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.
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.

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.

Pathophysiology/Etiology

Categorized by the source of the problem: Hypothalamic, Pituitary, Ovarian, Uterine.

Diagnosis & Management

Follow a stepwise algorithm after excluding pregnancy and checking initial labs (TSH, Prolactin).

Step 1: Progestin Challenge Test

• Action: Give medroxyprogesterone for 5-10 days. This tests for the presence of adequate estrogen and a patent outflow tract.
• (+) Withdrawal Bleed:
  • Interpretation: Patient has sufficient estrogen (endometrium was built up), but is not ovulating (no progesterone was produced to trigger a withdrawal bleed). The outflow tract is patent.
  • Common Causes: PCOS (most common), obesity, anovulation.
  • Next Step: Workup for hyperandrogenism if indicated (testosterone, DHEAS). Manage underlying cause (e.g., lifestyle changes for PCOS, OCPs).
• (-) No Withdrawal Bleed:
  • Interpretation: Either there is low estrogen (endometrium didn’t build up) OR there is a uterine outflow obstruction.
  • Next Step: Proceed to Estrogen-Progestin Challenge Test.

Step 2: Estrogen-Progestin Challenge Test

• Action: Give estrogen to build the endometrium, followed by progestin to induce a bleed.
• (+) Withdrawal Bleed:
  • Interpretation: The uterus is functional, but there is not enough endogenous estrogen. The problem is either hypothalamic or ovarian.
  • Next Step: Check FSH level.
    • High FSH (>40 mIU/mL): Primary Ovarian Insufficiency (premature menopause). Karyotype may be needed.
    • Low/Normal FSH: Hypothalamic/Pituitary Dysfunction. Causes include functional hypothalamic amenorrhea (stress, excessive exercise, anorexia), Sheehan syndrome, or tumors. An MRI of the brain may be indicated.
• (-) No Withdrawal Bleed:
  • Interpretation: The uterus/endometrium itself is the problem; it cannot bleed despite hormonal stimulation.
  • Cause: Asherman Syndrome (intrauterine adhesions/scarring), often from prior D&C.
  • Dx/Tx: Hysteroscopy to visualize and resect adhesions.

Secondary amenorrhea

• 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