny, 2003, Elevated serum level of anti-Mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest, J Clin Endocrinol Metab source

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    Premisecitation

    A low-carbohydrate diet (20 to 40 g/d) and a hypocaloric diet (<40 g of fat per day) during 12 weeks improved weight and menstrual irregularities with no difference between the diets.

    “A low-carbohydrate diet (20 to 40 g/d) and a hypocaloric diet (<40 g of fat per day) during 12 weeks improved weight and menstrual irregularities with no difference between the diets.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [160] Lass, 2011, Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls, J Clin Endocrinol Metab source

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    • cites [164] Hoeger, 2008, The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials, J Clin Endocrinol Metab source

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    • cites [167] Marzouk, 2015, Effect of dietary weight loss on menstrual regularity in obese young adult women with polycystic ovary syndrome, J Pediatr Adolesc Gynecol source

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    • cites [168] Wong, 2016, A randomized pilot study of dietary treatments for polycystic ovary syndrome in adolescents, Pediatr Obes source

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    Premisecitation

    A low-energy diet compared with a healthy diet for 6 months was associated with weight loss, more regular menses, and decreased hirsutism.

    “A low-energy diet compared with a healthy diet for 6 months was associated with weight loss, more regular menses, and decreased hirsutism [167].”
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    • cites [167] Marzouk, 2015, Effect of dietary weight loss on menstrual regularity in obese young adult women with polycystic ovary syndrome, J Pediatr Adolesc Gynecol source

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    Premisecitation

    PCOM is an inconsistent finding in adolescent girls and is not associated with anovulation or metabolic abnormalities.

    “PCOM is an inconsistent finding in adolescent girls and is not associated with anovulation or metabolic abnormalities [147].”
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    • cites [147] Codner, 2011, Polycystic ovarian morphology in postmenarchal adolescents, Fertil Steril source

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    Premisecitation

    Nutrition education in addition to exercise training and behavioral therapy for 12 months resulted in weight loss, as well as improvement of menstrual irregularities and androgen levels in adolescents with obesity and PCOS.

    “Nutrition education in addition to exercise training and behavioral therapy for 12 months resulted in weight loss, as well as improvement of menstrual irregularities and androgen levels in adolescents with obesity and PCOS [160].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Lass, 2011, Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls, J Clin Endocrinol Metab source

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    Premisecitation

    A pilot study entailing serial hormone concentrations and ultrasound studies in ovulatory postmenarcheal girls revealed lower steroid (estrogen and progesterone) concentrations, slower dominant follicle growth rate, and longer follicular phases compared with adult women.

    “A pilot study entailing serial hormone concentrations and ultrasound studies in ovulatory postmenarcheal girls revealed lower steroid (estrogen and progesterone) concentrations, slower dominant follicle growth rate, and longer follicular phases compared with adult women; these data suggest that coordinated development of all components of the HPO axis may take up to 5 years postmenarche [136, 137]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [136] Sun, 2019, Healthy post-menarchal adolescent girls demonstrate multi-level reproductive axis immaturity, J Clin Endocrinol Metab source

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    • cites [137] Treloar, 1967, Variation of the human menstrual cycle through reproductive life, Int J Fertil

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    Premisecitation

    Additional comorbidities include decreased quality of life, depression, anxiety, eating disorders and disordered eating, and altered body image.

    “Additional comorbidities include decreased quality of life, depression, anxiety, eating disorders and disordered eating, and altered body image [192, 212–214].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [192] van Zuuren, 2016, Interventions for hirsutism excluding laser and photoepilation therapy alone: abridged Cochrane systematic review including GRADE assessments, Br J Dermatol source

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    • cites [214] Guidi, 2015, Psychological aspects of hyperandrogenic states in late adolescent and young women, Clin Endocrinol (Oxf) source

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    Premisecitation

    Spironolactone is an aldosterone antagonist that blocks the androgen receptor.

    “Spironolactone is an aldosterone antagonist that blocks the AR.”
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    • cites [191] Somani, 2014, Hirsutism: an evidence-based treatment update, Am J Clin Dermatol source

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    Finasteride is a topical medication that inhibits 5α-reductase.

    “Finasteride is a topical medication that inhibits 5α-reductase”
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    Premisecitation

    COCPs are associated with improvement in menstrual irregularity and acne according to a meta-analysis of metformin vs oral contraceptives in adolescents with PCOS.

    “Metformin at a dose of 1700 to 2000 mg/d is associated with greater improvement of BMI, and COCPs are associated with improvement in menstrual irregularity and acne according to a meta-analysis of metformin vs oral contraceptives in adolescents with PCOS and including four RCTs (170 adolescents) [164, 180–184].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [164] Hoeger, 2008, The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials, J Clin Endocrinol Metab source

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    • cites [180] Allen, 2005, Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with polycystic ovary syndrome, J Pediatr Endocrinol Metab source

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    • cites [182] Al-Zubeidi, 2015, Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome, J Pediatr Endocrinol Metab source

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    • cites [183] El Maghraby, 2015, Randomized controlled trial of the effects of metformin versus combined oral contraceptives in adolescent PCOS women through a 24 month follow up period, Middle East Fertil Soc J source

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    • cites [184] Al Khalifah, 2016, Metformin or oral contraceptives for adolescents with polycystic ovarian syndrome: a meta-analysis, Pediatrics source

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    Premisecitation

    Both metformin and oral contraceptives had similar beneficial effects on hirsutism, triglycerides, and high-density lipoprotein cholesterol, but the estimates of effect were derived from low-quality evidence involving small studies.

    “Both metformin and oral contraceptives had similar beneficial effects on hirsutism, triglycerides, and high-density lipoprotein cholesterol, but the estimates of effect were derived from low-quality evidence involving small studies [184].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [184] Al Khalifah, 2016, Metformin or oral contraceptives for adolescents with polycystic ovarian syndrome: a meta-analysis, Pediatrics source

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    Premisecitation

    Laser treatment was associated with a 50% reduction of hair at 6 months after treatment with mild side effects such as pain, skin redness, and perifollicular edema.

    “Laser treatment was associated with a 50% reduction of hair at 6 months after treatment with mild side effects such as pain, skin redness, and perifollicular edema [197].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Haedersdal, 2006, Laser and photoepilation for unwanted hair growth, Cochrane Database Syst Rev

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estrogens in the COCPs decrease free androgens by increasing hepatic production of SHBG and decrease ovarian and adrenal androgen production by suppressing LH levels.

    “Estrogens in the COCPs decrease free androgens by increasing hepatic production of SHBG and decrease ovarian and adrenal androgen production by suppressing LH levels [203].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Creatsas, 1993, Treatment of polycystic ovarian disease during adolescence with ethinylestradiol/cyproterone acetate versus a D-Tr-6-LHRH analog, Int J Gynaecol Obstet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    PCOS is a complex disorder involving multiple organ systems with onset during the early pubertal years.

    “PCOS is a complex disorder involving multiple organ systems with onset during the early pubertal years (Fig. 1).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Data from animal models consistently implicate testosterone as an important factor in the pathogenesis of PCOS.
35 of 35

  • The paper relies on this without support.

    Most available clinical data on PCOS communicate findings and outcomes in adult women.

    “Most available clinical data communicate findings and outcomes in adult women.”

  • The paper relies on this without support.

    The Rotterdam criteria are accepted for adult women, and different diagnostic criteria for PCOS in adolescent girls have been delineated.

    “Whereas the Rotterdam criteria are accepted for adult women, different diagnostic criteria for PCOS in adolescent girls have been delineated.”

  • The paper relies on this without support.

    The enzyme aldo-ketoreductase type 1C, encoded by the AKR1C3 gene, is expressed in adipose tissue and converts the preandrogen androstenedione to testosterone.

    “The enzyme aldo-ketoreductase type 1C, encoded by the AKR1C3 gene, is expressed in adipose tissue and converts the preandrogen androstenedione to testosterone.”

  • The paper relies on this without support.

    The enzyme 5α-reductase type 1, encoded by the SRD5A1 gene, converts testosterone to DHT and is expressed in adipose tissue.

    “Additionally, the enzyme 5α-reductase type 1, encoded by the SRD5A1 gene, converts testosterone to DHT and is expressed in adipose tissue.”

  • The paper relies on this without support.

    Contemporary understanding is that it takes 3 to 4 years postmenarche for adult menstrual cyclicity to mature.

    “Contemporary understanding is that it takes 3 to 4 years postmenarche for adult menstrual cyclicity to mature.”

  • The paper relies on this without support.

    The severity of hirsutism does not correlate with circulating androgen concentrations.

    “The severity of hirsutism does not correlate with circulating androgen concentrations.”

  • The paper relies on this without support.

    Insulin resistance, hyperinsulinemia, and obesity are commonly identified in women with PCOS.

    “Insulin resistance, hyperinsulinemia, and obesity are commonly identified in women with PCOS.”

  • The paper relies on this without support.

    Metformin is the single most studied insulin sensitizer in PCOS.

    “Metformin is the single most studied insulin sensitizer in PCOS.”

  • The paper relies on this without support.

    Cyproterone acetate is not available in the United States.

    “However, cyproterone acetate is not available in the United States.”

  • The paper relies on this without support.

    There are no RCTs evaluating the effect of flutamide alone or in combination with COCPs in adolescents.

    “but there are no RCTs evaluating the effect of flutamide alone or in combination with COCPs in adolescents.”

  • The paper relies on this without support.

    Data from animal models consistently implicate testosterone as an important factor in the pathogenesis of PCOS.

    “Data obtained from animal models have consistently implicated testosterone as an important factor in the pathogenesis of PCOS.”

  • The paper relies on this without support.

    Acne has a major negative impact on adolescent psychosocial well-being.

    “as acne has a major negative impact on adolescent psychosocial well-being.”

  • The paper relies on this without support.

    Psychosocial comorbidities will affect adherence to any interventions.

    “as these comorbidities will affect adherence to any interventions.”
13 of 13

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Cited prenatal-androgen study names a different species

    Minor

    The text describes the cited study as involving female rhesus monkeys, but reference 59 identifies its subjects as sheep.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Johnson T , KaplanL, OuyangP, RizzaP. National Institutes of Health Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome. NIH EbMW Reports. Bethesda, MD: National Institutes of Health, 2012;1:1–14. Available at: https://prevention.nih.gov/sites/default/files/2018-06/FinalReport.pdf. Accessed 17 February 2019.
  2. Goldenring, 1988, Getting into adolescents HEADS, Contemp Pediatr, 5, 75

Cited by

Sorted by citations

Related

Authors
Witchel, S. F., Oberfield, S. E., & Peña, A. S.
Affiliations
  • University of Pittsburgh (US)
  • Morgan Stanley Children's Hospital (US)
  • The University of Adelaide (AU)
Corresponding author
Witchel, Selma Feldman
ORCID
Venue
Journal of the Endocrine Society
Publisher
The Endocrine Society
Published
2019-06-14
Volume
3
Issue
8
Pages
1545-1573
ISSN
2472-1972 (ISSN-L)
DOI
10.1210/js.2019-00078
PMC
PMC6676075
OpenAlex
W2949825098
Semantic Scholar
816223b3ea8123d377e6d647d277d34a5897a1ba
Cited by
653
References
225
Citations by year
2026: 74 · 2025: 101 · 2024: 134 · 2023: 140 · 2022: 100 · 2021: 63 · 2020: 37 · 2019: 3 · 2018: 1
FWCI
7.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the Endocrine Society (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc-nd)
Funders
Australian National Health and Medical Research Council Center (APP1078444)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Health Sciences › Medicine › Dermatology › Acne and Rosacea Treatments and Effects
Keywords
polycystic ovary syndrome, adolescent girls, hyperandrogenism, anovulation, menstrual irregularity, PCOS diagnostic criteria, Rotterdam criteria, PCOS pathophysiology, lifestyle intervention, metformin, oral contraceptives, spironolactone, hirsutism, acne, PCOS comorbidities, transition to adult care

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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