15.6 Evaluating Abnormal Uterine Bleeding & the Amenorrhea Workup

Diagnostic Evaluation Algorithm for AUB

Diagnostic Evaluation Algorithm for Reproductive-Age AUB
├── 1. Mandatory First Step: Sensitive Urine or Serum hCG (Rule out Pregnancy!)
├── 2. History & Physical: Vitals, Hemodynamic stability, Speculum & Bimanual Exam
├── 3. Core Laboratory Panel
│   ├── Complete Blood Count (CBC) with Platelets (Assess anemia & thrombocytopenia)
│   ├── Ferritin (Detect occult iron deficiency without overt anemia)
│   ├── Thyroid-Stimulating Hormone (TSH) & Serum Prolactin
│   ├── Cervical NAAT Screening (Chlamydia/Gonorrhea) & Pap cytology (if due)
│   └── Targeted Coagulation Panel (if AUB-C screening criteria positive)
├── 4. First-Line Pelvic Imaging: Transvaginal Ultrasound (TVUS) ± Saline Infusion (SIS)
│   └── Evaluate endometrial stripe thickness, myometrial architecture, focal lesions
└── 5. Histological Tissue Sampling: Endometrial Biopsy (EMB)
    ├── Age ≥45 years with AUB
    └── Age <45 years with high-risk factors (unopposed estrogen, obesity BMI ≥30,
        PCOS, failed medical therapy, or persistent bleeding)

[!CRITICAL] AMCB Board Rule on Endometrial Biopsy Indications: An in-office endometrial biopsy (EMB) is non-negotiable for any patient aged 45 or older presenting with AUB, and for any patient under 45 with chronic unopposed estrogen exposure (e.g., obesity BMI ≥30 kg/m², PCOS), prolonged amenorrhea, failed medical management, or persistent abnormal bleeding. Never start hormonal therapy in these high-risk cohorts without first obtaining tissue histology to exclude endometrial adenocarcinoma and atypical hyperplasia!

Amenorrhea Workup: Primary vs. Secondary

Amenorrhea is broadly classified into primary and secondary variants, each requiring distinct diagnostic pathways.

Primary Amenorrhea

Defined clinically as:

1. Absence of menses by age 15 years in an individual with normal growth and normal female secondary sexual characteristics (e.g., breast budding / thelarche). Or,
2. Absence of menses by age 13 years in an individual with complete absence of secondary sexual characteristics (no breast development).

Primary Amenorrhea Etiological Triage
├── Breasts Present, Uterus Absent (Normal Thelarche, Anatomic Defect)
│   ├── 1. Müllerian Agenesis (MRKH Syndrome, 46,XX)
│   │   └── Normal ovaries, normal female testosterone, normal pubic/axillary hair
│   └── 2. Androgen Insensitivity Syndrome (AIS, 46,XY)
│       └── Cryptorchid testes, elevated adult male testosterone, absent pubic/axillary hair
├── Breasts Present, Uterus Present (Intact Anatomy, Outflow Obstruction or Endocrine)
│   ├── Imperforate Hymen / Transverse Vaginal Septum (Cyclic pain, hematocolpos, bulging membrane)
│   └── Secondary Amenorrhea Etiologies (PCOS, Hyperprolactinemia, Hypothalamic)
├── Breasts Absent, Uterus Present (Hypogonadism / Estrogen Deficiency)
│   ├── Hypergonadotropic Hypogonadism (Elevated FSH/LH >30–40 mIU/mL)
│   │   └── Turner Syndrome (45,XO gonadal dysgenesis, streak gonads, webbed neck, short stature)
│   └── Hypogonadotropic Hypogonadism (Low/Normal FSH/LH)
│       └── Hypothalamic failure (Kallmann syndrome with anosmia, severe malnutrition/stress)
└── Breasts Absent, Uterus Absent (Extremely rare: 17,20-desmolase deficiency)

Secondary Amenorrhea

Defined clinically as the absence of menses for ≥3 consecutive months in an individual with previously regular menstrual cycles, OR ≥6 consecutive months in an individual with previously irregular menstrual cycles.

Stepwise Secondary Amenorrhea Cascade

1. Rule Out Pregnancy: Order a sensitive serum or urine hCG. Pregnancy is the single most common cause of secondary amenorrhea in reproductive-age individuals.
2. Initial Biochemical Triage: Simultaneously evaluate TSH, Serum Prolactin, and FSH/Estradiol.
   • Elevated TSH: Hypothyroidism increases thyrotropin-releasing hormone (TRH), which directly stimulates anterior pituitary lactotrophs, producing secondary hyperprolactinemia and anovulation.
   • Elevated Prolactin (>25–30 ng/mL): Repeat fasting prolactin. Hyperprolactinemia suppresses pulsatile hypothalamic GnRH secretion. If sustained, perform contrast-enhanced pituitary MRI to evaluate for pituitary adenoma (prolactinoma).
   • Elevated FSH (>30–40 mIU/mL) on two occasions drawn 4–6 weeks apart: Diagnostic of Premature Ovarian Insufficiency (POI) in individuals <40 years of age.
   • Low or Inappropriately Normal FSH and LH with low Estradiol: Diagnostic of Functional Hypothalamic Amenorrhea (FHA) secondary to eating disorders, intense athletic training, psychological stress, or chronic systemic illness.
3. The Progestin Challenge Test (Progesterone Withdrawal Challenge):
   • Administer Medroxyprogesterone Acetate (MPA) 10 mg PO daily for 10 days (or micronized progesterone 200 mg daily for 10 days).
   • Positive Withdrawal Bleeding (bleeding occurs within 2 to 7 days of completing the regimen): Confirms (a) an anatomically intact and patent outflow tract (cervix, vagina, uterus), (b) adequate endogenous circulating estrogen that has primed and proliferated the endometrium, and (c) anovulation as the definitive etiology (most frequently PCOS).
   • Negative Test (no withdrawal bleeding): Indicates either (a) severe hypoestrogenism (endometrium was never primed/proliferated) OR (b) an anatomical outflow tract obstruction or scarred, obliterated endometrium (Asherman syndrome from prior aggressive curettage or infection).
4. Estrogen-Progestin Challenge Test:
   • If the progestin challenge is negative, administer oral micronized 17β-estradiol 2 mg daily for 21 days, adding MPA 10 mg daily for the final 10 days (Days 12–21).
   • Bleeding Occurs: Proves the endometrium is capable of proliferating and the outflow tract is patent. The underlying cause is profound hypoestrogenism (FHA or ovarian failure).
   • No Bleeding Occurs: Confirms an irreversible anatomical outflow tract defect or endometrial synechiae (Asherman syndrome); diagnostic hysteroscopy is indicated.