II. Epidemiology
- Prevalence: 7% of reproductive-aged women in U.S. (most common endocrinopathy in this group)
III. Pathophysiology
- History
- First described by Stein and Leventhal in 1935
- Contributing Factors
- Obesity and hyperinsulinemia
- Increased adrenal function
-
Androgen Excess (Hyperandrogenism)
- Androstenedione increased
- Testosterone increased
- Free Testosterone increased
- Occurs with decreased Sex Hormone Binding Globulin
- Ovarian enlargement with Hyperthecosis
- Luteinization of theca interna
- Reduction of granulosa cells
IV. Symptoms
- Menstrual Disorders (80% of PCOS patients)
- Oligomenorrhea (36 to 180 day cycles) or Amenorrhea
- Anovulatory Bleeding (<6 Menses per year)
- Delayed menstrual regularity
- Infertility (74% of patients) or Recurrent Miscarriage
- Androgenic features
- See Hyperandrogenism
- Acne Vulgaris
- Hirsutism (69%)
- Male sweat changes
- Clitoris swelling
- Central Obesity (49% of PCOS patients)
- Weight gain starts in teens and twenties
- BMI over 27 (65% of PCOS patients)
V. Signs
- Hypertension
- Hirsutism
- Acne Vulgaris
- Alopecia
- Acathosis nigricans
- Skin Tags
- Bilateral ovary enlargement
VI. Differential Diagnosis (See Hyperandrogenism)
- HAIR-AN Syndrome
-
Cushing's Syndrome (buffalo hump, striae)
- Obtain 24 hour Urine Cortisol (or Dexamethasone Suppression Test)
-
Congenital Adrenal Hyperplasia (severe Virilization)
- Serum DHEAS > 700 ng/dl (Androgen Secreting tumor)
- Serum Total Testosterone >20 ng/dl (Androgen tumor)
- Obtain pelvic Ultrasound and Adrenal CT or MRI
- Primary Ovarian Insufficiency (Hot Flashes, atrophic urogenital symptoms)
- Hypothalamic Amenorrhea (e.g. Female Athlete Triad with low BMI, Eating Disorder, athlete)
- Acromegaly (protruding jaw, change in head or hand size, visual changes)
VII. Associated Conditions
- Metabolic Syndrome (RR 2)
- Type II Diabetes Mellitus (RR 4)
- Obesity (50% of PCOS patients)
- Nonalcoholic Fatty Liver Disease
- Obstructive Sleep Apnea
- Dyslipidemia
- Cardiovascular Disease
- Mood Disorders (e.g. Major Depression, Generalized Anxiety)
VIII. Imaging: Transvaginal Ultrasound
- Indications
- Ultrasound is not required for diagnosis of PCOS (diagnosis can be made clinically)
- Obtain if Rotterdam Criteria not met or ovarian pathology suspected (e.g. Ovarian tumor)
-
General features
- At least 12 (25 if new technology used) small follicles (2-9 mm diameter each) in various stages
- Ovary >10 ml in volume
- Thick ovarian capsule
- String of pearls appearance
- Criteria: Multiple Ovarian Cysts (seen in 80% of cases)
- Ten or more cysts in a single plane
- Each cyst <10 mm in diameter
- Dense stroma
- Interpretation
- Polycystic appearance is seen in up to 62% of women with normal Ovulation
- Polycystic appearance does not diagnose PCOS
- PCOS clinical features must be present for diagnosis
- Hassan (2003) Fertil Steril 80:966-75 [PubMed]
IX. Labs: Approach
- Consider Hyperandrogenism labs (if not evident from exam or severe Virilization of Congenital Adrenal Hyperplasia)
- Serum DHEAS > 700 ng/dl (Androgen Secreting tumor)
- Serum Total Testosterone >20 ng/dl (Androgen tumor)
- Obtain pelvic Ultrasound and Adrenal CT or MRI for severe Virilization of CAH (deep voice, clitoromegaly)
- Exclude other diagnoses
- Urine Pregnancy Test
- Thyroid Stimulating Hormone
- Morning 17a-hydroxyprogesterone (adrenal hyperplasia)
- Serum Prolactin
- Evaluate comorbid disease
- Blood Pressure
- Obtain at each visit
- Fasting Glucose (or other Diabetes Mellitus Screening)
- Obtain at diagnosis and re-screen at least every 3-5 years (or more often)
- Fasting Lipid Panel
- Obtain at time of diagnosis
- Blood Pressure
- Other tests to consider
- Serum LH (hypothalamic Amenorrhea)
- Serum FSH (hypothalamic Amenorrhea, Primary Ovarian Insufficiency)
- Serum Estradiol (hypothalamic Amenorrhea, Primary Ovarian Insufficiency)
- Other tests that have been used in past (listed for historical purposes)
- Glucose to Insulin Ratio < 4.5 is consistent with PCOS-related hyperinsulinemia
X. Labs: Review of laboratory changes in PCOS
-
Insulin Resistance Syndrome (70% of PCOS patients)
- Glucose to Insulin Ratio < 4.5
- Sensitive marker of Insulin Resistance in PCOS
- Insulin increased (C-Peptide increased)
- Fasting Serum Glucose increased
- Two hour Glucose Tolerance Test abnormal
- Glucose to Insulin Ratio < 4.5
- Gonadotropin increases
- Luteinizing Hormone (LH) exaggerated surge
- Serum LH to Serum FSH ratio exceeds 3.0 (30%)
- Serum Testosterone >20 ng/dl
- Serum Free Testosterone >2.57 pg/ml
- Androstenedione >2.7 ng/ml
- Associated endocrine abnormality testing
- Thyroid Stimulating Hormone (TSH)
- Serum Prolactin
- Consider adrenal function testing
- Associated dyslipidemia
- Total Cholesterol increased
- LDL Cholesterol increased
- HDL Cholesterol decreased
- Triglycerides increased
XI. Diagnosis
- Delay diagnostic evaluation until at least 2 years after Menarche
- Diagnosis may be made in many patients based on history, exam and limited laboratory testing
- Rotterdam Criteria from 2003 (2 of 3 required in adults, 3 of 3 in adolescents)
- Hyperandrogenism
- Ovulatory Dysfunction
- Polycystic Ovaries
XII. Management: Obesity
- Weight loss of 10% in Overweight patients
- Insulin Resistance decreases with weight loss
- Results in 75% conception rate in PCOS
XIII. Management: Ovulatory Dysfunction (Anovulation, Oligomenorrhea or irregular Menses)
- Fertility desired
- First-line
- Clomiphene (Clomid) or Letrozole (Femara)
- Adunctive in Overweight women (if clomiphene ineffective alone)
- First-line
- Fertility not desired
- First-line (Unopposed Estrogen management)
- Levonorgestrel-releasing Intrauterine Device (Mirena IUD) or other hormonal contraceptive
- Provera 10 mg orally daily for 7 days repeated every 3 months or
- Seasonal Oral Contraceptive Cycle (e.g. Seasonale) or
- Oral Contraceptive with low Androgenic Activity (preferred first line agents)
- Second-line
- First-line (Unopposed Estrogen management)
XIV. Management: Hirsutism
- See HAIR-AN Syndrome
- See Hirsutism
- Fertility desired
- Fertility not desired
- First-line agents
- Second-Line Agents
- Spironolactone (Aldactone) 50 mg orally twice daily (Teratogen risk, use with Hormonal Contraception)
- Eflornithine (Vaniqa) 13.9% applied to face daily
- Finasteride (Propecia)
- Flutamide (Eulexin)
- Third-Line Agents
XV. Management: Acne Vulgaris
- Fertility desired
- Fertility not desired
- First-line agents
- Second-line agents
- Spironolactone (with Contraception to prevent pregnancy due to Teratogenicity)
XVI. Management: Insulin Resistance
-
Metformin (Glucophage)
- Primarily indicated in comorbid Diabetes Mellitus, history of Gestational Diabetes or Metabolic Syndrome
- May be used in those trying to conceive
- Consider in irregular Menses in women unable to take Oral Contraceptives
- Start at 500 mg PO daily and advance to 1500-2000 mg daily divided bid
- Effect not seen until dose >1000 mg/day
- Induces Ovulation in up to 46% of PCOS cases
- Barbieri (2003) Obstet Gynecol 101:785-93 [PubMed]
- Lord (2003) BMJ 327:951-6 [PubMed]
-
Glitazones
- Not recommended in general due to risk of weight gain and Miscarriage
- Pioglitazone (Actos) 30 mg orally daily
- Rosiglitazone (Avandia) 2-8 mg orally daily (best effect with higher doses)
- No longer available in U.S. due to adverse effects
- Cataldo (2006) Hum Reprod 21(1): 109-20 [PubMed]
XVII. Management: Advanced
- Gonadotropins (e.g. Metrodin, Pergonal)
- Risk of Ovarian Hyperstimulation Syndrome (OHSS)
- FSH with hCG
-
Glucocorticoids (Prednisone, Dexamethasone)
- Indicated in adrenocortical hyperplasia
- GnRH-Agonist
- Indicated prior to Ovulation induction
XVIII. Management: Surgical
- Ovarian wedge resection
- Normal cycles resume in 80% of patients
- Conception occurs in 63%
- Risk of peritubular and ovarian adhesions
- Laparoscopic ovarian drilling
- Similar results to ovarian wedge resection
- Minimally invasive
XIX. Complications
- Infertility
- Increased Breast Cancer risk
- Increased Endometrial Cancer risk
- Associated with Unopposed Estrogen
- Increased cardiovascular disease risk
XX. References
- Acien (1999) Fertil Steril 72:32-40 [PubMed]
- Chang (1999) Endocrinol Metab Clin North Am 28:397-408 [PubMed]
- Futterweit (1999) Obstet Gynecol Surv 54:403-13 [PubMed]
- Pasquali (1999) Clin Endocrinol 50:517-27 [PubMed]
- Richardson (2003) Am Fam Physician 68(4):697-704 [PubMed]
- Taylor (1998) Endocrinol Metab Clin North Am 27:877-902 [PubMed]
- Williams (2016) Am Fam Physician 94(2): 106-13 [PubMed]