Polycystic Ovarian Syndrome - PCOS

Polycystic ovarian syndrome (PCOS) is a common endocrinopathy caused by androgen excess and is the leading cause of anovulatory infertility. Because it is associated with increased cardiovascular risk as well as other adverse effects, diagnosis is essential for both treatment and monitoring reasons.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Irregular menses, infertility, hirsutism, acne

Criteria for Diagnosis

Two of 3 of the following criteria in the absence of other etiology (American Association of Clinical Endocrinologists [AACE]/American College of Endocrinology [ACE]/Androgen Excess and Polycystic Ovarian Syndrome Society, 2015).

Menstrual irregularities
Hyperandrogenism (clinical or biological)
Polycystic ovaries

Criteria for Defining Polycystic Ovarian Syndrome (PCOS)
Androgen Excess and PCOS Society Guidelines (developed in 2006, reaffirmed in 2015 [Goodwin, 2015])	Amsterdam European Society of Human Reproduction and Embryology (ESHRE)/American Society for Reproductive Medicine (ASRM) Consensus (3rd PCOS Consensus 2012) – reaffirmed use of Rotterdam 2003 criteria
PCOS is a disorder of androgen excess or hyperandrogenism Diagnosis requires all 3 of the following elements Hyperandrogenism^a Clinical (hirsutism) and/or biochemical signs (elevated levels of total or free testosterone) Ovarian dysfunction and/or polycystic ovaries (prominent but not universal feature of PCOS) Polycystic ovarian morphology defined as per guidelines (Dewailey, 2014) ≥25 follicles/ovary – recommended criterion over ovarian volume ≥10 mL ovarian volume Exclusion of other androgen excess disorders	Adult female PCOS is a disorder of androgen excess or hyperandrogenism Presence of 2 of the following 3 elements confirms PCOS Hyperandrogenism^a Clinical (hirsutism) or biochemical signs Oligo-ovulation and/or anovulation Polycystic ovaries on ultrasound Presence of ≥12 follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume >10 cm³ Exclusion of other androgen excess disorders Adolescent female Risk of overdiagnosis of PCOS in this population All 3 of the following elements must be present to confirm diagnosis Oligomenorrhea or amenorrhea for ≥2 years after menarche (or primary amenorrhea at 16 years) Polycystic ovaries on ultrasound (size >10 cm³) Hyperandrogenemia
^aHyperandrogenism Usually defined as >2.5 standard deviations above mean for assay Measure between day 4 and 10 of menstrual cycle Lab testing to confirm Testosterone is the hormone usually measured May have poor validity in some labs Assay should measure testosterone levels for female and children Androstenedione and dehydroepiandrosterone sulfate (DHEA-S) are informative markers but not necessary in most cases

Laboratory Testing

Initial testing
- Serum free testosterone
  - Mass spectrometry – gold standard
  - Mass spectrometry with liquid chromatography (LC-MS/MS) – acceptable
  - Radioimmunoassay (RIA) that includes purification – acceptable
  - Assay that measures levels for females and children should be used
  - Sample should be collected between day 4 and 10 of menstrual cycle
  - Testosterone is elevated if >2.5 standard deviations above the mean
    - Value >200 ng/dL should prompt evaluation for androgen-secreting tumor
  - Testing should be performed by laboratories that use appropriate methods

Additional testing

Serum 17-hydroxyprogesterone
- Test for nonclassic 21-hydroxylase deficiency – patients with this deficiency will present with same clinical signs and symptoms as those with PCOS

Anti-Mullerian hormone (AMH)

AMH testing can be used in place of ovarian morphology assessment

AMH reference intervals for females (age dependent)

AMH Reference Intervals for Females
Age	Reference Interval (ng/mL)
6 mos-14 yrs	0.256-6.345
15-17 yrs	0.861-10.451
18-29 yrs	0.401-16.015
30-39 yrs	0.176-11.705
40-45 yrs	≤6.282
46-50 yrs	≤0.064
Postmenopausal	≤0.003

Progesterone
- Test midcycle to confirm anovulation
- Not required for diagnosis

Other hormone testing not indicated
- Dehydroepiandrosterone (DHEA) – measurement does not add significantly to diagnosis
- 11β-hydroxyandrostenedione and androstenedione – generally not needed to assist with diagnosis
- Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) – not indicated

Imaging Studies

Transvaginal ultrasound
- Presence of polycystic ovaries alone is not sufficient to establish diagnosis
Magnetic resonance imaging (MRI)/computed tomography (CT) – most useful to rule out adrenal/ovarian tumors if testosterone level is moderately elevated

Differential Diagnosis

Pregnancy
- Measure beta human chorionic gonadotropin (β-hCG) level
Adrenal hyperfunction (Cushing syndrome)
Late onset congenital adrenal hyperplasia (CAH)
- Present in <5% of hyperandrogenic women
- Measure 17-hydroxyprogesterone
  - Morning testing preferred
  - If result is >200 ng/mL, further assessment is necessary to rule out CAH
Androgen-secreting tumors (ovarian, adrenal)
- Present in 0.2% of hyperandrogenic women
- Testosterone >200 ng/dL combined with dehydroepiandrosterone sulfate (DHEA-S) >700 µg/dL suggests ovarian or adrenal tumor
Metabolic syndrome
Prolactinoma
- Measure prolactin
Idiopathic hirsutism
Acromegaly
Thyroid dysfunction/hypothyroidism
- Measure thyroid-stimulating hormone (TSH)
Drug related
- Testosterone
- Danazol
- Androgenic progestins
- Valproic acid
- Acetazolamide
- Minoxidil
- High-dose glucocorticosteroids

Monitoring

Monitoring is recommended for long-term health consequences associated with polycystic ovarian syndrome (PCOS)
- Metabolic syndrome
- Cardiovascular disease
- Impaired glucose tolerance and diabetes
- Increased endometrial cancer risk
Laboratory testing (after diagnosis) to evaluate for metabolic complications of PCOS
- Fasting 2-hour glucose tolerance test or hemoglobin A1c
- Fasting lipid profile (see Atherosclerotic Cardiovascular Disease [ASCVD] Risk Markers)
- Liver function testing (alanine aminotransferase, aspartate aminotransferase)

Background

Epidemiology

Prevalence – 10-15% of adult females worldwide (Azziz, Androgen Excess and Polycystic Ovarian Syndrome Society, 2009).

Genetics

Family incidence nearly 40%
Appears to be autosomal dominant

Pathophysiology

Etiology is unknown
Excess androgen production (hyperandrogenism) and insulin resistance play a role in disease pathogenesis

Clinical Presentation

Irregular menses or amenorrhea
Infertility
Signs of hyperandrogenism, including
- Acne
- Hirsutism
  - Increased number of terminal hairs
  - Hatch modification of the Ferriman-Gallwey scale should be used to evaluate
- Alopecia – similar to male pattern baldness
High rate of type 2 diabetes mellitus (T2DM), metabolic syndrome, sleep apnea, and obesity

Pediatrics

Epidemiology

Prevalence – affects 5-10% of adolescent females
40% develop type 2 diabetes mellitus (T2DM) or impaired glucose tolerance by age 40

Clinical Presentation

Hirsutism
- Increased number of terminal hairs
- Hatch modification of the Ferriman-Gallwey scale should be used to evaluate
- Ethnic differences affect hirsutism
Alopecia – similar to male pattern baldness
Acne – consider diagnosis of polycystic ovarian syndrome (PCOS) if acne is severe or does not respond to standard therapies
Irregular menses of >2 years duration
Obesity (central or refractory)

Indications for Testing

Irregular menses, hirsutism, acne, infertility

Laboratory Testing

Initial testing
- Diagnosis may be more difficult in adolescents, but PCOS is important to be aware of and address early due to the risks associated with nontreatment
- Symptoms in patients <18 years may represent transient adolescent hormonal changes
- Serum or urine human chorionic gonadotropin (hCG) should be measured to rule out pregnancy
Refer to main Laboratory Testing subsection within Diagnosis
Refer to Secondary Amenorrhea Testing Algorithm

Imaging Studies

Transvaginal ultrasound to evaluate ovaries
- Complicated by increased number of cysts normally occurring in adolescents
- Required by Amsterdam criteria, but not by Androgen Excess and Polycystic Ovarian Syndrome Society criteria

Differential Diagnosis

Late-onset congenital adrenal hyperplasia (CAH)
Androgen secreting tumors (ovarian, adrenal)
Thyroid dysfunction
Prolactinoma
Pregnancy

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Testosterone, Free and Total (Includes Sex Hormone Binding Globulin), Females or Children 0081056
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
The concentration of free testosterone is derived from a mathematical expression based on the constant for the binding of testosterone to sex hormone binding globulin.

Recommended Use

Recommended initial test in the evaluation of suspected hyperandrogenemia in women and children

Acceptable test for evaluating androgen deficiency in men

Dehydroepiandrosterone Sulfate, Serum 0070040
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Indicator of adrenal androgen production

Aid in the investigation of virilizing endocrinopathies in conjunction with other sex steroids

Not recommended for initial evaluation of polycystic ovarian syndrome (PCOS)

Androstanediol Glucuronide Quantitative, Serum or Plasma 2005419
Method: Quantitative High Performance Liquid Chromatography/Tandem Mass Spectrometry

Recommended Use

Not generally recommended

Adjunct tool for the evaluation of hirsutism

Androstenedione 2001638
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Recommended Use

Aid in the investigation of virilizing endocrinopathies and in managing congenital adrenal hyperplasia (CAH) in conjunction with other sex steroids

Not recommended for initial evaluation of PCOS

17-Hydroxyprogesterone Quantitative by HPLC-MS/MS, Serum or Plasma 0092332
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Recommended Use

Detect enzyme deficiencies causing CAH

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Recommended Use

Screening for anterior pituitary tumor

Cortisol Urine Free by LC-MS/MS 0097222
Method: Quantitative Liquid Chromatography-Tandem Mass Spectrometry

Recommended Use

Rule out Cushing syndrome

Cortisol, Saliva 0081117
Method: Quantitative Enzyme Immunoassay

Recommended Use

Rule out Cushing syndrome

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Assess thyroid function

Reflex pattern – if the thyroid stimulating hormone is outside the reference interval, then free thyroxine (free T4) testing will be added

Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Recommended Use

Diagnose and manage diabetes mellitus (DM) and other carbohydrate metabolism disorders

Lipid Panel, Extended 0020468
Method: Quantitative Spectrophotometry/Quantitative Enzymatic

Recommended Use

Assess cardiovascular disease risk and guide therapy

Panel includes cholesterol, serum or plasma; triglycerides, serum or plasma; HDL cholesterol; LDL cholesterol, direct; VLDL, calculated; non-HDL cholesterol; appearance chemistry

Aspartate Aminotransferase, Serum or Plasma 0020007
Method: Quantitative Enzymatic

Recommended Use

Monitor liver function

Alanine Aminotransferase, Serum or Plasma 0020008
Method: Quantitative Enzymatic

Recommended Use

Monitor liver function

Medical Experts

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology and Automated Core Laboratory at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF, Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006; 91(11): 4237-45. PubMed
Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF, Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009; 91(2): 456-88. PubMed
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004; 81(1): 19-25. PubMed
Fauser BC, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, Carmina E, Chang J, Yildiz BO, Laven JS, Boivin J, Petraglia F, Wijeyeratne CN, Norman RJ, Dunaif A, Franks S, Wild RA, Dumesic D, Barnhart K. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012; 97(1): 28-38.e25. PubMed
Dewailly D, Lujan ME, Carmina E, Cedars MI, Laven J, Norman RJ, Escobar-Morreale HF. Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2014; 20(3): 334-52. PubMed
Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad H, Pasquali R, Welt CK, Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013; 98(12): 4565-92. PubMed
Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E, American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE), Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society Disease State Clinical Review: Guide to the Best Practices in the Evaluation and Treatment of Polycystic Ovary Syndrome--Part 1. Endocr Pract. 2015; 21(11): 1291-300. PubMed
Witchel SF, Oberfield S, Rosenfield RL, Codner E, Bonny A, Ibáñez L, Pena A, Horikawa R, Gomez-Lobo V, Joel D, Tfayli H, Arslanian S, Dabadghao P, Rudaz CG, Lee PA. The diagnosis of polycystic ovary syndrome during adolescence. Horm Res Paediatr. 2015; PubMed

General References

Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab. 2006; 91(3): 781-5. PubMed

Benjamins LJ, Barratt MS. Evaluation and management of polycystic ovary syndrome. J Pediatr Health Care. 2009; 23(5): 337-43. PubMed

Bruni V, Dei M, Nannini S, Balzi D, Nuvolone D. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2010; 1205: 175-84. PubMed

Carmina E, Oberfield SE, Lobo RA. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol. 2010; 203(3): 201.e1-5. PubMed

Hassan A, Gordon CM. Polycystic ovary syndrome update in adolescence. Curr Opin Pediatr. 2007; 19(4): 389-97. PubMed

Lorenz LB, Wild RA. Polycystic ovarian syndrome: an evidence-based approach to evaluation and management of diabetes and cardiovascular risks for today's clinician. Clin Obstet Gynecol. 2007; 50(1): 226-43. PubMed

Setji TL, Brown AJ. Polycystic ovary syndrome: update on diagnosis and treatment. Am J Med. 2014; 127(10): 912-9. PubMed

Yii MF, Lim CE, Luo X, Wong WS, Cheng NC, Zhan X. Polycystic ovarian syndrome in adolescence. Gynecol Endocrinol. 2009; 25(10): 634-9. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology^®

Büttler RM, Martens F, Fanelli F, Pham HT, Kushnir MM, Janssen MJ, Owen L, Taylor AE, Soeborg T, Blankenstein MA, Heijboer AC. Comparison of 7 Published LC-MS/MS Methods for the Simultaneous Measurement of Testosterone, Androstenedione, and Dehydroepiandrosterone in Serum. Clin Chem. 2015; 61(12): 1475-83. PubMed

Büttler RM, Martens F, Kushnir MM, Ackermans MT, Blankenstein MA, Heijboer AC. Simultaneous measurement of testosterone, androstenedione and dehydroepiandrosterone (DHEA) in serum and plasma using Isotope-Dilution 2-Dimension Ultra High Performance Liquid-Chromatography Tandem Mass Spectrometry (ID-LC-MS/MS). Clin Chim Acta. 2015; 438: 157-9. PubMed

Caanen MR, Kuijper EA, Hompes PG, Kushnir MM, Rockwood AL, Meikle WA, Homburg R, Lambalk CB. Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome. Eur J Endocrinol. 2016; 174(1): 25-32. PubMed

Moller AT, Backstrom T, et al. Diurnal Variations of Endogenous Steroids in the Follicular Phase of the Menstrual Cycle. Neurochemistry & Neuropharmacology. [Published: Feb 2016; Accessed: Apr 2017]

Ray JA, Kushnir MM, Rockwood AL, Meikle W. Direct Measurement of Free Estradiol in Human Serum and Plasma by Equilibrium Dialysis-Liquid Chromatography-Tandem Mass Spectrometry. Methods Mol Biol. 2016; 1378: 99-108. PubMed

Testing Algorithms

Secondary Amenorrhea Testing Algorithm

Read more about Secondary Amenorrhea Testing Algorithm

Educational Videos

Content Review:

September 2017

Last Update: December 2018

Polycystic Ovarian Syndrome - PCOS

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Differential Diagnosis

Monitoring

Background

Epidemiology

Genetics

Pathophysiology

Clinical Presentation

Pediatrics

Epidemiology

Clinical Presentation

Indications for Testing

Laboratory Testing

Imaging Studies

Differential Diagnosis

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology^®

Secondary Amenorrhea Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Polycystic Ovarian Syndrome - PCOS. ARUP Consult^©. Retrieved December 17, 2018, from: https://arupconsult.com/content/polycystic-ovarian-syndrome

Polycystic Ovarian Syndrome - PCOS

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Imaging Studies

Differential Diagnosis

Monitoring

Background

Epidemiology

Genetics

Pathophysiology

Clinical Presentation

Pediatrics

Epidemiology

Clinical Presentation

Indications for Testing

Laboratory Testing

Imaging Studies

Differential Diagnosis

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

Secondary Amenorrhea Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult

References from the ARUP Institute for Clinical and Experimental Pathology^®