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CliniCal Guidelines Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline Authors: Richard s. legro, silva a. arslanian, david a. ehrmann, Kathleen M. Hoeger, M. Hassan Murad,
Renato Pasquali, and Corrine K. Welt
Affiliations: The Penn state university College of Medicine (R.s.l.), Hershey, Pennsylvania 17033; Children's
Hospital of Pittsburgh (s.a.a.), university of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224;
university of Chicago (d.a.e.), Chicago, illinois 60637; university of Rochester Medical Center (K.M.H.),
Rochester, new York 14627; Mayo Clinic (M.H.M.), Rochester, Minnesota 55905; Orsola-Malpighi Hospital,
university alma Mater studiorum, (R.P.), 40126 Bologna, italy; and Massachusetts General Hospital (C.K.W.),
Boston, Massachusetts 02114
Co-Sponsoring Associations: european society of endocrinology.
Disclaimer: Clinical Practice Guidelines are developed to be of assistance to endocrinologists and other health
care professionals by providing guidance and recommendations for particular areas of practice. The Guidelines
should not be considered inclusive of all proper approaches or methods, or exclusive of others. The Guidelines
cannot guarantee any specific outcome, nor do they establish a standard of care. The Guidelines are not intended
to dictate the treatment of a particular patient. Treatment decisions must be made based on the independent
judgment of health care providers and each patient's individual circumstances.
The endocrine society makes no warranty, express or implied, regarding the Guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. The society shall not be liable for direct, indirect, special, incidental, or consequential damages related to the use of the information contained herein.
First published in Journal of Clinical Endocrinology & Metabolism, December 2013, JCEM jc.2013–2350. endocrine society, 2013 CliniCal Guidelines Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline Table of Contents Method of development of evidence-Based Clinical Practice Guidelines . . . . . . . . . . . . . . . .14 Reprint information, Questions & Correspondences . . . . . . . . . . . . . . . . . inside Back Cover Accreditation StatementThe endocrine society is accredited by the accreditation Council for Continuing Medical education to provide continuing medical education for physicians. The endocrine society has achieved accreditation with Commendation. The endocrine society designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Learning Objectivesupon completion of this educational activity, learners will be able to: • Evaluate patients and perform differential diagnosis to distinguish PCOS from other menstrual disorders. • Identify the lack of accepted diagnostic criteria in adolescents with PCOS.
• Identify appropriate treatment for a woman with PCOS to address clinical hyperandrogenism and • Identify adverse risk factors and potential benefits for OCP use in women with PCOS.
• Identify risk factors for serious adverse events for thromboembolism and related cardiovascular events in women taking hormonal contraceptives.
Target AudienceThis continuing medical education activity should be of substantial interest to endocrinologists and other health care professionals that treat patients with PCOs.
Statement of Independenceas a provider of continuing medical education (CMe) accredited by the accreditation Council for Continuing Medical education, The endocrine society has a policy of ensuring that the content and quality of this educational activity are balanced, independent, objective, and scientifically rigorous. The scientific content of this activity was developed under the supervision of The PCOs Guidelines Task Force.
Disclosure PolicyThe faculty, committee members, and staff who are in position to control the content of this activity are required to disclose to The endocrine society and to learners any relevant financial relationship(s) of the individual or spouse/partner that have occurred within the last 12 months with any commercial interest(s) whose products or services are related to the CMe content. Financial relationships are defined by remuneration in any amount from the commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (e.g., stocks, stock options, or ownership interest excluding diversified mutual funds); honoraria or other payments for participation in speakers' bureaus, advisory boards, or boards of directors; or other financial benefits. The intent of this disclosure is not to prevent CMe planners with relevant financial relationships from planning or delivery of content, but rather to provide learners with information that allows them to make their own judgments of whether these financial relationships may have influenced the educational activity with regard to exposition or conclusion.
The endocrine society has reviewed all disclosures and resolved or managed all identified conflicts of interest, as applicable.
The following task force members who planned and/or reviewed content for this activity reported relevant
financial relationships:

Silva A. Arslanian, MD is on the advisory board for sanofi-aventis, novo nordisk and Bristol-Myers squibb. she
is a consultant for Gilead and Boehringer engelheim.
David A. Ehrmann, MD is on the advisory board for astra-Zeneca.
Corrine K. Welt, MD is a consultant for astra-Zeneca.
The following committee members who planned and/or reviewed content for this activity reported no relevant
financial relationships:
Richard S. Legro, MD (chair); M. Hassan Murad, MD; Kathleen M. Hoeger; and
Renato Pasquali, MD.

endocrine society staff associated with the development of content for this activity reported no relevant financial relationships.
Use of professional judgment:
The educational content in this activity relates to basic principles of diagnosis and therapy and does not substitute for individual patient assessment based on the health care provider's examination of the patient and consideration of laboratory data and other factors unique to the patient. standards in medicine change as new data become available. Drugs and dosages:
When prescribing medications, the physician is advised to check the product information sheet accompanying each drug to verify conditions of use and to identify any changes in drug dosage schedule or contraindications.
Policy on Unlabeled/Off-Label Use The endocrine society has determined that disclosure of unlabeled/off-label or investigational use of commercial product(s) is informative for audiences and therefore requires this information to be disclosed to the learners at the beginning of the presentation. uses of specific therapeutic agents, devices, and other products discussed in this educational activity may not be the same as those indicated in product labeling approved by the Food and drug administration (Fda). The endocrine society requires that any discussions of such "off-label" use be based on scientific research that conforms to generally accepted standards of experimental design, data collection, and data analysis. Before recommending or prescribing any therapeutic agent or device, learners should review the complete prescribing information, including indications, contraindications, warnings, precautions, and adverse events.
Privacy and Confidentiality StatementThe endocrine society will record learner's personal information as provided on CMe evaluations to allow for issuance and tracking of CMe certificates. The endocrine society may also track aggregate responses to questions in activities and evaluations and use these data to inform the ongoing evaluation and improvement of its CMe program. no individual performance data or any other personal information collected from evaluations will be shared with third parties.
Acknowledgement of Commercial SupportThis activity is not supported by educational grant(s) from commercial supporters.
AmA PrA Category 1 Credit ™ (CmE) InformationTo receive a maximum of 2 AMA PRA Category 1 Credits™ participants must complete an activity evaluation, as well as a post-test achieving a minimum score of 70%. if learners do not achieve a passing score of 70%, they have the option to change their answers and make additional attempts to achieve a passing score. learners also have the option to clear all answers and start over. To claim your CMe credit, please go to https://www.endocrine.org/education-and-practice-management/continuing-medical-education/publication-cme.
method of ParticipationThis enduring material is presented in print and online. The estimated time to complete this activity, including review of material, is 2 hours. System RequirementsTo complete this activity, participants must: Have access to a computer with an Internet connection. Use a major web browser, such as Internet Explorer 7+, Firefox 2+, Safari, Opera, or Google Chrome; in addition, cookies and Javascript must be enabled in the browser's options. Last Review Date:
Activity Release Date:
Activity Expiration Date: november 2016
(date after which this enduring material is no longer certified for AMA PRA Category 1 Credits™)
For technical assistance or questions about content or obtaining CMe credit, please contact the endocrine society at education@endocrine.org. Objective: The aim was to formulate practice guide- Conclusions: We suggest using the Rotterdam criteria lines for the diagnosis and treatment of polycystic for diagnosing PCOs (presence of two of the following ovary syndrome (PCOs).
criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). establishing a diagnosis of PCOs Participants: an endocrine society-appointed Task is problematic in adolescents and menopausal women. Force of experts, a methodologist, and a medical Hyperandrogenism is central to the presentation in writer developed the guideline.
adolescents, whereas there is no consistent phenotype in postmenopausal women. evaluation of women Evidence: This evidence-based guideline was with PCOs should exclude alternate androgen-excess developed using the Grading of Recommendations, disorders and risk factors for endometrial cancer, assessment, development, and evaluation (GRade) mood disorders, obstructive sleep apnea, diabetes, and system to describe both the strength of recommenda- cardiovascular disease. Hormonal contraceptives are tions and the quality of evidence.
the first-line management for menstrual abnormalities and hirsutism/acne in PCOs. Clomiphene is currently Consensus Process: One group meeting, several the first-line therapy for infertility; metformin is bene- conference calls, and e-mail communications enabled ficial for metabolic/glycemic abnormalities and for consensus. Committees and members of the endo- improving menstrual irregularities, but it has limited crine society and the european society of endocri- or no benefit in treating hirsutism, acne, or infertility. nology reviewed and commented on preliminary Hormonal contraceptives and metformin are the drafts of these guidelines. Two systematic reviews were treatment options in adolescents with PCOs. The conducted to summarize supporting evidence.
role of weight loss in improving PCOs status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study.
J Clin Endocrinol Metab, December 2013, JCEM
Abbreviations: BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; HC, hormonal contraceptive; HDL, high-density lipoprotein; HgbA1c, hemoglobin A1c; IGT, impaired glucose tolerance; IR, insulin resistance; IVF, in vitro fertilization; LDL, low-density lipoprotein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OGTT, oral glucose tolerance test; 17-OHP, 17-hydroxyprogesterone; OHSS, ovarian hyperstimulation syndrome; OR, odds ratio; OSA, obstructive sleep apnea; PCO, polycystic ovary (or ovaries); PCOS, polycystic ovary syndrome; RR, relative risk; T2DM, type 2 DM. 2.0. Associated morbidity and evaluation SUmmARy Of RECOmmEnDATIOnS 2.1. We recommend that a physical examination should document cutaneous manifestations of PCOs: terminal hair growth (see hirsutism guidelines, Ref. 1.0. Diagnosis of PCOS 1), acne, alopecia, acanthosis nigricans, and skin tags (1 Diagnosis in adults 1.1. We suggest that the diagnosis of polycystic ovary syndrome (PCOs) be made if two of the three 2.2. Women with PCOs are at increased risk of following criteria are met: androgen excess, ovulatory anovulation and infertility; in the absence of anovula- dysfunction, or polycystic ovaries (PCO) (Tables 1 tion, the risk of infertility is uncertain. We recom- and 2), whereas disorders that mimic the clinical mend screening ovulatory status using menstrual features of PCOs are excluded. These include, in all history in all women with PCOs seeking fertility. women: thyroid disease, hyperprolactinemia, and some women with PCOs and a eumenorrheic nonclassic congenital adrenal hyperplasia (primarily menstrual history may still experience anovulation 21-hydroxylase deficiency by serum 17-hydroxypro- and a midluteal serum progesterone may be helpful as gesterone [17-OHP]) (Table 3). in select women with an additional screening test (1 amenorrhea and more severe phenotypes, we suggest more extensive evaluation excluding other causes 2.3. We recommend excluding other causes of infer- tility, beyond anovulation, in couples where a woman has PCOs (1 Diagnosis in adolescents 1.2. We suggest that the diagnosis of PCOs in an adolescent girl be made based on the presence of 2.4. Because women with PCOs are at increased risk clinical and/or biochemical evidence of hyperan- of pregnancy complications (gestational diabetes, drogenism (after exclusion of other pathologies) in preterm delivery, and pre-eclampsia) exacerbated by the presence of persistent oligomenorrhea. anovula- obesity, we recommend preconceptual assessment of tory symptoms and PCO morphology are not suffi- body mass index (BMi), blood pressure, and oral cient to make a diagnosis in adolescents, as they may glucose tolerance (1 be evident in normal stages in reproductive matura-tion (2 Fetal origins Diagnosis in perimenopause and menopause 2.5. The evidence for intrauterine effects on develop- ment of PCOs is inconclusive. We suggest no specific 1.3. although there are currently no diagnostic interventions for prevention of PCOs in offspring of criteria for PCOs in perimenopausal and menopausal women with PCOs (2 women, we suggest that a presumptive diagnosis of PCOs can be based upon a well-documented long- term history of oligomenorrhea and hyperandrogenism during the reproductive years. The presence of PCO 2.6. Women with PCOs share many of the risk factors associated with the development of endometrial morphology on ultrasound would provide additional cancer including obesity, hyperinsulinism, diabetes, supportive evidence, although this is less likely in a menopausal woman (2 and abnormal uterine bleeding. However, we suggest against routine ultrasound screening for endometrial thickness in women with PCOs (2 TABLE 1. Summary of Proposed Diagnostic Criteria for PCOS in Adults
Specific Abnormality Remaining Criteria) Clinical hyperandrogenism may include hirsutism (defined as excessive terminal hair that appears in a male pattern) (1, 295), acne, or androgenic alopecia.
Biochemical hyperandrogenism refers to an elevated serum androgen level and typically includes an elevated total, bioavailable, or free serum T level. Given variability in T levels and the poor standardization of assays (31), it is difficult to define an absolute level that is diagnostic of PCOS or other causes of hyperandrogenism, and the Task Force recommends familiarity with local assays.
Anovulation may manifest as frequent bleeding at intervals <21 d or infrequent bleeding at intervals >35 d. Occasion- ally, bleeding may be anovulatory despite falling at a normal interval (25–35 d). A midluteal progesterone documenting anovulation may help with the diagnosis if bleeding intervals appear to suggest regular ovulation.
The PCO morphology has been defined by the presence of 12 or more follicles 2–9 mm in diameter and/or an increased ovarian volume >10 mL (without a cyst or dominant follicle) in either ovary (78).
The Task Force suggests using the Rotterdam criteria for the diagnosis of PCOS, acknowledging the limitations of each of the three criteria (Table 2). All criteria require exclusion of other diagnoses (listed in Table 3) that cause the same symptoms and/or signs (6, 7, 8, 9). X, may be present for diagnosis; XX, must be present for diagnosis.
a Clinical or biochemical hyperandrogenism is included as one criterion in all classification systems. If clinical hyperandrogenism is present with the absence of virilization, then serum androgens are not necessary for the diagnosis. Similarly, when a patient has signs of hyperandrogenism and ovulatory dysfunction, an ovarian ultrasound is not necessary.
2.7. increased adiposity, particularly abdominal, is 2.8. We suggest screening women and adolescents associated with hyperandrogenemia and increased with PCOs for depression and anxiety by history and, metabolic risk (see cardiovascular disease prevention if identified, providing appropriate referral and/or guidelines, Ref. 2). Therefore, we recommend screening adolescents and women with PCOs for increased adiposity, by BMi calculation and measure-ment of waist circumference (1 TABLE 2. Diagnostic Strengths and Weaknesses of the main features of PCOS as Adapted from the nIH Evidence-Based
methodology Workshop on PCOS Diagnostic Criteria Included as a component in all Measurement is performed only in blood.
major classifications A major clinical concern for patients Concentrations differ during time of day.
Animal models employing androgen Concentrations differ with age. Normative data are not excess resembling but not fully clearly defined. Assays are not standardized across mimicking human disease laboratories. Clinical hyperandrogenism is difficult to quantify and may vary by ethnic group, eg, low rates of hirsutism in women with PCOS from east Asia. Tissue sensitivity is not assessed.
Included as a component in all Normal ovulation is poorly defined.
major classifications A major clinical concern for patients Normal ovulation varies over a woman's lifetime.
Infertility a common clinical Ovulatory dysfunction is difficult to measure objectively. Anovulatory cycles may have bleeding patterns that are interpreted as normal.
Historically associated with syndrome May be associated with hypersensi- Difficult to obtain standardized measurement. Lack of tivity to ovarian stimulation normative standards across the menstrual cycle and lifespan (notably in adolescence). May be present in other disorders that mimic PCOS. Technology required to accurately image not universally available. Transvaginal imaging possibly inappropriate in certain circumstances (eg, adolescence) or certain cultures.
TABLE 3. Other Diagnoses to Exclude in All Women Before making a Diagnosis of PCOS
Reference for further Evaluation and Treatment of Abnormal findings; first Author, year (Ref.) TSH > the upper limit of normal suggests Ladenson, 2000 (10) hypothyroidism; TSH < the lower limit, usually < 0.1 mIU/L, suggests > Upper limit of normal for the assay Melmed, 2011 (11) Early morning (before 200–400 ng/dL depending on the assay Speiser, 2010 (12) congenital adrenal 8 am) serum 17-OHP (applicable to the early follicular phase of a normal menstrual cycle as levels rise with ovulation), but a cosyntropin stimula- tion test (250 µg) is needed if levels fall near the lower limit and should stimulate 17-OHP > 1000 ng/dL TABLE 4. Diagnoses to Consider Excluding in Select Women, Depending on Presentation
Reference for further Suggestive features in the Presentation Tests to Assist in the Diagnosis Treatment of Abnormal findings; first Author, Amenorrhea (as opposed to oligo- Serum or urine hCG (positive) Morse, 2011 (17) menorrhea), other signs and symptoms of pregnancy including breast fullness, uterine cramping, etc.
Amenorrhea, clinical history of low Serum LH and FSH (both low to body weight/BMI, excessive exercise, low normal), serum estradiol (low) and a physical exam in which signs of androgen excess are lacking; multi- follicular ovaries are sometimes present Amenorrhea combined with symptoms of Serum FSH (elevated), serum Nelson, 2009 (296) estrogen deficiency including hot flashes and urogenital symptoms Virilization including change in voice, Serum T and DHEAS levels Carmina, 2006 (16) male pattern androgenic alopecia, and (markedly elevated), ultrasound clitoromegaly; rapid onset of symptoms imaging of ovaries, MRI of adrenal glands (mass or tumor Many of the signs and symptoms of 24-h urinary collection for urinary Nieman, 2008 (19) PCOS can overlap with Cushing's free cortisol (elevated), late (ie, striae, obesity, dorsocervical fat night salivary cortisol (elevated), (ie, buffalo hump, glucose intolerance); overnight dexamethasone however, Cushing's is more likely to be suppression test (failure to present when a large number of signs suppress morning serum cortisol and symptoms, especially those with high discriminatory index (eg, myopathy, plethora, violaceous striae, easy bruising) are present, and this presenta- tion should lead to screening Oligomenorrhea and skin changes Serum free IGF-1 level (elevated), Melmed, 2009 (20) (thickening, tags, hirsutism, hyper- MRI of pituitary (mass or tumor hidrosis) may overlap with PCOS. However, headaches, peripheral vision loss, enlarged jaw (macrognathia), frontal bossing, macroglossia, increased shoe and glove size, etc., are indica- tions for screening Abbreviations: DHEAS, dehydroepiandrosterone sulfate; HA, hypothalamic amenorrhea; hCG, human chorionic gonadotropin; MRI, magnetic resonance imaging.
a Additionally there are very rare causes of hyperandrogenic chronic anovulation that are not included in this table because they are so rare, but they must be considered in patients with an appropriate history. These include other forms of congenital adrenal hyperplasia (eg, 11β-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase), related congenital disorders of adrenal steroid metabolism or action (eg, apparent/cortisone reductase deficiency, apparent DHEA sulfotransferase deficiency, glucocorticoid resistance), virilizing congenital adrenal hyperplasia (adrenal rests, poor control, fetal programming), syndromes of extreme IR, drugs, portohepatic shunting, and disorders of sex development.
Sleep-disordered breathing/obstructive sleep Type 2 diabetes mellitus (T2Dm) apnea (OSA) 2.11. We recommend the use of an oral glucose 2.9. We suggest screening overweight/obese adoles- tolerance test (OGTT) (consisting of a fasting and cents and women with PCOs for symptoms suggestive 2-hour glucose level using a 75-g oral glucose load) to of Osa and, when identified, obtaining a definitive screen for impaired glucose tolerance (iGT) and diagnosis using polysomnography. if Osa is diag- T2dM in adolescents and adult women with PCOs nosed, patients should be referred for institution of because they are at high risk for such abnormalities appropriate treatment (2 ). a hemoglobin a1c (Hgba1c) test may be considered if a patient is unable or unwilling to Nonalcoholic fatty liver disease (NAFLD) and complete an OGTT (2 ). Rescreening is nonalcoholic steatohepatitis (NASH) suggested every 3–5 years, or more frequently if clin-ical factors such as central adiposity, substantial 2.10. We suggest awareness of the possibility of weight gain, and/or symptoms of diabetes develop naFld and nasH but recommend against routine 2.12. We recommend that adolescents and women with PCOs be screened for the following cardio- TABLE 5. Cardiovascular Risk Stratification in
vascular disease risk factors (Table 5): family history of early cardiovascular disease, cigarette smoking, iGT/T2dM, hypertension, dyslipidemia, Osa, and At risk—PCOS women with any of the following obesity (especially increased abdominal adiposity) Obesity (especially increased abdominal adiposity) Cigarette smoking Hormonal contraceptives (HCs): indications and Dyslipidemia (increased LDL-cholesterol and/or 3.1. We recommend HCs (ie, oral contraceptives, Subclinical vascular disease patch, or vaginal ring) as first-line management for the menstrual abnormalities and hirsutism/acne of Impaired glucose tolerance PCOs (refer to hirsutism guidelines in Ref. 1 , recom- Family history of premature cardiovascular disease mendation 2.1.1), which treat these two problems (<55 y of age in male relative; <65 y of age in At high risk—PCOS women with: 3.2. We recommend screening for contraindications to HC use via established criteria (see Table 6 and Metabolic syndrome ). For women with PCOs, we do not suggest one HC formulation over another (2 Overt vascular or renal disease, cardiovascular diseases role of exercise in lifestyle therapy The Androgen Excess and Polycystic Ovary Syndrome Society relied 3.3. We suggest the use of exercise therapy in the upon evidence-based studies and concluded that women with PCOS be management of overweight and obesity in PCOs stratified as being either at risk or at high risk for cardiovascular disease using the criteria shown (167).
). although there are no large randomized TABLE 6. Considerations for Use of Combined HCs, Including Pill, Patch, and Vaginal Ring, in Women with PCOS
Based on Relevant Conditions further Classification A condition that health risk if the Menarche to <40 y Age ≥35 y and smokes <15 cigarettes/d Age ≥35 y and smokes ≥15 cigarettes/d History of gestational Adequately controlled Elevated blood pressure levels (properly taken measurements): systolic, 140–159 mm Hg; or diastolic, 90–99 mm Hg Elevated blood pressure levels (properly taken measurements): systolic, ≥160 mm Hg; or Known hyperlipidemias Depressive disorders Before evaluationa further Classification History of gestational Nonvascular diabetes, insulin or non-insulin Vascular disease including neuropathy, retinopathy, nephropathy b Diabetes duration >20 yb The boxes indicate the recommendation for the condition. The four possible recommendations are a spectrum ranging from condition 1, which favors the use of the pill, to condition 4, which discourages the use of the pill. [Adapted from: U.S. Medical Eligibility Criteria for Contraceptive Use. MMWR Recomm Rep. 2010;59:1–86 (3), with permission. Centers for Disease Control and Prevention.]a If pregnancy or an underlying pathological condition (such as pelvic malignancy) is suspected, it must be evaluated and the category adjusted after evaluation.
b The category should be assessed according to the severity of the condition.
trials of exercise in PCOs, exercise therapy, alone or Treatment of infertility in combination with dietary intervention, improves 3.7. We recommend clomiphene citrate (or compa- weight loss and reduces cardiovascular risk factors and rable estrogen modulators such as letrozole) as the diabetes risk in the general population.
first-line treatment of anovulatory infertility in women with PCOs (1 role of weight loss in lifestyle therapy 3.8. We suggest the use of metformin as an adjuvant 3.4. We suggest that weight loss strategies begin with therapy for infertility to prevent ovarian hyperstimu- calorie-restricted diets (with no evidence that one lation syndrome (OHss) in women with PCOs type of diet is superior) for adolescents and women undergoing in vitro fertilization (iVF) (2 with PCOs who are overweight or obese (2 Weight loss is likely beneficial for both reproductive Use of other drugs and metabolic dysfunction in this setting. Weight loss is likely insufficient as a treatment for PCOs in 3.9. We recommend against the use of insulin sensi- tizers, such as inositols (due to lack of benefit) or thiazolidinediones (given safety concerns), for the Use of metformin treatment of PCOs (1 3.5. We suggest against the use of metformin as a 3.10. We suggest against the use of statins for treat- first-line treatment of cutaneous manifestations, for ment of hyperandrogenism and anovulation in PCOs prevention of pregnancy complications, or for the until additional studies demonstrate a favorable risk- treatment of obesity (2 benefit ratio (2 ). However, we suggest statins in women with PCOs who meet current indications 3.6. We recommend metformin in women with for statin therapy (2 PCOs who have T2dM or iGT who fail lifestyle ). For women with PCOs Treatment of adolescents with menstrual irregularity who cannot take or do not tolerate HCs, we suggest metformin as second-line 3.11. We suggest HCs as the first-line treatment in adolescents with suspected PCOs (if the therapeutic goal is to treat acne, hirsutism, or anovulatory symp- quality. The Task Force has confidence that persons toms, or to prevent pregnancy) (2 who receive care according to the strong recommen- suggest that lifestyle therapy (calorie-restricted diet dations will derive, on average, more good than harm. and exercise) with the objective of weight loss should Weak recommendations require more careful consid- also be first-line treatment in the presence of over- eration of the person's circumstances, values, and weight/obesity (2 ). We suggest metformin as preferences to determine the best course of action. a possible treatment if the goal is to treat iGT/meta- linked to each recommendation is a description of the bolic syndrome (2 ). The optimal duration of evidence and the values that panelists considered in HC or metformin use has not yet been determined.
making the recommendation; in some instances, there are remarks, a section in which panelists offer tech- 3.12. For premenarchal girls with clinical and nical suggestions for testing conditions, dosing, and biochemical evidence of hyperandrogenism in the monitoring. These technical comments reflect the presence of advanced pubertal development (ie, ≥ best available evidence applied to a typical person Tanner stage iV breast development), we suggest being treated. Often this evidence comes from the unsystematic observations of the panelists and their values and preferences; therefore, these remarks are considered.
mETHOD Of DEVELOPmEnT The endocrine society maintains a rigorous conflict Of EVIDEnCE-BASED CLInICAL of interest review process for the development of clin-ical practice guidelines. all Task Force members must PRACTICE GUIDELInES declare any potential conflicts of interest, which are reviewed before they are approved to serve on the Task Force and periodically during the development The Clinical Guidelines subcommittee of the endo- of the guideline. The conflict of interest forms are crine society deemed the diagnosis and treatment of vetted by the Clinical Guidelines subcommittee PCOs a priority area in need of practice guidelines (CGs) before the members are approved by the soci- and appointed a Task Force to formulate evidence- ety's Council to participate on the guideline Task based recommendations. The Task Force followed the Force. Participants in the guideline development must approach recommended by the Grading of Recom- include a majority of individuals without conflict of mendations, assessment, development, and evalua- interest in the matter under study. Participants with tion (GRade) group, an international group with conflicts of interest may participate in the develop- expertise in development and implementation of ment of the guideline, but they must have disclosed evidence-based guidelines (4). a detailed description all conflicts. The CGs and the Task Force have of the grading scheme has been published elsewhere reviewed all disclosures for this guideline and resolved (5). The Task Force used the best available research or managed all identified conflicts of interest.
evidence to develop the recommendations. The Task Force also used consistent language and graphical Conflicts of interest are defined by remuneration in descriptions of both the strength of a recommenda- any amount from the commercial interest(s) in the tion and the quality of evidence. in terms of the form of grants; research support; consulting fees; strength of the recommendation, strong recommen- salary; ownership interest (eg, stocks, stock options, or dations use the phrase "we recommend" and the ownership interest excluding diversified mutual number 1, and weak recommendations use the phrase funds); honoraria or other payments for participation "we suggest" and the number 2. Cross-filled circles in speakers' bureaus, advisory boards, or boards of indicate the quality of the evidence, such that directors; or other financial benefits. Completed forms denotes very low quality evidence; are available through the endocrine society office.
, moderate quality; and Funding for this guideline was derived solely from the of the ovaries. We do not endorse the need for endocrine society, and thus the Task Force received universal screening with androgen assays or ultra- no funding or remuneration from commercial or other sound if patients already meet two of the three criteria clinically. it is recommended that the features leading to the diagnosis are documented. We recommend using the current definition of the Rotterdam criteria to document PCO morphology (at least one ovary 1.0. DIAGnOSIS Of PCOS with 12 follicles of 2–9 mm or a volume >10 ml in the absence of a dominant follicle >10 mm), in the absence of age-based criteria.
Diagnosis in adults disorders that mimic PCOs are comparatively easy to 1.1. We suggest that the diagnosis of PCOs be made exclude; therefore, all women should be screened with if two of the three following criteria are met: androgen a TsH, prolactin, and 17-OHP level (Table 3) excess, ovulatory dysfunction, or PCO (Tables 1 and (10–12). Hyperprolactinemia can present with amen- 2), whereas disorders that mimic the clinical features orrhea or hirsutism (13–14). Thyroid disease may of PCOs are excluded. These include, in all women: present with irregular menstrual cycles. in women thyroid disease, hyperprolactinemia, and nonclassic with hyperandrogenism, nonclassic congenital congenital adrenal hyperplasia (primarily 21-hydrox- adrenal hyperplasia should be excluded because it can ylase deficiency by serum 17-OHP) (Table 3). in be found in 1.5–6.8% of patients presenting with select women with amenorrhea and more severe androgen excess (15–16). in select women who phenotypes, we suggest more extensive evaluation present with amenorrhea, virilization, or physical excluding other causes (Table 4) (2 findings not associated with PCOs, such as proximal muscle weakness (Cushing's syndrome) or frontal bossing (acromegaly), other diagnoses should be considered and excluded (Table 4).
PCOs is a common disorder with systemic metabolic manifestations. its etiology is complex, heteroge- 1.1. Values and preferences neous, and poorly understood. There are three defini-tions for PCOs currently in use that variably rely on in the absence of evidence-based diagnostic criteria, androgen excess, chronic anovulation, and PCO to we have relied on the recommendations of the niH make the diagnosis (Table 1). However, all criteria are Panel as noted above. The presence of specific pheno- consistent in that PCOs is considered a diagnosis of typic features may result in different risk and comor- exclusion. all three sets of diagnostic criteria include bidity profiles. For example, hyperandrogenism may hyperandrogenism, either clinical or biochemical, be more highly associated with metabolic abnormali- and anovulation (6–9). The Rotterdam criteria were ties, whereas irregular menses and PCO morphology the first to incorporate ovarian morphology on ultra- may be more highly associated with infertility. When sound as part of the diagnostic criteria (8–9).
interpreting published research, clinicians should note that criteria different from their own may be used The panel from a recent national institutes of when performing research. The committee notes that Health (niH)-sponsored evidence-Based Method- the diagnosis of PCOs is problematic in women who ology workshop on PCOs endorsed the Rotterdam are perimenarchal or perimenopausal because amen- criteria, although they identified the strengths and orrhea and oligomenorrhea are natural stages in weaknesses of each of the three cardinal features reproductive maturation and senescence, as are (Table 2). These criteria allow the diagnosis to be changes in circulating androgens and ovarian made clinically (based upon a history of hyperandro- morphology. Therefore, we discuss the diagnosis of genic chronic anovulation) as well as biochemically PCOs separately in these groups. Finally, because with androgen assays or with ultrasound examination there is evidence of a genetic component to PCOs score was standardized only in adult Caucasians and and familial clustering of reproductive and metabolic may have a lower cut-point in adolescents (29). abnormalities in male and female relatives, a careful androgenic alopecia has not been studied in adoles- family history should be taken, and further screening cents and should be viewed cautiously in diagnosing of first-degree relatives is a consideration.
There is a lack of well-defined cutoff points for Diagnosis in adolescents androgen levels during normal pubertal maturation 1.2. We suggest that the diagnosis of PCOs in (30), as well as the lack of T assay standardization an adolescent girl be made based on the presence of (31). Furthermore, hyperandrogenemia appears to be clinical and/or biochemical evidence of hyperan- exacerbated by obesity because a significant propor- drogenism (after exclusion of other pathologies) in tion of obese girls have elevated androgen levels the presence of persistent oligomenorrhea. anovula- across puberty compared with normal-weight girls tory symptoms and PCO morphology are not suffi- (32). Hyperandrogenemia during puberty may be cient to make a diagnosis in adolescents, as they may associated with infertility in later life (33), and adult be evident in normal stages in reproductive matura- cutoffs should be used until appropriate pubertal levels are defined.
lastly, the Rotterdam ultrasound PCO criteria were not validated for adolescents. Recommending a trans- all PCOs diagnostic criteria were derived for adults vaginal ovarian ultrasound in this group raises prac- (Table 1), not adolescents. Furthermore, normal tical and ethical concerns. Transabdominal ultrasound, adolescent physiology may mimic symptoms of already limited in evaluating the ovaries, is rendered PCOs. Oligomenorrhea is common after menarche even less technically adequate with obesity, common during normal puberty and is therefore not specific to in adolescent PCOs (34). in addition, multifollicular adolescents with PCOs. anovulatory cycles comprise ovaries are a feature of normal puberty that subsides 85% of menstrual cycles in the first year after with onset of regular menstrual cycling (35) and may menarche, 59% in the third year, and 25% by the be difficult to distinguish from PCO morphology (20). sixth year. anovulatory cycles are associated with it is possible that elevated anti-Mullerian hormone higher serum androgen and lH levels (21). approxi- levels may serve as a noninvasive screening or diag- mately two-thirds of adolescents with PCOs will nostic test for PCO in this population, although there have menstrual symptoms, and for one-third it will are no well-defined cutoffs (36–37).
be the presenting symptom, with the spectrum from in summary, the diagnosis of PCOs in adolescents primary amenorrhea to frequent dysfunctional should be based on a complete picture that includes bleeding (22). Therefore, it is appropriate to evaluate clinical signs and symptoms of androgen excess, persistent oligomenorrhea or amenorrhea as an early increased androgen levels, and exclusion of other clinical sign of PCOs, especially when it persists 2 causes of hyperandrogenemia in the setting of years beyond menarche (23).
acne is common although transitory during adoles-cence (24); thus, it should not be used in isolation 1.2. Values and preferences to define hyperandrogenism in adolescents (25). Hirsutism may develop slowly and thus be less severe in making this recommendation, the committee in adolescents than in adults due to the shorter expo- acknowledges that the diagnosis of PCOs in adoles- sure to hyperandrogenism (26). However, hirsutism cents is less straightforward than in adults. a high was a major symptom in about 60% of adolescents in index of awareness is needed to initiate a thorough one study (27) and may be suggestive of PCOs in medical and laboratory evaluation of adolescent girls adolescents (28). The Ferriman-Gallwey hirsutism with signs and symptoms of PCOs, including a family history of PCOs. until higher quality evidence suggest an androgen-producing tumor in postmeno- becomes available, this recommendation places a pausal women.
higher value in making an early diagnosis of PCOs in adolescents for timely initiation of therapy, which 1.3. Values and preferences outweighs harms and burdens of misdiagnosis.
We recognize that the diagnosis of PCOs in post- Diagnosis in perimenopause and menopause menopausal women is problematic but feel that it is unlikely that a woman can develop PCOs in the peri- 1.3. although there are currently no diagnostic menopause or menopause if she has not had symptoms criteria for PCOs in perimenopausal and menopausal earlier. We recognize that there are few prospective women, we suggest that a presumptive diagnosis of studies to document the natural history of ovarian PCOs can be based upon a well-documented long- function with age in women with PCOs.
term history of oligomenorrhea and hyperandrogenism during the reproductive years. The presence of PCO morphology on ultrasound would provide additional supportive evidence, although this is less likely in a 2.0. ASSOCIATED mORBIDITy menopausal woman (2 The natural history of PCOs through perimenopause into menopause is poorly studied, but many aspects of 2.1. We recommend that a physical examination the syndrome appear to improve. Ovarian size, follicle should document cutaneous manifestations of PCOs: count, and anti-Mullerian hormone levels (a marker terminal hair growth (see hirsutism guidelines, Ref. of antral follicle count) decrease with normal aging in 1), acne, alopecia, acanthosis nigricans, and skin tags women with and without PCOs (38–40). However, the decline in ovarian volume and follicle count may be less in women with PCOs than in normal women (39, 41–42). similarly, androgen levels decline with age in women with and without PCOs (serum T The major clinical manifestations of hyperan- declines 50% between the ages of 20 and 40 y) drogenism include hirsutism, acne, and androgenic (43–45), with reports of improved menstrual frequency alopecia. The history of skin problems should assess in PCOs (46–47), although there is little evidence to the age at onset, the rate of progression, previous support a decline in serum T associated with the long-term treatments (including anabolic agents), menopause transition per se (43).
any change with treatment or with fluctuations in body weight, and the nature of the skin complaint The diagnosis of PCOs in postmenopausal women is relative to those of other family members. in rare more problematic than in adolescents. There are no instances, male pattern balding, increased muscle age-related T cutoffs for the diagnosis. Furthermore, T mass, deepening of the voice, or clitoromegaly may assays used to diagnose hyperandrogenemia in women occur, suggesting virilizing androgen levels and a are imprecise (31), even for assays utilizing tandem possible underlying ovarian or adrenal neoplasm or mass spectrometry technology (48). nevertheless, severe insulin-resistant states (9, 50) (Table 4). supporting studies have shown that peri- and post- notably, in obese, insulin-resistant women with menopausal mothers of women with PCOs with a PCOs, acanthosis nigricans is often present, as are history of irregular menses tended to have features of skin tags (51).
PCOs as well as metabolic abnormalities, implying that aspects of the PCOs phenotype may persist with age (49). Very high T levels and/or virilization may subjective. We place value on recognizing these particularly stressful symptoms, even if they do not The prevalence of hirsutism in the general popula- correlate with objective findings. alopecia and acne tion ranges from 5–15%, with relevant differences may be related to hyperandrogenism and are according to ethnicity and geographic location (9). distressing; therefore, our preference is to document in a large study of patients with clinical hyperan- and consider consultation with a dermatologist and to drogenism, 72.1% of 950 patients were diagnosed determine whether they are related to other etiologies with PCOs (16). Therefore, PCOs represents the in the case of alopecia or in the case of acne if unre- major cause of hirsutism, but the presence of hirsutism sponsive to HCs. More research is needed to quantify does not fully predict ovulatory dysfunction. Overall, the relationship between cutaneous signs of hyper- hirsutism is present in approximately 65–75% of androgenism and cardiovascular disease.
patients with PCOs (although lower in asian popu-lations) (15, 52). Hirsutism may predict the meta- bolic sequelae of PCOs (53) or failure to conceive with infertility treatment (54). Hirsutism often tends 2.2. Women with PCOs are at increased risk of to be more severe in abdominally obese patients (9). anovulation and infertility; in the absence of anovula- The most common method of visually assessing tion, the risk of infertility is uncertain. We recom- hirsutism is still the modified Ferriman-Gallwey mend screening ovulatory status using menstrual score (1, 55).
history in all women with PCOs seeking fertility. some women with PCOs and a eumenorrheic Acne and alopecia menstrual history may still experience anovulation and a midluteal serum progesterone may be helpful as acne is common in women with PCOs, particularly an additional screening test (1 in the teenage years, and the prevalence varies (14–25%), with some difference in relation to 2.3. We recommend excluding other causes of infer- ethnicity and patient age (56). The combined preva- tility, beyond anovulation, in couples where a woman lence of acne with hirsutism in PCOs is still poorly defined, although there is clinical evidence that the prevalence of each of these features is higher than the 2.2–2.3. Evidence combination of the two (57). androgenic alopecia may be graded by well-known subjective methods, infertility was one of the original symptoms of PCOs such as the ludwig score (58). androgenic alopecia is described by stein and leventhal (63) and is a less frequent and presents later, but it remains a common presenting complaint (64). among a large distressing complaint with significant psychopatho- series of women presenting with PCOs, close to 50% logical comorbidities (9). it may be associated with reported primary infertility, and 25% reported hirsutism and acne, although there is a poor correla- secondary infertility (65). Population-based studies of tion with biochemical hyperandrogenism. some infertility have suggested that anovulatory infertility studies have demonstrated an association between (encompassing PCOs) is common, accounting for androgenic alopecia with metabolic syndrome (59) 25–40% of cases (65–66). Furthermore, PCOs is esti- and insulin resistance (iR) (60–61). some studies mated to be the most common cause of ovulatory found that acne and androgenic alopecia are not good dysfunction, accounting for 70–90% of ovulatory markers for hyperandrogenism in PCOs, compared disorders (67). Prolonged periods of anovulation are with hirsutism (53, 62).
likely associated with increased infertility (68). Women with PCOs had a monthly spontaneous ovulation rate of 32% on placebo in a multicenter 2.1. Values and preferences trial that randomly assigned subjects to placebo or evaluating hirsutism, acne, and alopecia in women troglitazone (69). nevertheless, lifetime fecundity in with PCOs depends on careful grading, but is swedish women with PCOs was similar to controls, and almost three-fourths of women with PCOs pregnancy loss in women with PCOs (77–78). a conceived spontaneously (70).
meta-analysis of studies comparing iVF outcomes in women with and without PCOs demonstrated no some women with PCOs and a eumenorrheic significant difference in miscarriage rates between the menstrual history may still experience anovulation, two groups (odds ratio [OR], 1.0; 95% confidence and a midluteal serum progesterone may be helpful as interval [Ci], 0.5–1.8) (79).
an additional screening test. although the primary mechanism of infertility is presumed to be oligo- or The link between PCOs and gestational diabetes was anovulation, there are other potential factors initially suggested by retrospective data (80). a study including diminished oocyte competence (71–72) of 99 women with PCOs and 737 controls noted a and endometrial changes discouraging implantation higher rate of gestational diabetes, but it was largely (73–74). Other factors associated with PCOs, such as explained by a higher prevalence of obesity in the obesity, have also been associated with subfertility and PCOs group (81–82). in contrast, a meta-analysis in delayed conception (75). Male factor infertility or which confounding factors such as BMi were taken tubal occlusion must also be considered (one study in into account demonstrated that PCOs was indepen- PCOs found a nearly 10% rate of severe oligospermia dently associated with an increased risk for gestational and a 5% rate of bilateral tubal occlusion) (76).
diabetes and hypertension (83). This meta-analysis demonstrated a small but significant association between premature singleton births (<37 wk gesta- 2.2–2.3. Values and preferences tion) and PCOs (OR, 1.75; 95% Ci, 1.16–2.62), and in making this recommendation, we emphasize the between PCOs and pre-eclampsia (OR, 3.47; 95% overall increased infertility burden among women Ci, 1.95–6.17). Most studies reporting an association with PCOs and ovulatory dysfunction, although between hypertension or pre-eclampsia and preg- there are spontaneous conceptions, which may nancy in PCOs are small and poorly controlled and increase with improved menstrual frequency and show mixed results (82). in one of the largest studies, aging. The natural history of fertility in women with PCOs (n = 99) was not a significant predictor of PCOs and the influence of milder phenotypes lacking pre-eclampsia compared with control pregnancies ovulatory dysfunction are not well understood or (n = 737), when controlled for nulliparity (more common in PCOs) (81). although only a small abso-lute difference in gestational age was noted between cases and controls, increased neonatal morbidity was present (83).
2.4. Because women with PCOs are at increased risk of pregnancy complications (gestational diabetes, preterm delivery, and pre-eclampsia) exacerbated by 2.4. Values and preferences obesity, we recommend preconceptual assessment in making this recommendation, we believe that a of BMi, blood pressure, and oral glucose tolerance priority should be placed on reducing the overall increased morbidity from pregnancy complications such as gestational diabetes, pre-eclampsia, and preterm delivery in women with PCOs. Whether these increased risks are due to PCOs itself or the There is a growing body of evidence that PCOs has features associated with PCOs such as iR or obesity implications for adverse pregnancy outcomes. requires further study.
Confounders include iatrogenic multiple pregnancy due to ovulation induction, higher complications in Fetal origins pregnancies resulting from infertility treatment per se, and higher rates of obesity in women with 2.5. The evidence for intrauterine effects on develop- PCOs. some studies have suggested increased early ment of PCOs is inconclusive. We suggest no specific interventions for prevention of PCOs in offspring of women with PCOs (2 an association between PCOs and endometrial cancer was first described in 1949 (99). There have been few studies with cohorts large enough to adequately assess the risk of endometrial cancer in nonhuman primate models and sheep models suggest women with PCOs. in a long-term follow-up of that androgen exposure in utero may program the women with PCOs in the united Kingdom, morbidity fetus to express features characteristic of PCOs in data over 31 years were available on 319 compared adult life (84–86). Human data are limited, but there with 1,060 control women. Women with PCOs did is evidence of fetal programming by androgens in girls not have a higher all-cause mortality but did show a with classic adrenal hyperplasia or with a mother with 3.5 increased relative risk (RR) of development of a virilizing tumor (87–88). androgen levels may be endometrial cancer (100). a more recent meta-anal- increased in pregnant women with PCOs (89). ysis assessing the association between PCOs and nevertheless, an australian study of 2,900 pregnant endometrial cancer suggested that women with PCOs women demonstrated no relationship between T had an increased risk of developing endometrial levels at 18 and 34 weeks gestation and the presence cancer (RR = 2.7; 95% Ci, 1.0–7.29) (101), confirmed of PCOs in 244 female offspring aged 14–17 years by a subsequent systematic review with a 3-fold (90). The relationship between T levels during preg- increased risk (102).
nancy in women with PCOs to outcomes remains to be determined using accurate assay methodology.
several factors in the epidemiology of endometrial cancer suggest a link to PCOs. Young women with There is evidence that cardiovascular disease in endometrial cancer are more likely to be nulliparous humans is related to intrauterine events. intrauterine and infertile, have higher rates of hirsutism, and have growth restriction has been associated with increased a slightly higher chance for oligomenorrhea (103). rates of coronary heart disease, hypertension, and Obesity and T2dM, common in women with PCOs, T2dM, providing evidence for fetal programming of are also endometrial cancer risk factors (104–107). in adult diseases (91). There are limited data to suggest a woman with these risk factors, low physical activity that intrauterine growth restriction may be associated scores further elevated the cancer risk (108).
with subsequent development of PCOs in some popu-lations (92). in addition, a subset of girls born small There currently are no data supporting routine for gestational age are at risk for developing premature endometrial biopsy of asymptomatic women (109) or adrenarche, iR, or PCOs (93–94), although this has ultrasound screening of the endometrium (110). not been confirmed in longitudinal, population-based ultrasound screening in women without abnormal studies in northern europe (95). available data bleeding shows poor diagnostic accuracy for diag- support the concept that rapid postnatal weight gain nosing intrauterine pathology (110–111). The amer- and subsequent adiposity can exacerbate metabolic ican Cancer society recommends against routine abnormalities and PCOs symptoms (94, 96–98).
cancer screening for endometrial cancer in women at average or increased risk (with the exception of lynch syndrome), but women should be counseled to report unexpected bleeding and spotting (112).
2.6. Women with PCOs share many of the risk factors associated with the development of endome- trial cancer including obesity, hyperinsulinism, 2.6. Values and preferences diabetes, and abnormal uterine bleeding. However, in making this recommendation for increased aware- we suggest against routine ultrasound screening ness of endometrial cancer risk in women with PCOs, for endometrial thickness in women with PCOs particularly those with abnormal uterine bleeding, prolonged amenorrhea, diabetes, and/or obesity, we believe that a priority should be placed on the conse- chronic oligoanovulation are more frequent than in quences of development of endometrial cancer, and normal-weight women (118). Obese women with this priority offsets the limited data available for inde- PCOs exhibit a blunted responsiveness and lower pendent association with PCOs.
pregnancy rates to pharmacological treatments for ovulation induction, such as clomiphene citrate, gonadotropins, or pulsatile GnRH (54, 68, 122).
2.7. increased adiposity, particularly abdominal, is Obesity increases the risk of the metabolic syndrome, associated with hyperandrogenemia and increased iGT/diabetes mellitus (dM), dyslipidemia, and iR metabolic risk (see cardiovascular disease prevention (118–119, 123–128). longitudinal studies have guidelines, Ref. 2). Therefore, we recommend shown that iR may worsen over time (125). Conse- screening adolescents and women with PCOs for quently, obesity has a negative impact that may increased adiposity by BMi calculation and measure- exceed that of the PCOs status per se.
ment of waist circumference (1 2.7. Values and preferences in making this recommendation, the committee believes that excess weight and obesity may have an Prevalence of obesity in PCOS important impact on the early development of PCOs The prevalence of obesity varies greatly across the and on the clinical presentation (93, 129, 130). world; however, studies in different countries with Obesity may change in degree and possibly in distribu- significantly different background rates of obesity tion from adolescence to postmenopausal age, and (30–70%) have yielded similar rates for the preva- these changes should be monitored.
lence of PCOs (52, 113). Whether the incidence of PCOs may parallel the growing epidemic of obesity is unknown, although a modest but nonsignificant trend in the prevalence of PCOs with increasing BMi has 2.8. We suggest screening women and adolescents been reported (114). Obesity may also cluster in with PCOs for depression and anxiety by history and, PCOs families (97, 115), and referral bias to specialty if identified, providing appropriate referral and/or clinics may also elevate the association of PCOs with obesity (116).
Impact of obesity on the phenotype of PCOS small observational community- and patient-based Obesity in general and abdominal obesity in partic- case control studies consistently demonstrate an ular cause relative hyperandrogenemia, characterized increased prevalence of depression in women with by reduced levels of sHBG and increased bioavailable PCOs. in women with PCOs compared with non- androgens delivered to target tissues (117–118). BMi-matched controls, self-rated questionnaires abdominal obesity is also associated with an increased demonstrate an increased rate of depressive symptoms T production rate and a non-sHBG-bound androgen (131–133). similarly, in studies with direct psychi- production rate of dehydroepiandrosterone and atric interviews, there was a higher lifetime incidence androstenedione (119). estrogen levels, particularly of a major depression episode and recurrent depres- estrone, may also be higher in PCOs (120).
sion (OR, 3.8; 95% Ci, 1.5–8.7; P = .001) and a history of suicide attempts that was seven times higher Menstrual disorders are frequent when the onset of in PCOs cases vs. controls (134). in a longitudinal excess weight occurs during puberty rather than study examining changes in depression scores, the during infancy (121). in adult overweight and obese incidence of depression was 19% in 1–2 years of women with PCOs, menstrual abnormalities and follow-up (135). The increased prevalence of depres- postmenopausal women treated with hormone sion and depressive symptoms in women with PCOs replacement therapy (143). Finally, women with appears to be independent of obesity, androgen levels, PCOs had a significantly higher mean apnea- hirsutism, acne, and infertility (131–133, 135–137). hypopnea index compared with weight-matched Thus, studies of depression using different patient controls (22.5 ± 6.0 vs. 6.7 ± 1.7; P < .01), with the groups and methods of identification demonstrate an difference most pronounced in rapid eye movement increased prevalence of depression in women with sleep (41.3 ± 7.5 vs. 13.5 ± 3.3; P < .01) (143). Thus, the risk imparted by obesity is not sufficient to account for the high prevalence of sleep-disordered breathing Community- and clinic-based case-control studies in PCOs, suggesting that additional factors must be and studies using psychiatric interviews demonstrate higher rates of anxiety and panic disorders in women with PCOs (134, 137, 139). in addition, eating Continuous positive airway pressure treatment of disorders are more common in women with PCOs Osa in patients with PCOs demonstrated modestly (OR, 6.4; 95% Ci, 1.3-31; P = .01) (132) and include improved iR after controlling for BMi (P = .013) binge-eating disorder (12.6 vs. 1.9%; P < .01) (133). (144). in young obese women with PCOs, successful although a history of depression or anxiety may be treatment of Osa improves insulin sensitivity, present in many women and adolescents with PCOs, decreases sympathetic output, and reduces diastolic for those without a prior diagnosis, a simple office blood pressure. The magnitude of these beneficial screen using a two-item questionnaire such as the effects is modulated by the hours of continuous PHQ-2 may be helpful (140). Those identified with positive airway pressure use and the degree of obesity.
depression or anxiety should be referred for further therapy.
2.9. Values and preferences it is difficult to diagnose sleep abnormalities on the basis of a history and physical or by questionnaire. 2.9. We suggest screening overweight/obese adoles- Polysomnography, when performed, should occur in a cents and women with PCOs for symptoms suggestive certified sleep laboratory with proper accreditation. of Osa, and when identified, obtaining a definitive The interpretation and recommendation(s) for treat- diagnosis using polysomnography. if Osa is diag- ment of sleep-disordered breathing/Osa should be nosed, patients should be referred for institution of made by a board-certified expert in sleep medicine.
appropriate treatment (2 NAFLD and NASH 2.10. We suggest awareness of the possibility of Women with PCOs develop Osa at rates that equal naFld and nasH but recommend against routine or exceed those in men. The high prevalence of Osa is thought to be a function of hyperandrogenism (a defining feature of PCOs) as well as obesity (common in PCOs) (141–142), although these factors alone do not fully account for the finding. even after control- naFld is characterized by excessive fat accumula- ling for BMi, women with PCOs were 30 times more tion in the liver (steatosis), whereas nasH defines a likely to have sleep-disordered breathing and nine subgroup of naFld in which steatosis coexists with times more likely than controls to have daytime sleep- liver cell injury and inflammation (after exclusion of iness (141). it also appeared that women with PCOs other causes of liver disease (viral, autoimmune, taking oral contraceptives were less likely to have genetic, alcohol consumption, etc). Primary naFld/ sleep-disordered breathing (141), consistent with the nasH is most commonly associated with iR and its lower likelihood of sleep-disordered breathing in phenotypic manifestations (145). The prevalence of ultrasound-documented naFld in the general popu- Rescreening is suggested every 3–5 years, or more lation is 15–30% (146). Risk factors pertinent to frequently if clinical factors such as central adiposity, PCOs include increasing age, ethnicity, and meta- substantial weight gain, and/or symptoms of diabetes bolic dysfunction (obesity, hypertension, dyslipid- emia, diabetes). Because many women with PCOs have metabolic dysfunction, the association of PCOs with naFld is not surprising, but the available liter-ature, especially in reference to the risk of nasH, is adolescents and adult women with PCOs are at incomplete (147). Clinical studies report a 15–60% increased risk for iGT and T2dM (125–126, 157). a prevalence of naFld in the population, depending diagnosis of PCOs confers a 5- to 10-fold increased on the index used to define liver damage (increased risk of developing T2dM (125–126, 157). The overall serum alanine aminotransferase or ultrasound), the prevalence of glucose intolerance among u.s. women presence of obesity, and ethnicity (147–153). Whether and adolescents with PCOs was 30–35%, and 3–10% androgen excess may be involved in the pathophysi- had T2dM. nonobese women with PCOs had a ology of naFld in women with PCOs is still unclear 10–15% prevalence of iGT and a 1–2% prevalence of (153–155). Thus, women with PCOs and metabolic T2dM (125–126, 157). limited studies have shown risk factors and/or iR may be screened using serum poor sensitivity of glycohemoglobin measure for markers of liver dysfunction. if serum markers are detecting iGT (158–159). Those with T2dM had a elevated, noninvasive quantification of fibrosis by significantly higher prevalence of first-degree relatives ultrasound and liver biopsy may be considered (156).
with T2dM, confirming family history as an impor-tant risk factor. Multiple studies have also shown deterioration in glucose tolerance with follow-up 2.10. Values and preferences (126, 158, 160).
in making this recommendation we believe that a Because of the high risk of iGT and T2dM in PCOs, priority should be placed on identifying this poten- periodic screening of patients to detect early abnor- tially major complication in women with PCOs with malities in glucose tolerance is recommended by iR and/or metabolic syndrome. However, there is several scientific organizations, although an interval currently no simple and reliable screening test for for screening has not been specified (161–163).
naFld because elevated serum transaminases have low sensitivity and specificity. We also believe that investigating the true prevalence of naFld in 2.11. Values and preferences collaboration with gastroenterologists and hepatolo- in making this recommendation, the committee gists who can identify and apply reliable markers of believes in the strength of the evidence for a tight link nasH should be a research priority for future recom- between PCOs and diabetes and believes that mendations. Finally, there is no approved drug to treat reducing morbidity of iGT/diabetes through early naFld, although lifestyle therapy, insulin sensitizers, diagnosis and treatment outweighs any unforeseen and antioxidants are thought to be beneficial.
harm or burdens resulting from the screening. We have recommended an OGTT over an Hgba1c Type 2 diabetes mellitus because of the potential increased association between 2.11. We recommend the use of an OGTT (consisting iGT and cardiovascular disease in women (164–165) of a fasting and a 2-hour glucose level using a 75-g oral and the potential to identify women at risk for gesta- glucose load) to screen for iGT and T2dM in adoles- tional dM before pregnancy. Women with PCOs and cents and adult women with PCOs because they are iGT early in pregnancy are at greater risk for devel- at high risk for such abnormalities (1 oping gestational dM (166), but there are currently Hgba1c may be considered if a patient is unable or insufficient data to recommend earlier screening for unwilling to complete an OGTT (2 gestational dM in women with PCOs. Given the lack of evidence of the ideal period for rescreening, we and myocardial infarction, has been noted in PCOs have arbitrarily recommended a period of 3–5 years.
compared with age-matched control women (174). another marker of atherosclerosis, coronary artery calcification, is more common in women with PCOs than in controls, even after adjusting for the effects of 2.12. We recommend that adolescents and women age and BMi (175–177). echocardiography revealed with PCOs be screened for the following cardio- both anatomic and functional differences between vascular disease risk factors (Table 5): family history women with PCOs and controls including an of early cardiovascular disease, cigarette smoking, increased left atrial size, increased left ventricular iGT/T2dM, hypertension, dyslipidemia, Osa, and mass index, lower left ventricular ejection fraction obesity (especially increased abdominal adiposity) (178), and diastolic dysfunction (179–180). Of note, the left ventricular mass index was linearly related to the degree of iR (178).
some, but not all, studies (181–183) demonstrate Members of the androgen excess and Polycystic impaired endothelial function in women with PCOs, Ovary syndrome society conducted a systematic as reflected in reduced brachial artery reactivity to analysis and published a consensus statement hyperemia (184–185) and reduced vascular compli- regarding assessment of cardiovascular risk and ance, independent of obesity, iR, total T, or total prevention of cardiovascular disease in women with cholesterol (186). improved endothelial function has PCOs (167) (Table 5). in addition to elevations in been documented when iR is attenuated with insulin- triglycerides and decreases in high-density lipoprotein lowering medication or through weight loss (187– (Hdl)-cholesterol, women with PCOs have higher 190). discrepant findings between studies may be the low-density lipoprotein (ldl)-cholesterol and non- result of the heterogeneous nature of the populations Hdl-cholesterol, regardless of BMi (117, 167). Women with PCOs should have BMi and blood pres- despite the increased prevalence of cardiovascular sure measured at each clinic visit (and consider waist risk factors in women with PCOs, there are limited circumference if nonobese; ≥36 inches is abnormal), longitudinal studies, and those are too small to detect and upon diagnosis of PCOs, additional testing differences in event rates (191). nevertheless, epide- should include a complete fasting lipid profile (total miological data consistently point to increased cardio- cholesterol, ldl-cholesterol, non-Hdl-cholesterol, vascular risk in women with stigmata of PCOs. The Hdl-cholesterol, and triglycerides).
nurses' Health study noted an adjusted RR of 1.53 although hypertension has been an inconsistent (95% Ci, 1.24–1.90) for coronary heart disease in finding, women with PCOs appear to be at risk, at women with a history of irregular menstrual cycles least later in life (168–170). although in many studies (192). in addition, a case-control study based on data both systolic and diastolic blood pressures are normal in the Women's Health study database found that (168–171), in others, mean arterial pressures and women who developed cardiovascular events had ambulatory systolic pressures are elevated in women lower sHBG and higher calculated free androgen with PCOs compared with controls (172). in addi- index (193). among postmenopausal women evalu- tion, the nocturnal drop in mean arterial blood pres- ated for suspected ischemia, clinical features of PCOs sure is lower, a finding that has also been demonstrated were associated with more angiographic coronary in obese adolescents with PCOs (171, 173).
artery disease and worsening cardiovascular event- free survival (194).
anatomic evidence of early coronary and other vascular disease in PCOs has been documented using varied techniques. increased carotid artery intima- media thickness, an independent predictor of stroke 2.12. Values and preferences HCs, insulin sensitivity, and glucose tolerance We acknowledge that there is a paucity of studies The impact of HCs on carbohydrate metabolism in identifying the rates of cardiovascular events and age PCOs women is still in doubt because available of onset in women with PCOs; therefore, we have studies are small and short-term, and they utilize focused on cardiovascular disease risk factors. varying methodologies assessing endpoints. studies, However, these may not necessarily equate with mostly cross-sectional in healthy women, found events or mortality.
decreased insulin sensitivity and increased glucose response to a glucose load during HC use, although these results varied according to the estrogen dose and the type of progestin used (197–202). The residual androgenic activity of the progestin contained in the HC formulation may influence glucose metabolism more than the dose of ethinyl estradiol (203–207). HCs: indications and screening some of these studies found that HCs had deleterious effects on glucose tolerance in obese, but not in lean, 3.1. We recommend HCs (ie, oral contraceptives, women with PCOs (208–210), but our systematic patch, or vaginal ring) as first-line management for review did not confirm this (211).
the menstrual abnormalities and hirsutism/acne of PCOs (refer to hirsutism guidelines in Ref. 1 , recom- no data are available assessing the long-term effect of mendation 2.1.1), which treat these two problems HCs on glucose tolerance in nondiabetic and diabetic women with PCOs. a Cochrane meta-analysis concluded that HCs do not have a significant effect 3.2. We recommend screening for contraindications on glucose tolerance, although this conclusion was to HC use via established criteria (see Table 6 and based on limited and low-quality evidence (203). On ). For women with PCOs, we the other hand, long-term studies performed in do not suggest one HC formulation over another healthy women are promising because HC use did not result in an increased incidence of T2dM either in the general population (202) or in women with a history of gestational dM (205–206) and was not 3.1–3.2. Evidence associated with an increased risk of complications in in women with PCOs, the progestin in HCs suppresses women with type 1 diabetes (205). Therefore, the lH levels and thus ovarian androgen production, and american diabetes association along with the the estrogen increases sHBG, thus reducing bioavail- Centers for disease Control and Prevention (CdC) able androgen. in addition, some progestins have concluded that HCs are not contraindicated in antiandrogenic properties, due to their antagonizing women with diabetes without vascular complications effects on the androgen receptor and/or to the inhibi- tion of 5α-reductase activity (195), which have led to claims of increased efficacy for specific formulations HCs and lipids without supporting level 1 clinical trial evidence. The as with glucose metabolism, the effect of HCs on choice of oral vs. parenteral HC (ie, patch or vaginal lipid balance appears to be related to the formulation ring) is uncertain, although risk-benefit ratios may used. When estrogenic activity prevails, there is an vary among preparations and with different progestins increase in Hdl-cholesterol and a decrease in ldl- in oral contraception. There is some evidence that cholesterol levels, whereas the opposite occurs when extended-cycle HCs (vs. cyclic therapy) offer greater androgenic activity is higher (198, 202, 205, 213–215). hormonal suppression and prevent rebound ovarian However, lipids seem to be less sensitive to the residual function during the pill-free interval (196).
androgenic properties of the progestins (198, 213, 216–218). The ability of HCs to increase Hdl- trials of exercise in PCOs, exercise therapy, alone or cholesterol levels is the most favorable and promising in combination with dietary intervention, improves metabolic effect in PCOs and may overcome the weight loss and reduces cardiovascular risk factors and negative impact on triglycerides and ldl-cholesterol diabetes risk in the general population.
because low Hdl-cholesterol may be the critical link between PCOs and the metabolic syndrome (208, it is well recognized in the general population that HCs and body weight cardiovascular fitness, as measured by maximal oxygen consumption during exercise, is an independent The impact of HCs on body weight and fat distribu- predictor of cardiovascular mortality (229). This tion is similar between healthy women and women remains significant after adjustment for age, smoking, with PCOs. in particular, BMi and the waist-to-hip cholesterol measures, diabetes, hypertension, and ratio were unchanged (209, 211, 220, 224–226) or family history of cardiovascular disease. Overall, there occasionally improved, independent of coexistent is good evidence in the general population that meta- obesity (227).
bolic status is improved with exercise alone, and this reduces the risk of diabetes (230). Thirty minutes per 3.1–3.2. Values and preferences day of moderate to vigorous physical activity is effec-tive in reducing the development of metabolic in evaluating the benefits and risks of HC treatment syndrome and diabetes (231–232). There are few in women with PCOs, we believed concerns related trials of exercise therapy targeting women with PCOs, to untreated menstrual dysfunction and quality of life and no large randomized trials are available (233), but related to anovulatory bleeding and hirsutism to be there is a suggestion of weight loss, improved ovula- the primary considerations. screening recommenda- tion, and decreased iR (234–239).
tions follow the current World Health Organization and CdC medical eligibility guidelines (Table 6) (3, 228). in making these recommendations, the 3.3. Values and preferences committee strongly believes that larger controlled despite the limited evidence in PCOs, we suggest studies should be performed to evaluate the risk of that the benefits of exercise in improving metabolic long-term HC use in women with PCOs, particularly disease are strong enough to favor its recommenda- in the presence of obesity, iR, and lipid disorders. tion, despite a paucity of controlled trials available for There are insufficient data about whether women with PCOs face increased risk of thromboembolism on particular HC preparations, although preparations role of weight loss in lifestyle therapy may vary with respect to thromboembolic risk in the general population. There are insufficient data to 3.4. We suggest that weight loss strategies begin with define the optimal duration of treatment with HCs. calorie-restricted diets (with no evidence that one Women with severe hirsutism or contraindications to type of diet is superior) for adolescents and women hormonal contraception may require other therapies with PCOs who are overweight or obese (2 such as antiandrogens (spironolactone, flutamide, Weight loss is likely beneficial for both reproductive finasteride, etc.) or mechanical hair removal (laser, and metabolic dysfunction in this setting. Weight loss electrolysis, etc.) (see hirsutism guidelines in Ref. 1).
is likely insufficient as a treatment for PCOs in normal-weight women.
role of exercise in lifestyle therapy 3.3. We suggest the use of exercise therapy in the management of overweight and obesity in PCOs ). although there are no large randomized document additional benefits to the lack of well-designed studies in this area. despite the relative lack Weight loss is generally recommended as a first-line of evidence that weight loss improves PCOs per se, therapy for obese women with PCOs. Weight loss in we recommend lifestyle change in overweight and PCOs has been accomplished via lifestyle modifica- obese women with PCOs. There may also be some tion, use of medications designed for weight loss, and benefit in prevention of weight gain in women with bariatric surgery (239–242). studies performed after PCOs who exercise regularly and eat sensibly.
sustained weight loss (up to 61% of initial weight) by bariatric surgery (241) or long-term dietary interven- Use of metformin in adults tion (242) demonstrate that normalization of hyper-androgenemia can be achieved in obese women with 3.5. We suggest against the use of metformin as a PCOs. However, few data document subsequent first-line treatment of cutaneous manifestations, for improvements in hirsutism (243–244). Menstrual prevention of pregnancy complications, or for the function is improved in some women with as little as treatment of obesity (2 5–10% reduction in body weight (243); however, 3.6. We recommend metformin in women with there are no long-term data available to assess the PCOs who have T2dM or iGT who fail lifestyle sustainability of menstrual cycling and few data on ). For women with PCOs pregnancy outcomes after weight reduction. in the with menstrual irregularity who cannot take or do not short term, there is some evidence for improved preg- tolerate HCs, we suggest metformin as second-line nancy rates and a decreased requirement for use of ovulation induction or other fertility treatments in small uncontrolled trials of weight reduction (245–246), although there are no randomized controlled 3.5–3.6. Evidence trials supporting weight loss in the improvement of Metformin use has been suggested for a number of pregnancy rates. The response to weight loss is vari- comorbidities in women with PCOs. some of these able; not all individuals have restoration of ovulation have been discussed in other guidelines including or menses despite similar weight reduction (241–242, hirsutism (1) and treatment of cardiovascular risk 247–248). although improvements in reproductive factors in the primary prevention of cardiovascular and metabolic status in PCOs have been described disease and T2dM in patients at metabolic risk (2). with all weight loss methods, there are no long-term We agree with the suggestion that metformin should studies available in the literature for any of these not be used for hirsutism. Metformin studies have not approaches. Our own meta-analysis showed that been sufficiently powered to study acne (253–254). weight loss had minimal effects on hirsutism and We agree with the recommendation that lifestyle fertility, although there were significant improve- management be considered first-line therapy for ments in some metabolic parameters (mainly glycemic women with PCOs at increased metabolic risk (2).
effects related to improvements in fasting blood glucose and insulin levels) (249–250).
Metformin has been associated with weight loss in some trials (76, 230), but not in our meta-analysis 3.4. Values and preferences (211). a systematic review and meta-analysis demon-strated that there was significant weight loss in trials Taken together, the data in general populations and in using metformin compared with placebo in women our meta-analysis in women with PCOs support the with PCOs (255). The absolute weight lost was esti- role of lifestyle change for prevention and treatment mated to be 2.7 kg, equaling a 2.9% decrease in body of metabolic dysfunction. We found little evidence to weight, comparable to what occurs with orlistat treat- support lifestyle change as an infertility treatment, ment (256). However, metformin did not increase although other reports (251) and national guidelines weight loss in patients using diet and exercise programs (252) have found a benefit. We attribute the failure to (255, 257). Taken together, when weight loss and lifestyle modifications are used to treat obesity, there provide an option for treatment of iGT in those is no benefit to adding metformin. Therefore, diet and women who fail lifestyle management.
exercise, not metformin, should be the first line of therapy in obese women with PCOs. Metformin may Treatment of infertility remain a treatment consideration if the patient fails 3.7. We recommend clomiphene citrate (or compa- with diet and exercise.
rable estrogen modulators such as letrozole) as the One of the most important clinical outcomes demon- first-line treatment of anovulatory infertility in strated during metformin treatment was the improve- women with PCOs (1 ment in menstrual cyclicity (258), leading to the 3.8. We suggest the use of metformin as an adjuvant possibility that metformin could be used to regulate therapy for infertility to prevent OHss in women menses (258). a systematic review and meta-analysis with PCOs undergoing iVF (2 demonstrated an improvement in ovulation rate in women taking metformin (254). it is unknown whether ovulation occurs at a rate that is adequate 3.7–3.8. Evidence to protect against endometrial carcinoma. Trials Clomiphene and metformin have been studied exten- directly comparing metformin with oral contracep- sively for infertility in PCOs with multiple large tives demonstrate that metformin is not as effective as multicenter trials (76, 262–265). in almost all of oral contraceptives for menstrual cycle regulation these, clomiphene has had improved pregnancy rates vs. metformin, as well as providing comparable rates in patients with iGT, lifestyle modification with exer- to injectable gonadotropins (266). a recent meta- cise and diet can decrease the progression to T2dM analysis of insulin sensitizers for the treatment of by 58% vs. a 31% decrease with metformin (230). infertility in PCOs concluded that "the use of Furthermore, these benefits persist for up to 10 years metformin for improving reproductive outcomes in after initiation, with lifestyle modification reducing women with PCOs appears to be limited" (254). in diabetes incidence by 34% and metformin reducing it this review, there was no evidence that metformin by 18% (230). However, intensive lifestyle modifica- improved live birth rates, whether it was used alone tion, not metformin, was the only therapy that (pooled OR, 1.00; 95% Ci, 0.16–6.39) or in combina- restored normal glucose tolerance in subjects with tion with clomiphene (pooled OR, 1.05; 95% Ci, iGT (230, 260). similar trials in women with PCOs 0.75–1.47) (254). Metformin has been recommended and iGT are too small and limited in duration to for use in infertility treatment partly because it is determine whether metformin prevented T2dM or thought to be associated with monofollicular ovula- caused regression to normal glucose tolerance (259, tion and lower multiple pregnancy rates. none of the 261). Metformin is recommended for prevention of trials have been adequately powered to detect differ- diabetes in women with PCOs and iGT when life- ences in multiple pregnancy rates, although multiple style modification is not successful.
pregnancies with metformin have been rare in these trials (≤5%) (76, 262–266) and more common (around 5%) with clomiphene. The benefit of multiple 3.5–3.6. Values and preferences pregnancy reduction must be balanced against the The committee believes that a priority should be substantially lower pregnancy rates and lower fecun- placed on effective treatment. although the preferred dity per ovulation with metformin alone (76).
treatment for prevention of T2dM is diet and lifestyle aromatase inhibitors have been proposed as oral modification, there are a significant number of women agents, and although current cumulative evidence who will fail this option. although metformin treat- suggests an uncertain risk/benefit ratio to treat ment incurs expense and has the potential for side infertility (267), a recent large niH-sponsored, effects, the committee feels that metformin may multicenter, double-blind, randomized, clinical trial (n = 750 subjects) has been completed with a marked that publication of the finding and digestion, debate, superiority in live birth rate of letrozole over clomi- and independent confirmation in other studies are phene for the treatment of anovulatory infertility in necessary to establish letrozole as front-line infertility women with PCOs (with a comparable safety and therapy. The committee also acknowledges that tolerance profile between drugs) (268). These results metformin may have some benefit as an adjuvant may alter recommendations for front-line treatment agent in the treatment of infertility in obese women, in subsequent revisions of this guideline. although despite conflicting systematic reviews on the topic. concerns about the relative teratogenicity of letrozole Other national guidelines have favored metformin compared to clomiphene remain, this trial and more than in the current guidelines (252). We recom- other publications are reassuring (269). The relative mend discontinuing metformin (when used to treat success of two drugs that modulate estrogen action to PCOs as opposed to T2dM) with a positive preg- achieve pregnancy further underscores this class of nancy test, given the lack of benefit associated with its drugs as first-line treatment when compared with routine use during pregnancy. in the face of resistance (anovulation) or failure (no conception despite ovula-tion) with front-line oral agents, referral to a subspe- Metformin may have some use as an adjuvant agent cialist in infertility for further care is recommended.
for infertility in select women with PCOs, although it is likely to be more effective in obese women than Use of other drugs nonobese women (74, 267, 270). a systematic review of metformin noted that in clomiphene-resistant 3.9. We recommend against the use of insulin sensi- women, metformin plus clomiphene led to higher live tizers, such as inositols (due to lack of benefit) or thia- birth rates than clomiphene alone (RR, 6.4; 95% Ci, zolinediones (given safety concerns), for the treatment 1.2–35); metformin also led to higher live birth rates than laparoscopic ovarian drilling (RR, 1.6; 95% Ci, 3.10. We suggest against the use of statins for the 1.1–2.5) (271). in addition, metformin may prevent treatment of hyperandrogenism and anovulation in the development of OHss in women with PCOs PCOs until additional studies demonstrate a favor- receiving gonadotropin therapy for iVF (249, 272).
able risk-benefit ratio (2 The routine use of metformin during pregnancy in suggest statins in women with PCOs who meet women with PCOs is unwarranted, although it may current indications for statin therapy (2 be useful to treat gestational diabetes (273). a meta- analysis of randomized, controlled trials demonstrated 3.9–3.10. Evidence no effect of metformin on abortion rate (OR, 0.89; 95% Ci, 0.59-1.75; P = .9) (238). a large, random- although a large phase ii study sponsored by a phar- ized, controlled trial demonstrated no difference in maceutical company provided evidence of a dose- the prevalence of pre-eclampsia, preterm delivery, or response improvement in reproductive and metabolic gestational dM in women with PCOs treated with abnormalities in PCOs with troglitazone (76), there metformin during pregnancy (274). Metformin was have been no subsequent large randomized trials of associated with a significantly higher incidence of thiazolidinediones in PCOs (254). The u.s. Food gastrointestinal disturbance, but no serious maternal and drug administration has removed troglitazone or fetal adverse effects (76, 254, 274).
from the market due to hepatic toxiticity and restricted the use of rosiglitazone due to excess cardiovascular events. a recent Fda advisory linked pioglitazone to 3.7–3.8. Values and preferences bladder cancer. The risk-benefit ratio may also be less The committee recognizes that the use of letrozole for favorable for infertility because animal studies suggest the treatment of infertility in PCOs is promising. that thiazolidinediones may be associated with fetal However, we believe, as with all recent discoveries, loss (Fda Pregnancy Category C). although there are no known serious adverse events related to symptoms or to prevent pregnancy) (2 d-chiro-inositol therapy, there are concerns about the suggest that lifestyle therapy (calorie-restricted diet formulation of the drug and limited evidence of its and exercise) with the objective of weight loss should efficacy (275).
also be first-line treatment in the presence of over-weight/obesity (2 ). We suggest metformin dyslipidemia, including elevations in circulating as a possible treatment if the goal is to treat iGT/ ldl-cholesterol, the precursor to sex steroid biosyn- metabolic syndrome (2 ). The optimal dura- thesis, is common in women with PCOs. statins have tion of HC or metformin use has not yet been multiple actions that include inhibition of the enzyme hydroxymethylglutaryl coenzyme a reductase, which leads to decreased production of cholesterol (thus 3.12. For premenarchal girls with clinical and reducing circulating concentrations of cholesterol). biochemical evidence of hyperandrogenism in the in addition, there is some evidence that ovarian T presence of advanced pubertal development (ie, ≥ production may be reduced by administration of Tanner stage iV breast development), we suggest statins (276–277). This effect may be due, at least in part, to inhibition of theca cell growth and by decreasing the concentration of precursor for produc- 3.11–3.12. Evidence tion of androstenedione (278). Furthermore, statins appear to have antioxidant properties. Clinical trials The treatment of PCOs in adolescents is controver- of statins alone or in combination with other medica- sial. Many support the symptom-driven approach, tions among women with PCOs are limited in whereas others support an approach targeting the number, and conclusive evidence that statins amelio- underlying reproductive/hormonal and metabolic rate PCOs symptoms is lacking, although improve- abnormalities associated with PCOs (30). There are ments in hyperandrogenemia have been noted (276, no adequately powered, randomized, double-blind, 279–281). Further recent data show that statin use placebo-controlled trials in adolescents with PCOs. may increase the risk for developing T2dM (282).
The dual goal of treating hyperandrogenism and providing contraception prompts the use of HCs as the mainstay of therapy for adolescents with PCOs 3.9–3.10. Values and preferences (29, 283–284). additionally, benefits such as normal There are few data to support the use of newer diabetes menses and decreased acne and hirsutism are typically drugs that improve insulin action, such as the of the greatest importance to an adolescent (285). glucagon-like peptide-1 analogs or the dipeptidyl some of these can also be improved by lifestyle peptidase-4 inhibitors in women with PCOs. There therapy and weight loss.
are potential serious side effects to statins (myopathy nonetheless, the initiation of HCs in early adoles- and renal impairment), which may be more common cence is controversial, and few data exist to guide in women then men, and these drugs are theoretically recommendations. after excluding other causes of teratogenic (Pregnancy Category X), which merits primary amenorrhea, HCs could be considered in a caution in their use. until additional studies demon- patient with proven hyperandrogenism if the patient strate a clear risk-benefit ratio favoring statin therapy has achieved a sexual maturity of Tanner stage 4–5 for other aspects of PCOs, statins should only be used when menarche should have occurred (286). The best in women with PCOs who meet current indications HC for adolescents and the appropriate duration of for statin treatment.
therapy are uncertain (287). a longer duration of treatment with a combined HC may lead to a lower Treatment of adolescents chance of developing signs of hyperandrogenism as an 3.11. We suggest HCs as the first-line treatment in adult (23). some authors suggest continuing with HC adolescents with suspected PCOs (if the therapeutic until the patient is gynecologically mature (defined by goal is to treat acne, hirsutism, or anovulatory these authors as 5 years postmenarcheal) or has lost a placed on treating PCOs not only as a hormonal/ substantial amount of weight (288).
reproductive disorder, but also as a dysmetabolic syndrome characterized by iR; and 3) the safety of small, short-term studies demonstrate that metformin metformin and its reported outcomes outweigh the restores menstrual regularity and improves hyperan- limited data. Because adolescents have higher user drogenemia, iR, and glucose intolerance in obese and failure rates for hormonal contraception and because nonobese adolescents with PCOs (289–291). Two of the known teratogenicity of antiandrogens during sequential, randomized, placebo-controlled trials of pregnancy, we have avoided any specific recommen- metformin in adolescents with PCOs demonstrated dation of antiandrogens in this population; however, improvements in hyperandrogenemia, ovulation, and these agents may be beneficial in selected individuals. dyslipidemia (223). These promising but limited data We note that our treatment recommendations in lead to the impression that metformin may be more adolescents do not extend to girls with precocious beneficial for adolescents with PCOs than it is for pubarche, given the uncertain risk-benefit ratio in this adults with this condition (292–293). The necessary duration of treatment is yet to be established, and the limited available data are conflicting. in one study, the beneficial effects of metformin on menstrual cycles persisted for 6 months after discontinuation of metformin (294), but in another study the effects were lost 3 months after discontinuing the medication (290). There is no literature regarding long-term use in adolescents.
Given the limited data, it is necessary to extrapolate from adult data in making adolescent treatment recommendations. Thus, lifestyle therapy should be recommended in overweight/obese adolescents. Metformin therapy may also be considered for treat-ment of PCOs based on the limited studies cited above. Because lifestyle change and/or metformin may increase ovulatory frequency and because cuta- neous manifestations are common, appropriate contraception must be recommended to a sexually active teenager.
3.11–3.12. Values and preferences in making these suggestions the committee recom- mends individualizing therapy of PCOs and weighing the pros and cons of one therapeutic approach against the other until such time when strong evidence from well-performed, long-term, randomized, controlled trials in adolescents becomes available. in recom- mending metformin in adolescents with PCOs, the committee believes that: 1) early treatment with metformin and/or lifestyle changes may yield prom- ising and preventative results; 2) priority should be Martin KA, Chang RJ, Ehrmann DA, et al. evaluation and
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Tic ovary synDrome What goes into our Clinical Guidelines is a story worth telling Developed independently by a team of experts, evidence- Endocrine Society Clinical Guidelines based, and vetted through a rigorous, multi-step peer • Diabetes and Pregnancy review process, the Diagnosis and Treatment of Polycystic • Evaluation and Treatment of Ovary Syndrome clinical practice guideline addresses: • Maternal Thyroid Dysfunction • Diagnosing different subpopulations • Osteoporosis in Men• Management of Hyperglycemia in Hospital- • Associated morbidities, including infertility, obesity, ized Patients in Non-Critical Care Setting • Continuous Glucose Monitoring endometrial cancer, and depression • Vitamin D • Treatment through hormonal contraceptives, lifestyle • Adult Growth Hormone Deficiency• Pituitary Incidentaloma changes, and other medications • Hyperprolactinemia• Post-Bariatric Surgery Patient• Congenital Adrenal Hyperplasia• Testosterone Therapy in Adult Men Other Endocrine Society Guidelines COMING SOON • Endocrine Treatment of Transsexual Persons• Adult Hypoglycemic Disorders • Acromegaly • Menopause • Pediatric Obesity • Adrenal Insufficiency • Osteoporosis in Women • CVD and Type 2 Diabetes in Patients at Metabolic Risk • Hyponatremia • Paget's Disease of the Bone • Patients with Primary Aldosteronism • Hypothalamic Amenorrhea • Pharmacological Management of • The Diagnosis of Cushing's Syndrome • Medical Therapies of the Obese Patient • Hirsutism in Premenopausal Women • Androgen Therapy in Women To purchase available guidelines visit:
https://www.endocrine.org/store/clinical-practice-guidelines.
To view patient guides (companion pieces to the clinical guidelines),
visit The Hormone Health Network's Web site at www.hormone.org.
Visit http://www.guidelinecentral.com to purchase pocket cards developed from
select Endocrine Society guidelines.
2013 Endocrine Society® AcknowledgmentsThe members of the Task Force thank the endocrine society Clinical Guidelines subcommittee and Clinical affairs Core Committee for their careful critical review of earlier versions of this manuscript and their helpful comments and suggestions. We also thank the members of the endocrine society who kindly reviewed the draft version of this manuscript when it was posted on the society's website and who sent additional comments and suggestions. We express our great appreciation to stephanie Kutler and lisa Marlow for their administrative support and to deborah Hoffman for her writing assistance in the process of developing this guideline. lastly, the Chair wishes to personally expresses his gratitude to his fellow committee members for their perseverance, dedication, and camaraderie during this guideline's lengthy and challenging gestation.
financial Disclosure of Task force
Silva A. Arslanian, MD is on the advisory board for sanofi-aventis, novo nordisk and Bristol-Myers squibb. she
is a consultant for Gilead and Boehringer engelheim. David A. Ehrmann, MD is on the advisory board for
astra-Zeneca. Corrine K. Welt, MD is a consultant for astra-Zeneca. Richard S. Legro, MD (chair), M. Hassan
Murad, MD, Kathleen M. Hoeger,
and Renato Pasquali, MD have no relevant financial relationships to declare.
* Evidence-based reviews for this guideline were prepared under contract with the Endocrine Society. Tic ovary synDrome Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline CmE Learning Objectives and Post-Test Questions LEARnInG OBJECTIVES upon completion of this educational activity, learners will be able to: • Evaluate patients and perform differential diagnosis to distinguish PCOS from other menstrual disorders. • Identify the lack of accepted diagnostic criteria in adolescents with PCOS.
• Identify appropriate treatment for a woman with PCOS to address clinical hyperandrogenism and • Identify adverse risk factors and potential benefits for OCP use in women with PCOS.
• Identify risk factors for serious adverse events for thromboembolism and related cardiovascular events in women taking hormonal contraceptives.
Educational Objective: Evaluate patients and perform differential diagnosis to distinguish PCOS from other menstrual
disorders.

a 31-year-old female, with a history of hirsutism since her early 20s, comes to you for evaluation. she had been on hormonal contraception for birth control starting at age 25 years, but stopped 2 years ago. Her cycles have been occurring every 45–60 days. she does not exercise and has no history of eating disorders. Her physical exam demon-strates a BMi 25.2 kg/m2, a Ferriman Gallwey score of 19 (normal <10) and no evidence of clitoromegaly, Cushing syndrome or acromegalic features. laboratory exams demonstrate a normal TsH, prolactin, FsH and a negative pregnancy test.
What is the next test that should be ordered? a) Total testosterone level B) Ovarian ultrasoundC) dHeas level d) 17 OH progesterone levele) lH level Educational Objective: Identify the lack of accepted diagnostic criteria in adolescents with PCOS.
a 14-year-old Caucasian girl presents to your office with chief complaints of excessive hair growth and irregular menses. Menarche occurred 1.5 years ago, and she has 4–5 menses per year. she is the only child of her parents, who conceived after fertility treatment. On physical exam, she is Tanner breast stage 5, obese (BMi-for-age percen-tile 97), and has facial hirsutism.
What tests are necessary to diagnose this patient with PCOs?a) serum dHeas levelB) serum luteinizing Hormone levelC) Transabdominal ultrasound examd) anti-Mullerian Hormone levele) none of the above.
Educational Objective: Identify appropriate treatment for a woman with PCOS to address clinical hyperandrogenism
and menstrual irregularity.

a 25-year-old woman with obesity (BMi 36 kg/m2) seeks treatment for chronic excessive hair growth and irregular, infrequent menses ( 6 per year; lMP 3 weeks ago). she denies symptoms of estrogen deficiency and is not currently sexually active and does not smoke. Clinical features do not suggest functional hypothalamic amenorrhea, Cush-ing's syndrome, or acromegaly. exam reveals blood pressure 120/72, mild-moderate hirsutism (Ferriman-Gallwey score 16), and acanthosis nigricans. labs: Testosterone levels are upper limits of normal, normal values for TsH, prolactin, and 17-hydroxyprogesterone. a 75g OGTT reveals normal fasting glucose and normal glucose tolerance. a fasting lipid profile is normal.
What is the most appropriate first line treatment option for this patient's primary symptoms?a) Metformin B) Hormonal contraceptives C) diet and exercise aiming for 5–10% weight loss Tic ovary synDrome Educational Objective: Identify adverse risk factors and potential benefits for OCP use in women with PCOS.
a 32-year-old woman with a BMi of 30.5 kg/m2 presents with a primary complaint of heavy and irregular menses. she is interested in using OCP for her irregular bleeding and worsening hirsutism. she has a diagnosis of PCOs and is not interested in becoming pregnant at this time. she had a prior pregnancy 2 years ago complicated by gesta-tional diabetes and pre-eclampsia. Her oral glucose challenge test postpartum was notable for impaired glucose tolerance but not diabetes. she has a normal blood pressure and metabolic panel otherwise including a normal lipid profile.
What is the appropriate recommendation in this case?a) she should avoid the use of OCPs due to her increased risk of diabetes.
B) Her BMi of >30 kg/m2 constitutes an absolute contraindication for use of OCP.
C) she is a candidate for OCPs but needs frequent monitoring of her lipid panel due to increased risk for d) she is a candidate for OCPs and should be advised regarding lifestyle change to moderate her diabetes risk.
e) Her prior history of pre-eclampsia is a contraindication to OCP use.
Educational Objective: Identify risk factors for serious adverse events for thromboembolism and related cardiovascular
events in women taking hormonal contraceptives.

a 22-year-old african american woman has been referred to you for evaluation and management of oligomenor-rhea since menarche (age 12 years) and hirsutism. Your evaluation confirms the diagnosis of PCOs based upon her history (fewer than six menstrual cycles per year), the presence of significant hirsutism and pustular acne on phys-ical examination, and the presence of elevated testosterone concentrations (both total and free) on blood sampling. The remainder of her hormonal evaluation is unremarkable. On physical examination, the patient is obese with a BMi of 34 kg/m2 and also has acanthosis nigricans as well as the hirsutism and acne for which she seeks treatment. The patient is not taking any medications and has not received prior treatment for her symptoms. Her family history indicates that her mother was diagnosed with type 2 diabetes at 56 years of age.
Which of the following would be the best next step? a) Measurement of insulin concentration on a fasting blood sample.
B) Measurement of the glucose concentration on a fasting blood sample.
C) Perform a fasting lipid profile and 2h 75gm oral glucose tolerance test.
d) Begin pharmacologic treatment without further testing.
e) none of the above.
To claim your CMe credit, please go to https://www.endocrine.org/education-and-practice-management/continuing-medical-education/publication-cme.
Tic ovary synDrome Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline CmE Answers and Explanations Correct answer: D.
Discussion: PCOs is a diagnosis of exclusion. Therefore, other disorders causing the same symptoms must be ruled out. The work up has already ruled out causes of irregular menses including hyperprolactinemia, thyroid disease and primary ovarian insufficiency, and she is not pregnant. Hyperandrogenism is present on physical exam and has been long standing; therefore, there is no need to check a testosterone or dHeas level, which would only be required to evaluate her for ovarian and adrenal tumors. The presentation of non-classic congenital adrenal hyperplasia can be very similar to that of PCOs. if the 17OH progesterone level is normal, the diagnosis of PCOs is appropriate. she does not need an ultrasound because she meets two out of three of the Rotterdam criteria already (irregular menses and hyperandrogenism). When PCOs is the final diagnosis, the physician should document the criteria resulting in PCOs because the three different features may identify her future comorbidities and risks.
Correct answer: E.
Discussion: diagnostic criteria for PCOs in adolescents are controversial. diagnosing PCOs in adolescents is difficult because normal pubertal maturation can involve a relative hyperandrogenemia including dHeas levels (with no clear cutoffs for abnormal during puberty), menstrual irregularity and infrequency for months to years post menarche, and a multifollocular ovary that may overlap with a polycystic ovary. Therefore there may be significant overlap between adult PCOs diagnostic criteria and normal puberty in adolescents. Routine ultrasonography is not necessary in this population and may confound the diagnosis given the overlap in ovarian morphology between normal and symptomatic adolescents. Other pathologies, such as congenital adrenal hyperplasia, thyroid dysfunc- tion, and prolactin excess can however be routinely excluded. The guidelines recommend focusing on hyper- androgenism as the primary pathology in adolescents likely to develop PCOs, especially clinical hyperandrogenism such as hirsutism. Further clinicians should treat these complaints in an adolescent, even if the diagnosis is Correct answer: B.
Discussion: This patient is primarily seeking treatment of her hirsutism and her unpredictable menses. Hormonal contraceptives will improve menstrual frequency and improve clinical hyperandrogenism, including hirsutism and acne. anti-diabetic drugs, such as pioglitazone and metformin may lower hyperandrogenemia, but have only modest effects if any on hirsutism. Weight loss may have similar modest effects on her main complaints. Finally there is little evidence that statins improve hirsutism and normalize menses. The risk benefit ratio of hormonal contraceptive must be assessed in each patient. increasing the risk for a serious adverse event in this patient is her obesity. However she is young, without any known vascular disease (and few risk factors beyond her obesity), and does not have a smoking history. Therefore she has no absolute contraindications to hormonal contraception.
Correct answer: D.
Discussion: absolute contraindications to OCP use based on current WHO medical eligibility guidelines include a history of or acute venous or arterial thrombosis or pulmonary embolism, known thrombogenic mutation, systemic lupus erythematosus with antiphospholipid antibodies, acute active liver disease, smoking more than 15 cigarettes/day in women over the age of 35, multiple risk factors for cardiovascular disease including evidence of vascular disease or history of ischemic heart disease, blood pressure ≥160/100, stroke, migraine headaches with aura, breast cancer, diabetes with vascular disease or neuropathy/retinopathy, and immediate postpartum state. Risk of devel-oping diabetes in the future itself is not a contraindication to OCP use. While obesity is associated with slightly higher risk with OCP use, it is not a contraindication to use. While a history of hyperlipidemia is a relative contra-indication for OCP use, in the setting of normal triglycerides it is not necessary to monitor triglyceride levels in routine OCP use. a history of pre-eclampsia in the setting of current normal blood pressure is not a contraindica-tion to use of OCP.
Correct answer: C.
Discussion: Women with PCOs are insulin resistant as a consequence of PCOs per se and, when present, excess adiposity. a fasting insulin concentration is not needed to establish a diagnosis of insulin resistance in this patient nor will it help in choosing among the therapeutic options. a fasting glucose concentration is often normal at the time of presentation among women with PCOs. in contrast, approximately 35% of women with PCOs will have evidence of impaired glucose tolerance (iGT) or frank type 2 diabetes at presentation. This is particularly true in this patient given the presence of multiple risk factors (positive family history of type 2 diabetes, race, obesity, PCOs). Because iGT and type 2 diabetes are important to recognize and treat, a 75 gm 2hr OGTT is indicated. Fasting concentrations of lipids are also useful to obtain prior to starting treatment in this population.
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Androgen Therapy in Women Case Detection, Diagnosis & Treatment of Patients with Primary Aldosteronism Congenital Adrenal Hyperplasia Due to Steroid 21-hydroxylase Deficiency Continuous Glucose Monitoring Diabetes and Pregnancy (with CME) The Diagnosis of Cushing's Syndrome Diagnosis and Treatment of Polycystic Ovary Syndrome (with CME) Diagnosis & Treatment of Hyperprolactinemia Endocrine & Nutritional Management of the Post-bariatric Surgery Patient Evaluation & Management of Adult Hypoglycemic Disorders Evaluation & Treatment of Adult Growth Hormone Deficiency (with CME) Evaluation & Treatment of Hirsutism in Premenopausal Women Evaluation & Treatment of Hypertriglyceridemia Evaluation, Treatment, and Prevention of Vitamin D Deficiency Endocrine Treatment of Transsexual Persons Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Set ing Executive Summary Management of Thyroid Dysfunction during Pregnancy and Postpartum (with CME) Osteoporosis in Men Pituitary Incidentaloma Prevention & Treatment of Pediatric Obesity Primary Prevention of Cardiovascular Disease & Type 2 Diabetes in Patients at Metabolic Risk Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes (with CME) All prices include sales tax PAYMENT INFORMATION:
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Influence of antihypertensive therapy on cerebral perfusion in patients with metabolic syndrome: relationship with cognitive function and 24&#x2010;h arterial blood pressure monitoring

ORIGINAL RESEARCH ARTICLE Influence of Antihypertensive Therapy on Cerebral Perfusion inPatients with Metabolic Syndrome: Relationship with CognitiveFunction and 24-h Arterial Blood Pressure Monitoring Nataliya Y. Efimova,1,2 Vladimir I. Chernov,1,2 Irina Y. Efimova1 & Yuri B. Lishmanov1,2 1 Federal State Budgetary Scientific Institution, Research Institute for Cardiology, Tomsk, Russia2 National Research Tomsk Polytechnic University, Tomsk, Russia

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Effects of essential oils from medicinal plants used in Brazil against epec and etec Duarte, M. C. T.; Leme;Delarmelina, C.; Figueira, G. M.; Sartoratto, A.; Rehder, V. L. G.CPQBA/UNICAMP (Research Center for Chemistry, Biology and Agriculture), CP 6171, CEP 13083-970, Campinas(SP), Brazil.E-mail: mduarte@cpqba.unicamp.br ABSTRACT: Effects of essential oils from medicinal plants used in brazil against epec and etec escherichia coli .