13.5 Abnormal Uterine Bleeding, Endometrial Disease & Gynecologic Cancer Screening

1. Abnormal Uterine Bleeding (AUB) & Postmenopausal Bleeding

FIGO PALM-COEIN Classification for Premenopausal AUB

The International Federation of Gynecology and Obstetrics (FIGO) categorizes abnormal uterine bleeding in non-pregnant reproductive-aged women into structural (PALM) and non-structural (COEIN) etiologies:

• Structural Causes (PALM):
  • P - Polyp: Endometrial or endocervical polyps; diagnosed via transvaginal ultrasound (TVUS), saline infusion sonohysterography (SIS), or hysteroscopy. Managed with hysteroscopic polypectomy.
  • A - Adenomyosis: Presence of ectopic endometrial glands and stroma within the myometrium. Presents with heavy menstrual bleeding, severe dysmenorrhea, and a uniformly enlarged, globular, boggy, symmetrically tender uterus on bimanual pelvic examination. First-line medical: Levonorgestrel IUD, continuous combined OCPs, or tranexamic acid; definitive: total hysterectomy.
  • L - Leiomyoma (Uterine Fibroids): Benign myometrial smooth muscle neoplasms. Classified as Submucosal (protrude into cavity, cause heavy bleeding and subfertility), Intramural (within wall), or Subserosal (external surface, cause pelvic pressure/bulk). Medical: NSAIDs, tranexamic acid, combined OCPs, LNG-IUD, GnRH agonists (Leuprolide), or oral GnRH antagonists with add-back (Relugolix/Elagolix); Surgical: hysteroscopic myomectomy, abdominal/laparoscopic myomectomy, uterine artery embolization (UAE), or hysterectomy.
  • M - Malignancy & Hyperplasia: Endometrial adenocarcinoma or endometrial intraepithelial neoplasia (EIN).
• Non-Structural Causes (COEIN):
  • C - Coagulopathy: von Willebrand disease (vWD, most common inherited bleeding disorder, presenting as severe menorrhagia at menarche), platelet dysfunction, or anticoagulant therapy.
  • O - Ovulatory Dysfunction: Anovulatory bleeding characterized by irregular, unpredictable, heavy bleeding due to lack of progesterone and continuous unopposed estrogen stimulation. Etiologies: PCOS, perimenopause, hypothyroidism, hyperprolactinemia, anorexia, extreme exercise.
  • E - Endometrial: Primary endometrial vasoconstrictor deficiency (endothelin-1, prostaglandin F2a) with regular ovulatory cycles.
  • I - Iatrogenic: Copper IUD, progestin implants/IUDs (breakthrough bleeding), psychotropic medications causing hyperprolactinemia, anticoagulants.
  • N - Not otherwise classified.

Evaluation of Postmenopausal Bleeding (PMB)

• Cardinal Clinical Rule: ANY uterine bleeding occurring >=12 months after amenorrhea in a postmenopausal woman is ENDOMETRIAL CANCER until proven otherwise (~10% of PMB represents endometrial adenocarcinoma; ~60-80% is due to vulvovaginal or endometrial atrophy).
• Diagnostic Protocol:
  1. Initial investigation: Transvaginal Ultrasound (TVUS) OR office Endometrial Biopsy (EMB).
  2. TVUS Interpretation:
     • Endometrial Thickness <= 4 mm: High negative predictive value (>99%) for endometrial cancer. If the endometrial stripe is <=4 mm, uniform, thin, and no focal lesion is present, endometrial cancer is reliably excluded. Reassure the patient; if bleeding recurs, proceed to EMB.
     • Endometrial Thickness > 4 mm, Heterogeneous Stripe, or Fluid in Cavity: Mandatory immediate Endometrial Biopsy (EMB).
  3. Endometrial Biopsy (EMB): Office Pipelle aspiration biopsy has >90-95% sensitivity for detecting endometrial cancer.
  4. Hysteroscopy with Dilation & Curettage (D&C): Indicated if office EMB is non-diagnostic, insufficient tissue is obtained, cervical stenosis prevents sampling, or persistent/recurrent bleeding occurs despite a benign biopsy.

2. Endometrial Hyperplasia & Endometrial Cancer

Pathology & Progression Risk

Endometrial hyperplasia results from prolonged, chronic unopposed estrogen stimulation without cyclic progestin opposition, driving abnormal glandular proliferation:

Endometrial Cancer Risk Factors

• Obesity (peripheral aromatization of androstenedione to estrone by adipose tissue)
• Polycystic Ovary Syndrome (PCOS) / chronic anovulation
• Unopposed systemic estrogen therapy
• Early menarche (<12y) / Late menopause (>55y) / Nulliparity
• Tamoxifen therapy (agonist effect on endometrium)
• Lynch Syndrome (HNPCC): Germline DNA mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2); confers a 40% to 60% lifetime risk of endometrial cancer. Screening with annual endometrial biopsy starting at age 30-35, and prophylactic hysterectomy with BSO after childbearing is complete.

3. Cervical and Ovarian Cancer Screening & Prevention

Cervical Cancer Screening Guidelines (USPSTF / ASCCP)

• Age < 21 Years: No screening recommended, regardless of sexual debut or risk factors.
• Age 21 to 29 Years: Cervical cytology (Pap smear) alone every 3 years.
  • Critical Pearl: Do NOT perform HPV testing in women aged 21-29 because transient, oncogenically benign HPV infections are extremely prevalent and clear spontaneously.
• Age 30 to 65 Years: Three acceptable screening strategies:
  1. Primary High-Risk HPV (hrHPV) testing alone every 5 years (preferred by ASCCP and ACS), OR
  2. Co-testing (hrHPV testing + cervical cytology) every 5 years, OR
  3. Cervical cytology alone every 3 years.
• Discontinuation at Age 65: Stop screening if the patient has adequate prior negative screening:
  • 3 consecutive negative cytology results, OR 2 consecutive negative hrHPV/co-test results within the past 10 years, with the most recent test performed within the past 5 years;
  • AND no history of CIN 2, CIN 3, or cervical cancer within the past 20 years.
• Hysterectomy Exception: Women who have had a total hysterectomy (removal of uterus and cervix) for benign indications and who have no prior history of CIN 2+ or cervical cancer do NOT require screening.

Management of Abnormal Cervical Screening Results (ASCCP Risk-Based Guidelines)

• HPV Genotypes 16 or 18 Positive: Immediate Colposcopy regardless of cytology result (due to high risk of occult high-grade precancer).
• Atypical Squamous Cells of Undetermined Significance (ASC-US):
  • If hrHPV positive -> Colposcopy.
  • If hrHPV negative -> Repeat co-test in 3 years.
• High-Grade Squamous Intraepithelial Lesion (HSIL): Immediate Colposcopy with endocervical curettage (ECC) OR immediate Loop Electrosurgical Excision Procedure (LEEP) diagnostic excision in non-pregnant women aged >=25 years.
• Atypical Glandular Cells (AGC): High risk of significant cervical adenocarcinoma or endometrial cancer. Mandatory evaluation includes Colposcopy + Endocervical Curettage (ECC) + Endometrial Biopsy (EMB) in all women aged >=35 years or in women <35 years with risk factors for endometrial neoplasia.

Ovarian Cancer Screening & Prevention

• Average-Risk Screening: The USPSTF gives a Grade D recommendation (recommends AGAINST routine screening) using serum CA-125, transvaginal ultrasound, or bimanual pelvic examination in asymptomatic, average-risk postmenopausal or premenopausal women. Clinical trials (PLCO, UKCTOCS) demonstrated that screening yields false-positive results leading to unnecessary major surgeries without reducing ovarian cancer mortality.
• Hereditary Ovarian Cancer Syndromes:
  • BRCA1: ~40-50% lifetime risk of epithelial ovarian/fallopian tube cancer; ~70% lifetime breast cancer risk.
  • BRCA2: ~15-20% lifetime risk of ovarian cancer; ~70% lifetime breast cancer risk.
  • Risk-Reducing Bilateral Salpingo-Oophorectomy (RRSO): Standard-of-care prevention. Recommended at age 35 to 40 years for BRCA1, and age 40 to 45 years for BRCA2 (or after childbearing is complete). RRSO reduces ovarian/tubal cancer risk by 80-90% and reduces all-cause mortality.

4. Polycystic Ovary Syndrome (PCOS)

Diagnostic Criteria & Differential Diagnosis

• Rotterdam Diagnostic Criteria: Requires at least 2 of the following 3 features (after excluding mimickers):
  1. Oligo- or Anovulation: Menstrual cycles >35 days apart or <8-9 periods per year.
  2. Clinical and/or Biochemical Hyperandrogenism:
     • Clinical: Hirsutism (modified Ferriman-Gallwey score >=8), severe cystic acne, androgenic alopecia.
     • Biochemical: Elevated total or free serum testosterone, elevated androstenedione, or elevated DHEAS.
  3. Polycystic Ovarian Morphology on Ultrasound: Presence of >=20 follicles per ovary (measuring 2 to 9 mm in diameter) and/or increased ovarian volume >=10 mL in either ovary.
• Mandatory Exclusion of Secondary Causes:
  • Non-Classic Congenital Adrenal Hyperplasia (NCCAH): Check early morning fasting 17-hydroxyprogesterone (if >200 ng/dL, perform ACTH stimulation test; 21-hydroxylase deficiency).
  • Hyperprolactinemia: Check serum Prolactin.
  • Thyroid Dysfunction: Check serum TSH.
  • Cushing Syndrome: 24-hour urine free cortisol or 1-mg overnight dexamethasone suppression test if cushingoid features.
  • Androgen-Secreting Adrenal/Ovarian Neoplasms: Rapid virilization (clitoromegaly, voice deepening), total testosterone >200 ng/dL, or DHEAS >700 µg/dL warrants immediate CT adrenal and pelvic imaging.

Long-Term Complications & Comprehensive Management

• Long-Term Risks: Endometrial adenocarcinoma (3-fold increased risk due to chronic unopposed estrogen), Type 2 Diabetes Mellitus (screen all PCOS patients with a 2-hour 75g OGTT), MASLD, Dyslipidemia, Obstructive Sleep Apnea, and Cardiovascular Disease.
• Management Pillars:
  1. Lifestyle Modification & Weight Loss: 5% to 10% weight loss improves insulin sensitivity, increases SHBG, lowers free androgens, and restores ovulatory cycles.
  2. First-Line for Cycle Regulation, Endometrial Protection & Hirsutism: Combined Oral Contraceptive Pills (COCPs).
     • Estrogen increases hepatic Sex Hormone-Binding Globulin (SHBG), binding free circulating testosterone.
     • Progestin suppresses pituitary LH secretion (decreasing theca cell androgen production) and prevents endometrial hyperplasia.
  3. Anti-Androgen Therapy for Persistent Hirsutism: Spironolactone (50-200 mg daily).
     • Competitively blocks androgen receptors and inhibits 5-alpha-reductase.
     • Critical Rule: Add only after >=6 months of COCP therapy; MUST be co-prescribed with effective contraception due to the teratogenic risk of feminization of a male fetus.
  4. Metformin (1500-2000 mg daily): Improves insulin sensitivity and glucose tolerance in patients with impaired glucose tolerance / T2D.
  5. Ovulation Induction for Infertility: Letrozole (Aromatase Inhibitor) is first-line gold standard for ovulation induction in PCOS (PPCOS II trial demonstrated superior live-birth and ovulation rates compared to Clomiphene Citrate).