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Polycystic Ovarian Syndrome (PCOS)
Maria De La Luz Nieto, MD
image BASICS
DESCRIPTION
  • Polycystic ovarian syndrome (PCOS) is a common endocrine disorder with heterogeneous manifestations that affects up to 7% of the U.S. population.
  • Hyperandrogenism leading to anovulation, typically presenting as amenorrhea or oligomenorrhea
  • Diagnosis is based on clinical assessment and ultrasound findings.
  • Diagnostic clinical characteristics include menstrual dysfunction, infertility, hirsutism, acne, obesity, and metabolic syndrome. The ovaries are often polycystic on imaging.
  • The etiology of PCOS is unknown but can be modified by lifestyle factors.
  • System(s) affected: reproductive, endocrine/metabolic, skin/exocrine
  • Synonym(s): Stein-Leventhal syndrome; polycystic ovary disease
EPIDEMIOLOGY
Prevalence
  • Incidence and prevalence are still highly debated due to a wide spectrum of diagnostic features: The National Institutes of Health (NIH) criteria require chronic anovulation in addition to clinical or biochemical signs of hyperandrogenism. The prevalence based on NIH criteria is 6.5-8%.
  • Predominant age: reproductive age
  • Predominant sex: females only
ETIOLOGY AND PATHOPHYSIOLOGY
  • PCOS is a multifactorial functional disorder of unclear etiology.
  • Recent evidence points to a primary role for insulin resistance with hyperinsulinemia.
  • Androgenism: Ovaries are the main source of excess androgens. Polycystic ovaries have thickened thecal layers, which secrete excess androgens in response to luteinizing hormone (LH). LH receptors are overexpressed in thecal and granulosa cells of polycystic ovaries.
  • Ovarian follicles: Abnormal androgen signaling may account for abnormal folliculogenesis causing polycystic ovaries. The mechanism that determines abnormal number of follicles is unknown but may be due to abnormal androgen signaling on the ovarian stroma.
  • Insulin resistance: Women with PCOS have insulin resistance similar to that in type 2 diabetes. Elevated levels of insulin decrease sex hormone-binding protein (SHBG), increasing bioavailability of testosterone. Insulin may also act directly on adrenal, ovary, and hypothalamus to regulate androgen and gonadotropin release. Insulin resistance causes elevated insulin levels.
  • Insulin resistance may cause the frequently associated metabolic syndrome and frank diabetes mellitus.
Genetics
Ultimate expression is likely a combination of polygenic and environmental factors.
RISK FACTORS
See “Commonly Associated Conditions”; cause and effect are difficult to extricate in this disorder.
GENERAL PREVENTION
None known; focus on early diagnosis and treatment to prevent long-term complications.
COMMONLY ASSOCIATED CONDITIONS
  • Infertility
  • Obesity
  • Obstructive sleep apnea
  • Hypertension
  • Diabetes mellitus
  • Endometrial hyperplasia/carcinoma
  • Fatty liver disease
  • Mood disturbances and depression
image DIAGNOSIS
PHYSICAL EXAM
  • Vital signs: body mass index (BMI), high BP
  • General appearance: central obesity, deepened voice, hirsutism, acne
  • Skin: hair pattern and growth, acne, seborrhea, acanthosis nigricans
  • Genitalia: clitoromegaly and ovarian enlargement
DIFFERENTIAL DIAGNOSIS
  • Cushing syndrome
  • HAIR-AN syndrome
  • Testosterone-producing ovarian or adrenal tumor
  • Prolactin-producing pituitary adenoma
  • Hyperthecosis
  • Adult-onset adrenal hyperplasia
  • Partial congenital adrenal hyperplasia (21-hydroxylase deficiency)
  • 11&bgr;-hydroxylase deficiency
  • 17&bgr;-hydroxysteroid dehydrogenase deficiency
  • Acromegaly
  • Drug-induced hirsutism, oligo-ovulation (e.g., danazol, steroids, valproic acid)
  • Thyroid disease
DIAGNOSTIC TESTS & INTERPRETATION
  • The value of measurement of circulating androgens to document PCOS is uncertain but should include measuring free testosterone concentration directly by equilibrium dialysis.
  • Most common diagnostic criteria used is Rotterdam criteria (need 2 of 3):
    • Oligo- or anovulation
    • Clinical and/or biochemical signs of hyperandrogenism
    • Transvaginal ultrasonographic polycystic ovaries and exclusion of other etiologies; therefore, consider exclusion of Cushing disease, congenital adrenal hyperplasia, and androgen-secreting tumors.
  • More recent criteria also focus on similar criteria while acknowledging that there may be forms of PCOS without overt evidence of hyperandrogenism (2,3)[C].
Initial Tests (lab, imaging)
  • Screening workup should include human chorionic gonadotropin (hCG), TSH, prolactin, FSH (exclude premature ovarian failure), DHEAS, 17-OH progesterone, and testosterone level.
  • LH determination may be ordered but is not usually necessary:
    • Hirsute women should have a testosterone or free testosterone determination and a DHEAS determination.
    • Consider 17-OH progesterone if congenital adrenal hyperplasia is a possibility.
  • LH/FSH level ≥2.5 to 3/L in ˜50% of women with PCOS, but LH testing is not generally necessary.
  • Testosterone increased but <200 ng/dL (6.94 nmol/L).
  • Typical findings in PCOS include mild elevation in DHEAS but <800 &mgr;g/dL (20.8 &mgr;mol/L), mild increase in 17-OH progesterone level, increased estrogen level, and decreased SHBG.
  • Drugs that may alter lab results:
    • Oral contraceptives (OCs)
    • Steroids
    • Antidepressants
  • Transvaginal ultrasound findings: one or both ovaries with ≥12 follicles measuring 2 to 9 mm or increased ovarian volume to 10 cm3
Follow-Up Tests & Special Considerations
  • Consider fasting serum glucose, insulin level, and plasminogen activator inhibitor-1 determinations to establish presence of insulin resistance and glucose intolerance, especially if diagnosis is in doubt.
  • Overnight dexamethasone suppression test (Decadron 1 mg PO at 11:00 PM and fasting serum cortisol at 8:00 AM the next morning) to rule out Cushing syndrome in the appropriate setting
  • Endometrial biopsy to rule out hyperplasia and/or carcinoma, if indicated
  • If the syndrome is diagnosed, determination of fasting glucose and fasting lipid levels should be performed and formal glucose tolerance test is considered.
Test Interpretation
  • Ovary usually enlarged with a smooth white glistening capsule
  • Ovarian cortex lined with follicles in all stages of development, but most atretic
  • Thecal cell proliferation with an increase in the stromal compartment
P.823

image TREATMENT
GENERAL MEASURES
  • No ideal treatment exists.
  • Therapy must be individualized according to the needs and desires of each patient.
MEDICATION
Drug costs related to this condition are high.
First Line
  • The goal of treatment in PCOS depends on symptoms and patient's goals for fertility.
  • Treatment can be divided into five main categories: Lifestyle changes including appropriate nutrition and exercise to decrease body weight can restore ovulation and increase insulin sensitivity (4)[A],(5)[C].
  • Menstrual irregularity when pregnancy not desired:
    • Low-dose OCs (30 to 35 &mgr;g); newer formulations containing progestins with lower androgenicity (e.g., norethindrone, desogestrel, norgestimate, drospirenone) may be particularly beneficial, but all OCs increase SHBG and decrease excess androgen and estrogen. If unable to tolerate OCs, then intermittent medroxyprogesterone (Provera) 10 mg PO for 10 days given every 1 to 2 months.
    • Metformin may help to correct metabolic abnormalities in women who are shown to be insulin resistant. Initial dose is 500 mg daily for 1 week, increasing by 500 mg/week to a total of 1,500 to 2,000 mg/day divided BID; take with food.
      • Overall, data support the usefulness of metformin on both cardiometabolic risk and reproduction assistance in PCOS women.
      • Thiazolidinediones may increase likelihood of ovulation and treat insulin resistance.
  • If pregnancy is desired (6)[B]:
    • Ovulation induction with clomiphene (Clomid, Serophene) and/or exogenous gonadotropins. Birth rate with Clomid is 22.5%, 7.2% with metformin, and 26.8% in women who use both medications.
    • Metformin: 500 to 2,000 mg PO divided BID has been shown to improve hyperandrogenism and restore ovulation. Many times the drug is continued throughout the 1st trimester or the entire pregnancy if there is a history of spontaneous abortion or glucose intolerance. It does improve clinical pregnancy rates but does not improve live birth rates alone or in combination with clomiphene when used for ovulation induction.
    • Has been demonstrated that metformin reduces the incidence of gestational diabetes
Second Line
  • Spironolactone for androgen excess hirsutism not addressed by OC therapy
  • Cosmetic issues due to hyperandrogenism: Acne may respond best with OCs with low doses of cyproterone or drospirenone.
  • Eflornithine hydrochloride 13.9% cream to inhibit hair growth
ADDITIONAL THERAPIES
Weight loss in overweight women results in biochemical and symptomatic improvement in most.
ISSUES FOR REFERRAL
  • To reproductive endocrinologist for all women who cannot achieve pregnancy with Clomid
  • High-risk pregnancies
  • To endocrinologist if Cushing syndrome, congenital adrenal hyperplasia, or adrenal or ovarian tumors are found during the workup
SURGERY/OTHER PROCEDURES
  • Ovarian wedge resection and laparoscopic laser drilling are controversial and rarely used today.
  • Mechanical means of hair removal, including electrolysis, waxing, and depilatory, may improve cosmesis.
COMPLEMENTARY & ALTERNATIVE MEDICINE
Acupuncture assists with cycle normalization and weight loss.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Follow-up at 6-month intervals to evaluate response to therapy and to monitor weight as well as medication side effects.
Patient Monitoring
  • Counsel patient about the risk of endometrial and breast carcinoma, insulin resistance, and diabetes, as well as obesity and its role in infertility.
  • See patient frequently throughout the menstrual cycle, depending on which drug combination is used to induce ovulation.
DIET
In overweight patients, weight loss is the most successful therapy because it improves cardiovascular risk, insulin sensitivity, and menstrual patterns: Counsel on lifestyle dietary changes; consider referral to nutritionist and weight center.
PATIENT EDUCATION
  • Provide patient with information about PCOS, such as from http://www.acog.org/.
  • Discuss the chronic nature of this condition and the risks and benefits and side effects of potential treatments.
  • Review the importance of weight loss, if applicable. Modest weight loss of 5-10% of initial body weight has been demonstrated to improve many of the features of PCOS.
PROGNOSIS
  • Fertility prognosis is good but may need assisted reproductive technologies.
  • Proper follow-up and screening can prevent endometrial carcinoma.
  • Early detection of diabetes may decrease morbidity and mortality associated with cardiovascular risk factor.
REFERENCES
1. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91(2):456-488.
2. Carmina E, Oberfield SE, Lobo RA, et al. The diagnosis of polycystic ovary syndrome in adolescents. Am J Obstet Gynecol. 2010;203(3):201.e1-201.e5.
3. Chang RJ. A practical approach to the diagnosis of polycystic ovary syndrome. Am J Obstet Gynecol. 2004;191(3):713-717.
4. Tang T, Lord JM, Norman RJ, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2010;(1):CD003053.
5. Spritzer PM, Motta AB. Adolescence and polycystic ovary syndrome: current concepts on diagnosis and treatment. Int J Clin Pract. 2015;69(11):1236-1246.
6. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551-566.
Additional Reading
&NA;
  • Diamanti-Kandarakis E, Economou F, Palimeri S, et al. Metformin in polycystic ovary syndrome. Ann N Y Acad Sci. 2010;1205:192-198.
  • Lim CE, Wong WS. Current evidence of acupuncture on polycystic ovarian syndrome. Gynecol Endocrinol. 2010;26(6):473-478.
  • Moran LJ, Misso ML, Wild RA, et al. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010;16(4):347-363.
See Also
&NA;
Algorithm: Amenorrhea, Secondary
Codes
&NA;
ICD10
  • E28.2 Polycystic ovarian syndrome
  • L68.0 Hirsutism
Clinical Pearls
&NA;
  • In the United States, 40% of women with PCOS are not obese.
  • Chronic anovulation should be treated because chronic estrogen stimulation in absence of progesterone may lead to endometrial hyperplasia.
  • Specific therapies must be individualized according to the needs and desires of each patient.