Menopause

Epidemiology

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Etiology

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Pathophysiology

• Core Pathophysiology: Progressive depletion of ovarian follicles. This results in a decline in the production of inhibin B and estrogen.
  • Remaining follicles become resistant to FSH.
• Key Hormonal Changes:
  • 1st: ↓ Inhibin B → loss of negative feedback → ↑ FSH (most sensitive marker).
  • 2nd: Follicular failure → ↓↓ Estrogen.
  • Result: Markedly ↑ FSH, ↑ LH, ↓ Estrogen.
• Consequences of Estrogen Deficiency:
  • Vasomotor: Hot flashes (hypothalamic thermoregulatory dysfunction, likely due to estrogen withdrawal).
  • GU Syndrome: Vaginal/urogenital atrophy → dryness, dyspareunia, ↑ UTIs.
  • Bone: ↑ Osteoclast activity → Osteoporosis.
  • Cardiovascular: ↑ LDL, ↓ HDL → ↑ CAD risk.
  • Other: Insomnia, mood changes, skin thinning.

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Clinical features

• Vasomotor symptoms: Hot flashes, night sweats.
• Genitourinary Syndrome of Menopause (GSM):
  • Vaginal atrophy: Dryness, itching, dyspareunia (painful intercourse).
  • Urologic issues: Dysuria, urinary urgency, increased frequency of urinary tract infections.
• Psychological symptoms: Mood swings, insomnia, depression, anxiety, and memory changes (“brain fog”).
• Dermatologic symptoms: Skin thinning and hair loss.

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Subtypes and variants

Induced menopause

• Etiologies:
  • Surgical: Bilateral salpingo-oophorectomy (BSO) (e.g., BRCA1/2, endometriosis, malignancy).
  • Medical/Iatrogenic: Alkylating chemotherapy (e.g., cyclophosphamide), pelvic radiation (EBRT), or GnRH agonists/antagonists (leuprolide, elagolix). c
• Clinical Presentation:
  • Abrupt onset (no perimenopausal transition).
  • Severe Vasomotor Symptoms (VMS): Intense hot flashes, night sweats, diaphoresis.
  • Genitourinary Syndrome of Menopause (GSM): Vaginal dryness, pruritus, dyspareunia, dysuria, recurrent UTIs. c
  • Other: Mood lability, severe insomnia, marked ↓ libido (abrupt loss of ovarian androgens).
• Diagnosis:
  • Clinical: History of intervention + acute amenorrhea and VMS.
  • Initial Step: Exclude pregnancy with $\beta$-hCG (if uterus intact and non-surgical).
  • Labs: ↑↑ FSH (>25–40 IU/L), ↑ LH, ↓↓ Estradiol ($E_2$).
  • Imaging: Baseline DEXA scan to assess rapid bone demineralization.
• Management:
  • Systemic HRT (treat until median age of natural menopause, ~51 yrs):
    • Intact Uterus: Estrogen + Progestin (prevents endometrial adenocarcinoma).
    • Prior Hysterectomy: Estrogen-only.
    • Contraindications: Breast/endometrial cancer, active/history of VTE/PE, stroke/MI, active liver disease.
  • Non-Hormonal Alternatives for VMS (if HRT contraindicated):
    • Fezolinetant (NK3 receptor antagonist).
    • Venlafaxine (SNRI) or SSRIs (NBME trap: Avoid paroxetine/fluoxetine if patient is on Tamoxifen due to CYP2D6 inhibition).
    • Gabapentin (ideal for nocturnal symptoms/insomnia).
  • GSM Treatment: Vaginal moisturizers/lubricants $\to$ Low-dose local vaginal estrogen.
  • Bone Protection: Calcium + Vitamin D + weight-bearing exercise; Bisphosphonates if osteoporosis is confirmed and HRT is contraindicated.
• Complications:
  • Accelerated Osteoporosis: Rapid trabecular bone loss leading to early fragility fractures.
  • Premature Cardiovascular Disease (CAD): Loss of cardioprotective estrogen (↑ LDL, ↓ HDL).
  • Severe Urogenital Atrophy: Introital stenosis, chronic dyspareunia.

Diagnostics

Supportive studies to confirm menopause

• FSH: ↑↑; however, levels widely fluctuate during perimenopause
• Estradiol: ↓
• Rarely tested for as not routinely recommended: ↓ progesterone, ↓ inhibin B, and ↓ antimüllerian hormone

Studies to exclude differential diagnoses of menopause

• Pregnancy test: to rule out pregnancy as a cause of amenorrhea
• Prolactin: elevated in hyperprolactinemia
• LH: elevated in POI
• TSH: Both hypothyroidism and hyperthyroidism can cause menstrual irregularities.

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Treatment

1. Mild Symptoms or Isolated GSM:
   • Non-hormonal vaginal lubricants (during intercourse) and moisturizers (regular use).
   • Low-dose vaginal estrogen (cream, tablet, ring) if non-hormonal therapy fails (minimal systemic absorption, does not require progesterone co-administration).
2. Moderate-to-Severe Vasomotor Symptoms (VMS):
   • Systemic Hormone Replacement Therapy (HRT): Most effective treatment.
     • Intact uterus: Estrogen + Progesterone (unopposed estrogen increases risk of endometrial hyperplasia/cancer).
     • Prior hysterectomy: Estrogen-only therapy.
   • Non-hormonal alternatives (if HRT is contraindicated or refused):
     • SSRIs (e.g., paroxetine) or SNRIs (e.g., venlafaxine).
     • Gabapentin.
     • Fezolinetant (NK3 receptor antagonist).
3. Contraindications to Systemic HRT:
   • History of breast cancer or endometrial cancer.
   • Active/history of VTE/PE, stroke, or MI.
   • Coronary heart disease (CHD).
   • Active liver disease.
   • Unexplained vaginal bleeding.