Amenorrhea

Amenorrhea is the absence of menstruation. It is classified as primary (absence of menarche) or secondary (cessation of menses after it has been established).

Initial Workup (for both Primary and Secondary)

1. Exclude Pregnancy: First and most important step is to obtain a β-hCG. c
2. Initial Labs: Check TSH (rule out thyroid disease) and Prolactin (rule out hyperprolactinemia).
3. Physical Exam: Assess for signs of hyperandrogenism (hirsutism, acne) and development of secondary sexual characteristics (Tanner stage).

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Primary Amenorrhea

Definition: Absence of menses by age 15 with secondary sexual characteristics, OR by age 13 without secondary sexual characteristics. c

Diagnosis (Based on Uterus & Breast Development)

A pelvic ultrasound is crucial to determine the presence or absence of the uterus.

1. Uterus Present, Breasts Present

• Patho/Etiology: Likely an outflow tract obstruction.
• Classic Conditions:
  • Imperforate Hymen: Presents with cyclic pelvic pain, bulging bluish membrane at the introitus.
  • Transverse Vaginal Septum: Similar to imperforate hymen but obstruction is higher up.
• Dx: Clinical exam, pelvic US.
• Mgmt: Surgical correction.

2. Uterus Absent, Breasts Present

• Patho/Etiology: Suggests normal estrogen production (from ovaries or testes) but a developmental failure of Müllerian structures or androgen insensitivity.
• Classic Conditions:
  • Müllerian Agenesis (Mayer-Rokitansky-Küster-Hauser syndrome):
    • Patho: Congenital absence of uterus, cervix, and upper 1/3 of the vagina.
    • Dx: 46,XX karyotype, normal female testosterone levels, normal axillary/pubic hair.
    • Associations: Renal anomalies are common.
  • Androgen Insensitivity Syndrome (AIS):
    • Patho: Defect in androgen receptors in a genetically male individual.
    • Dx: 46,XY karyotype, male-range testosterone levels, minimal/absent axillary/pubic hair. Testes are present (often intra-abdominal).
• Mgmt: For AIS, gonadectomy is recommended (after puberty) to prevent malignancy. Vaginoplasty for both conditions if desired.

3. Uterus Present, Breasts Absent

• Patho/Etiology: Indicates insufficient estrogen. The key is to differentiate between a central (hypothalamic/pituitary) vs. ovarian problem with an FSH level.
• High FSH (Hypergonadotropic Hypogonadism): Problem is in the ovaries (ovarian failure).
  • Turner Syndrome:
    • Patho: 45,XO karyotype. Ovarian dysgenesis (“streak gonads”).
    • Presentation: Short stature, webbed neck, broad shield chest, coarctation of the aorta.
    • Dx: Karyotype is definitive. ↑FSH, ↑LH, ↓estrogen.
• Low/Normal FSH (Hypogonadotropic Hypogonadism): Problem is in the hypothalamus or pituitary.
  • Kallmann Syndrome: Defective migration of GnRH neurons. Presents with anosmia (can’t smell).
  • Constitutional Delay: “Late bloomer.” Bone age is delayed compared to chronological age. Family history is common.

4. Uterus Absent, Breasts Absent

• This is very rare and typically involves specific enzymatic defects (e.g., 17α-hydroxylase deficiency) or testicular regression syndrome. Low yield for USMLE.

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Secondary Amenorrhea

Definition: Absence of menses for >3 months in a woman with previously regular cycles, or >6 months in a woman with irregular cycles.

Etiology

• Pregnancy: most common cause of secondary amenorrhea
• Ovarian disorders (e.g., premature ovarian failure, polycystic ovary syndrome)
• Hypothyroidism (↓ T3/T4 → ↑ TRH → ↑ prolactin → ↓ GnRH → ↓ estrogens)
• Hyperthyroidism
• Hyperprolactinemia
• Cushing syndrome
• Hypergonadotropic hypogonadism
• Hypogonadotropic hypogonadism
• Functional hypothalamic amenorrhea: a dysfunction in the pulsatile secretion of GnRH
  • Etiology
    • Excessive exercise: e.g., in competitive athletes (also called exercise-induced amenorrhea)
    • Reduced calorie intake (e.g., in eating disorders like anorexia nervosa)
    • Stress
    • Female athlete triad syndrome: menstrual dysfunction, calorie deficit, and decreased bone density in athletic female young adults or adolescents
  • Pathophysiology: decreased leptin (low body fat) and/or increased cortisol (exercise/stress) → decreased pulsatile release of GnRH from the hypothalamus → decreased secretion of FSH and LH → decreased estrogen levels → anovulation and secondary amenorrhea → infertility

Diagnosis

• Initial Test: Urine or serum $\beta$-hCG (exclude pregnancy first).
• Key Labs (if $\beta$-hCG is negative):
  • TSH & Prolactin: Screen for thyroid disease and hyperprolactinemia. c
  • FSH:
    • ↑ FSH, ↓ Estrogen: POI (confirm with repeat FSH in 1 mo; karyotype if <30 y/o).
    • ↓/Normal FSH, ↓ Estrogen: FHA.
    • Normal FSH & Estrogen: PCOS or outflow obstruction.
• Withdrawal Testing:
  • Progesterone Challenge:
    • (+) Bleeding: Intact estrogen + anovulation (confirms PCOS).
    • (-) Bleeding: Hypoestrogenism (FHA, POI) OR anatomical obstruction.
  • Estrogen + Progesterone Challenge (if progesterone challenge negative):
    • (+) Bleeding: Hypoestrogenism confirmed (intact outflow tract).
    • (-) Bleeding: Outflow tract obstruction (Asherman).
• Imaging & Procedures:
  • Gold Standard (Asherman): Hysteroscopy (diagnostic & therapeutic).
  • Brain MRI: Indicated for PRL >100 ng/mL or visual/neurological deficits.