AUB-O: Ovulatory Etiology in Abnormal Uterine Bleeding

Classification Context

Pathophysiology

• In a normal cycle, ovulation produces progesterone, which converts proliferative endometrium to secretory endometrium and ensures organized, synchronous shedding.
• In anovulatory cycles, the corpus luteum never forms, so progesterone is absent. Estrogen stimulates endometrial proliferation without periodic, controlled shedding.
• The endometrium grows, becomes thickened and fragile, and undergoes dyssynchronous, irregular breakdown - producing the characteristic irregular and often heavy bleeding.

Causes of Ovulatory Dysfunction (AUB-O)

1. Physiologic (Normal) Causes

• Perimenarchal / Adolescence - immaturity of the hypothalamic-pituitary-ovarian (HPO) axis; anovulatory bleeding is usually minimal and painless; however, heavy bleeding in adolescence warrants evaluation for coagulopathy (e.g., von Willebrand disease, factor VIII deficiency)
• Perimenopause - incipient ovarian failure accounts for ~50% of all AUB cases
• Lactation / Postpartum
• Pregnancy (always exclude first)

2. Hypothalamic Dysfunction

• Functional Hypothalamic Amenorrhea (FHA) - the most common hypothalamic cause; results from non-organic reduction in GnRH pulsatility
  • Excessive exercise - particularly endurance athletes
  • Low body weight / rapid weight loss - eating disorders (anorexia nervosa, bulimia nervosa)
  • Psychological stress - there is a dose-response relationship between severity and number of stressors and the likelihood of anovulation; HPA axis activation is the key mediator (elevated cortisol suppresses GnRH)
  • Diagnosis of exclusion; key: intact ovarian reserve, no structural brain/pituitary lesion, no drug cause

3. Hyperandrogenic States

• Polycystic Ovary Syndrome (PCOS) - most common cause of chronic anovulation in reproductive-age women; present in 5-8% of adult women, many undiagnosed
  • Anovulatory cycles are characteristic
  • Insulin resistance and androgen excess disrupt follicular development
• Congenital Adrenal Hyperplasia (CAH)
• Androgen-secreting tumors (adrenal or ovarian)

4. Thyroid Disease

• Hypothyroidism - associated with heavy menstrual bleeding (menorrhagia) and menstrual cycle abnormalities; menstrual irregularity affects approximately 0.3-2.5% of hypothyroid patients. TSH should be measured in any woman with bleeding of undetermined origin or with a thyroid nodule/goiter.
• Hyperthyroidism (most commonly Graves' disease in premenopausal women) - can cause oligomenorrhea or amenorrhea; leads to elevated plasma estrogen levels

5. Hyperprolactinemia

• Elevated prolactin inhibits GnRH pulsatility, suppressing LH and FSH - classic cause of anovulation
• Causes: prolactinoma, medications (antipsychotics, antidepressants, metoclopramide), hypothyroidism (TRH stimulates prolactin), renal disease

6. Primary Ovarian Insufficiency (POI) / Premature Ovarian Failure (POF)

• Defined as ovarian insufficiency before age 40
• Prevalence: ~1 in 100 by age 40; 1 in 1,000 by age 30; 1 in 10,000 by age 20
• Patients often see multiple clinicians with oligomenorrhea/amenorrhea before diagnosis is made; frequently delayed
• FSH >25 IU/L on two occasions >4 weeks apart is diagnostic

7. Pituitary Disease

• Hypopituitarism (Sheehan syndrome, pituitary adenomas other than prolactinoma)
• Inadequate FSH/LH secretion fails to drive folliculogenesis

8. Systemic / Metabolic Conditions

• Diabetes mellitus - associated with anovulation through obesity, insulin resistance, and androgen excess
• Obesity - excess adipose tissue aromatizes androgens to estrogens, disrupting HPO axis feedback
• Chronic renal disease
• Liver disease - impaired estrogen metabolism

9. Iatrogenic / Medication-Induced

• Antipsychotics (dopamine antagonists raise prolactin)
• Antidepressants
• Radiation and chemotherapy - direct ovarian damage
• Exogenous hormones (inconsistent oral contraceptive use, Depo-Provera, etc.)

Key Clinical Features

Diagnostic Workup for AUB-O

1. Pregnancy test (always first)
2. TSH - thyroid disease is common and treatable
3. Prolactin - hyperprolactinemia
4. FSH, LH, estradiol - POI vs. hypothalamic vs. pituitary
5. Free/total testosterone, DHEA-S - PCOS, CAH, androgen-secreting tumors
6. Fasting glucose / insulin / HOMA-IR - PCOS/metabolic
7. Coagulation screen (including vWF) - especially in adolescents
8. CBC - assess anemia
9. Endometrial biopsy - mandatory in women >35 years or any prolonged anovulatory bleeding (risk of hyperplasia/carcinoma)
10. Pelvic ultrasound - assess endometrial thickness, ovarian morphology (PCOS)
11. MRI brain/pituitary - if hyperprolactinemia or hypothalamic etiology suspected

Management Principles

• Treat the underlying cause (thyroid replacement, dopamine agonist for prolactinoma, lifestyle modification for FHA/PCOS)
• Hormonal therapy for anovulatory bleeding:
  • Combined OCP (e.g., 1 tablet every 6 hours x5-7 days for acute heavy bleeding; then cyclic OCP maintenance)
  • Cyclic progestins (e.g., medroxyprogesterone acetate) - opposes unopposed estrogen
  • Levonorgestrel IUS (Mirena)
• Acute heavy bleeding: IV conjugated equine estrogen (25 mg IV q4-6h), tranexamic acid
• Insulin-sensitizing agents (metformin) for PCOS with insulin resistance
• Long-term: prevent endometrial hyperplasia with progestin exposure in all anovulatory patients

• Berek & Novak's Gynecology, Chapter 10 (AUB-O, Table 10-7)
• Goldman-Cecil Medicine, Chapter 220
• Tintinalli's Emergency Medicine, Chapter 96
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry (Functional Hypothalamic Amenorrhea)