Polycystic Ovary Disease

Aka: Polycystic Ovary Disease, Stein-Leventhal Syndrome, Polycystic Ovary Syndrome, Polycystic Ovaries, Functional Ovarian Hyperandrogenism, PCO Disease, PCOS

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II. Epidemiology

  1. Prevalence: 7-13% of reproductive-aged women in U.S. (most common endocrinopathy in this group)
  2. Subset of girls born Small for Gestational Age (SGA) will develop prepubertal PCOS
    1. Rapid catch-up weight gain (marker that can result in early diagnosis)
    2. Precocious Puberty
    3. Metabolic Syndrome or Insulin Resistance
    4. Visceral fat deposition

III. Pathophysiology

  1. History
    1. First described by Stein and Leventhal in 1935
  2. Contributing Factors
    1. Obesity and hyperinsulinemia (Insulin Resistance)
    2. Increased adrenal function
  3. Androgen Excess (Hyperandrogenism)
    1. Androstenedione increased
    2. Testosterone increased
    3. Free Testosterone increased
      1. Occurs with decreased Sex Hormone Binding Globulin
  4. Ovarian enlargement with Hyperthecosis
    1. Luteinization of theca interna
    2. Reduction of granulosa cells

IV. Symptoms

  1. Menstrual Disorders (80% of PCOS patients)
    1. Oligomenorrhea or Amenorrhea
      1. Primary Amenorrhea (>3 years after Breast development or by age 15 years)
      2. At 1 year after Menarche: >90 days/cycle
      3. At 1 to 3 years after Menarche: <21 days or >45 days/cycle
      4. At >3 years to Perimenopause: <21 days and >36 days/cycle
    2. Anovulatory Bleeding (<6 Menses per year)
    3. Delayed menstrual regularity
  2. Infertility (74% of patients)
    1. May also be associated with Recurrent Miscarriage
  3. Androgenic features
    1. See Hyperandrogenism
    2. Acne Vulgaris
    3. Hirsutism (69%)
    4. Male sweat changes
    5. Clitoris swelling
  4. Central Obesity (49% of PCOS patients)
    1. Weight gain starts in teens and twenties
    2. BMI over 27 (65% of PCOS patients)
      1. However, PCOS also occurs in lean patients (associated with delayed diagnosis)

V. Signs

  1. Hyperandrogenism
    1. Acne Vulgaris
    2. Androgenic Alopecia
    3. Hirsutism
      1. See Ferriman-Gallway Scale
  2. Insulin Resistance
    1. Obesity
    2. Hypertension
    3. Acathosis nigricans
    4. Skin Tags
  3. Genitourinary
    1. Bilateral ovary enlargement

VI. Differential Diagnosis (See Hyperandrogenism)

  1. HAIR-AN Syndrome
  2. Cushing's Syndrome (buffalo hump, striae)
    1. Obtain 24 hour Urine Cortisol (or Dexamethasone Suppression Test)
  3. Congenital Adrenal Hyperplasia (CAH) and androgen Secreting tumors (severe Virilization)
    1. Serum DHEAS > 700 ng/dl (Androgen Secreting tumor)
    2. Serum Total Testosterone >20 ng/dl (Androgen tumor)
    3. Obtain pelvic Ultrasound and Adrenal CT or MRI
    4. Consider morning 17-hydroxyprogesterone during Follicular Phase if suspect non-classic CAH
    5. Consider Inhibin B Level if suspect exogenous androgen intake
  4. Primary Ovarian Insufficiency (Hot Flashes, atrophic urogenital symptoms)
    1. Serum FSH
    2. Serum Estradiol
  5. Hypothalamic Amenorrhea (e.g. Female Athlete Triad with low BMI, Eating Disorder, athlete)
    1. Serum LH
    2. Serum FSH
    3. Serum Estradiol
  6. Acromegaly (protruding jaw, change in head or hand size, visual changes)
    1. Insulinlike Growth Factor 1
  7. Hyperprolactinemia
    1. Serum Prolactin
  8. Thyroid Disease
    1. Thyroid Stimulating Hormone (TSH) reflex to Free T4
  9. Type II Diabetes Mellitus
    1. Hemoglobin A1C

VII. Associated Conditions

  1. Metabolic Syndrome (RR 2)
  2. Type II Diabetes Mellitus (RR 4)
  3. Obesity (50% of PCOS patients)
  4. Nonalcoholic Fatty Liver Disease
  5. Obstructive Sleep Apnea
  6. Dyslipidemia
  7. Cardiovascular Disease
  8. Acanthosis Nigricans
  9. Hidradenitis Suppurativa
  10. Mental Health Disorders
    1. Major Depression (33%)
    2. Generalized Anxiety (13 to 16%)
    3. Eating Disorders (7%)
    4. Somatization

VIII. Diagnosis

  1. Delay diagnostic evaluation until at least 2 years after Menarche
  2. Diagnosis may be made in many patients based on history, exam and limited laboratory testing
  3. Rotterdam Criteria from 2003 (2 of 3 required in adults, 3 of 3 in adolescents)
    1. Hyperandrogenism (60% of patients, clinical or biochemical evidence)
    2. Ovulatory Dysfunction (oligoanovulation)
    3. Polycystic Ovaries (by Ultrasound) or elevated Anti-Mullerian Hormone

IX. Labs: Diagnostic Evaluation for Secondary Causes and Associated Conditions

  1. Exclude other diagnoses
    1. Urine Pregnancy Test
    2. Thyroid Stimulating Hormone
    3. Morning 17a-hydroxyprogesterone (adrenal hyperplasia)
    4. Serum Prolactin
  2. Consider Hyperandrogenism labs (if not evident from exam or severe Virilization of Congenital Adrenal Hyperplasia)
    1. Serum DHEAS > 700 ng/dl (Androgen Secreting tumor)
    2. Serum Total Testosterone >20 ng/dl (Androgen tumor)
    3. Obtain pelvic Ultrasound and Adrenal CT or MRI for severe Virilization (deep voice, clitoromegaly)
      1. Evaluate for Congenital Adrenal Hyperplasia
  3. Evaluate comorbid disease related to Insulin Resistance
    1. Blood Pressure
      1. Obtain at each visit
    2. Fasting Glucose (or other Diabetes Mellitus Screening)
      1. Obtain at diagnosis and re-screen at least every 3-5 years (or more often)
      2. Glucose to Insulin Ratio < 4.5 is consistent with PCOS-related hyperinsulinemia (listed for historical purposes)
    3. Fasting Lipid Panel
      1. Obtain at time of diagnosis
  4. Consider Oligomenorrhea/Amenorrhea secondary causes (hypothalamic and ovarian function labs)
    1. Indications
      1. Hypothalamic Amenorrhea (low body weight, Eating Disorder, athletes)
      2. Primary Ovarian Insufficiency (Hot Flushes, Atrophic Vaginitis symptoms)
    2. Serum LH (hypothalamic Amenorrhea)
    3. Serum FSH (hypothalamic Amenorrhea, Primary Ovarian Insufficiency)
    4. Serum Estradiol (hypothalamic Amenorrhea, Primary Ovarian Insufficiency)
  5. Consider Cushing Disease Evaluation (e.g. moon facies, thoracic kyphosis, Secondary Hypertension, purple striae)
    1. 24-hour Urinary Free Cortisol level
    2. Dexamethasone Suppression Test
  6. Consider Acromegaly Evaluation (e.g. increasing hat or glove size, prominent jaw, exopthalmos)
    1. Insulin-like growth factor 1

X. Labs: Review of Laboratory Changes Found in PCOS

  1. Insulin Resistance Syndrome (70% of PCOS patients)
    1. Glucose to Insulin Ratio < 4.5
      1. Sensitive marker of Insulin Resistance in PCOS
    2. Insulin increased (C-Peptide increased)
    3. Fasting Serum Glucose increased
    4. Two hour Glucose Tolerance Test abnormal
  2. Gonadotropin increases
    1. Luteinizing Hormone (LH) exaggerated surge
    2. Serum LH to Serum FSH ratio exceeds 3.0 (30%)
    3. Serum Testosterone >20 ng/dl
    4. Serum Free Testosterone >2.57 pg/ml
    5. Androstenedione >2.7 ng/ml
  3. Associated dyslipidemia
    1. Total Cholesterol increased
    2. LDL Cholesterol increased
    3. HDL Cholesterol decreased
    4. Triglycerides increased

XI. Imaging: Pelvic Ultrasound

  1. Imaging
    1. Transvaginal Ultrasound is preferred
    2. Transabdominal pelvic Ultrasound may be sufficient in teens
  2. Indications
    1. Ultrasound is not required for diagnosis of PCOS (diagnosis can be made clinically)
    2. Obtain if Rotterdam Criteria not met or ovarian pathology suspected (e.g. Ovarian tumor)
    3. Elevated Anti-Mullerian Hormone may be used as an alternative for diagnosis in adults (not teens)
  3. General features
    1. At least 12 (25 if new technology used) small follicles (2-9 mm diameter each) in various stages
    2. Ovary >10 ml in volume
    3. Thick ovarian capsule
    4. String of pearls appearance
  4. Criteria: Multiple Ovarian Cysts (seen in 80% of cases)
    1. Ten or more cysts in a single plane
    2. Each cyst <10 mm in diameter
    3. Dense stroma
  5. Interpretation
    1. Polycystic appearance is seen in up to 62% of women with normal Ovulation
    2. Polycystic appearance does not diagnose PCOS
    3. PCOS clinical features must be present for diagnosis
    4. Hassan (2003) Fertil Steril 80:966-75 [PubMed]

XII. Management: General

  1. Obesity
    1. See Obesity Management
    2. Calorie restricted diet
    3. Weight loss of 5-10% in Overweight patients may improve Metrorrhagia, Hirsutism, Infertility
      1. Insulin Resistance decreases with weight loss
        1. Kiddy (1992) Clin Endocrinol 36:105-11 [PubMed]
      2. Results in 75% conception rate in PCOS
        1. Bates (1982) Fertil Steril 38:406-9 [PubMed]
  2. Other Lifestyle Changes
    1. Regular Exercise
    2. Healthy Diet
    3. Tobacco Cessation

XIII. Management: Ovulatory Dysfunction (Anovulation, Oligomenorrhea or irregular Menses)

  1. Fertility desired
    1. First-line
      1. Letrozole (Femara)
        1. Start 2.5 mg orally daily for 5 days starting on day 3 of Menstrual Cycle (or days 2 to 5)
        2. May increase to 5 mg if not effective (maximum 7.5 mg/day)
        3. More effective than Clomiphene
          1. Liu (2023) Obstet Gynecol 141(3): 523-34 [PubMed]
    2. Second-Line
      1. Clomiphene (Clomid)
        1. Start 50 mg orally daily for 5 days starting on day 3 of Menstrual Cycle (or days 2 to 5)
        2. May increase dose if ineffective (maximum dose 100 mg), and may repeat for up to 6 cycles
    3. Adunctive in Overweight women (if Clomiphene ineffective alone)
      1. Metformin (Glucophage)
  2. Fertility not desired
    1. First-line (Unopposed Estrogen management)
      1. Levonorgestrel-releasing Intrauterine Device (Mirena IUD) or other hormonal contraceptive
      2. Provera 10 mg orally daily for 7 days repeated every 3 months or
      3. Seasonal Oral Contraceptive Cycle (e.g. Seasonale) or
      4. Oral Contraceptive with low Androgenic Activity (preferred first line agents)
        1. Ortho Tri-Cyclen
        2. Ortho-Cept or Desogen
        3. Modicon
        4. Ortho-Cyclen
        5. Yasmin
    2. Second-line
      1. Metformin (Glucophage)
        1. First-line agent in PCOS if type 2 diabetes, Prediabetes, Insulin Resistance or BMI>30 kg/m2
        2. Combined with lifestyle changes (Exercise, Healthy Diet, weight loss)
        3. Consider in Metrorrhagia when Oral Contraceptives are not tolerated or contraindicated

XIV. Management: Hirsutism

  1. See HAIR-AN Syndrome
  2. See Hirsutism
  3. Fertility desired
    1. See Hair Removal Technique
    2. Electrolysis
    3. Laser Hair Reduction
  4. Fertility not desired
    1. First-line agents
      1. See Hair Removal Technique
      2. Hormonal Contraception (see above)
    2. Second-Line Agents
      1. Consider if Estrogen agents are contraindicated (e.g. Migraine with Aura, VTE Risk)
      2. Spironolactone (Aldactone)
        1. Teratogen risk (use with Hormonal Contraception)
        2. Start at 50 mg orally once daily and advance to twice daily
        3. May advance up to 100 mg orally twice daily
      3. Eflornithine (Vaniqa) 13.9% applied to face daily
      4. Finasteride (Propecia)
      5. Flutamide (Eulexin)
    3. Third-Line Agents
      1. Metformin

XV. Management: Acne Vulgaris

  1. Fertility desired
    1. Benzoyl Peroxide
    2. Topical Antibiotics
  2. Fertility not desired
    1. First-line agents
      1. Hormonal Contraception
        1. See Adjunctive Acne Vulgaris Management
      2. Topical Agents
        1. See Acne Vulgaris Management
        2. Benzoyl Peroxide
        3. Retin-A
        4. Differin
        5. Topical Antibiotics
    2. Second-line agents
      1. Spironolactone
        1. Teratogen risk (use with Hormonal Contraception)

XVI. Management: Insulin Resistance

  1. Metformin (Glucophage)
    1. Primarily indicated in comorbid Diabetes Mellitus, history of Gestational Diabetes or Metabolic Syndrome
    2. May be used in those trying to conceive
    3. Consider in irregular Menses in women unable to take Oral Contraceptives
    4. Start at 500 mg PO daily and advance to 1500-2000 mg daily divided bid
    5. Effect not seen until dose >1000 mg/day
    6. Induces Ovulation in up to 46% of PCOS cases
    7. Barbieri (2003) Obstet Gynecol 101:785-93 [PubMed]
    8. Lord (2003) BMJ 327:951-6 [PubMed]
  2. Glitazones
    1. Not recommended in general due to risk of weight gain and Miscarriage
    2. Pioglitazone (Actos) 30 mg orally daily
      1. Ortega-Gonzalez (2005) J Clin Endocrinol Metab 90(3): 1360-5 [PubMed]
    3. Rosiglitazone (Avandia) 2-8 mg orally daily (best effect with higher doses)
      1. No longer available in U.S. due to adverse effects
      2. Cataldo (2006) Hum Reprod 21(1): 109-20 [PubMed]

XVII. Management: Advanced

  1. Gonadotropins (e.g. Metrodin, Pergonal)
    1. Risk of Ovarian Hyperstimulation Syndrome (OHSS)
  2. FSH with hCG
  3. Glucocorticoids (Prednisone, Dexamethasone)
    1. Indicated in adrenocortical hyperplasia
  4. GnRH-Agonist
    1. Indicated prior to Ovulation induction

XVIII. Management: Surgical

  1. Ovarian wedge resection
    1. Normal cycles resume in 80% of patients
    2. Conception occurs in 63%
    3. Risk of peritubular and ovarian adhesions
  2. Laparoscopic ovarian drilling
    1. Similar results to ovarian wedge resection
    2. Minimally invasive

XIX. Complications

  1. Infertility
  2. Increased Breast Cancer risk
  3. Increased Endometrial Cancer risk (RR 2)
    1. Associated with Unopposed Estrogen
  4. Increased cardiovascular disease risk
    1. Associated with PCOS associated Insulin Resistance, Hyperlipidemia and Hypertension
  5. Diabetes Mellitus

XX. References

  1. Acien (1999) Fertil Steril 72:32-40 [PubMed]
  2. Chang (1999) Endocrinol Metab Clin North Am 28:397-408 [PubMed]
  3. Futterweit (1999) Obstet Gynecol Surv 54:403-13 [PubMed]
  4. Pasquali (1999) Clin Endocrinol 50:517-27 [PubMed]
  5. Richardson (2003) Am Fam Physician 68(4):697-704 [PubMed]
  6. Taylor (1998) Endocrinol Metab Clin North Am 27:877-902 [PubMed]
  7. Teede (2023) J Clin Endocrinol Metab 108(10): 2447-69 [PubMed]
  8. Williams (2016) Am Fam Physician 94(2): 106-13 [PubMed]
  9. Williams (2023) Am Fam Physician 107(3): 264-72 [PubMed]

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