---

Menopausal Hormonal Therapy (MHT)

Berek & Novak's Gynecology - Postgraduate Level

---

1. Background and Rationale

• Early menopause: ages 40-45 years (~5% of women)
• Premature ovarian insufficiency (POI): <40 years (~1%), may not be permanent
• Surgical menopause: bilateral oophorectomy; symptoms are often more severe due to abrupt estrogen withdrawal

---

2. Physiology of Vasomotor Symptoms (VMS)

• A central hypothalamic trigger causing increased core body temperature, metabolic rate, and skin temperature
• Peripheral vasodilation and sweating as the response
• Noradrenergic, serotoninergic, and dopaminergic activation
• KNDy neurons (hypothalamic neurons containing kisspeptin, neurokinin B [NKB], and dynorphin receptors) play a key role - peripheral infusion of NKB induces a typical hot flash; blocking NKB reduces them
• Symptomatic postmenopausal women have a narrowed thermoneutral zone; small elevations in core temperature trigger flashes

---

3. Indications for MHT

Primary Indication

Other Indications

• Symptomatic vulvovaginal atrophy / genitourinary syndrome of menopause (GSM)
• Prevention of osteoporosis (FDA-approved)
• Urogenital symptoms (vaginal dryness, dyspareunia, urinary symptoms)
• Sexual dysfunction related to menopause

---

4. Approved Formulations (FDA-Approved Products)

Estrogen Products

Progestogens Used in Combination Therapy

Special Formulations

• Tissue-Selective Estrogen Complex (TSEC): Conjugated estrogens 0.45 mg + bazedoxifene (BZA) 20 mg (Duavee/Duavvee) - 1 tablet daily. BZA is a selective estrogen receptor modulator (SERM) that protects the endometrium, eliminating the need for a progestin.

---

5. Regimens

For Women WITH a Uterus

1. Sequential (cyclic) EPT: Estrogen daily + progestin for 12-14 days/month → results in regular, predictable withdrawal bleeding
2. Continuous-combined EPT: Estrogen + lower-dose progestin daily → majority achieve amenorrhea by 1 year, but early unpredictable bleeding is common
3. Low-dose combination (e.g., CE/MPA 0.45/1.5 mg or 0.3/1.5 mg/day): lower incidence of breakthrough bleeding and breast tenderness
4. Intermittent progestin (off-label): 14 days every 3 months with low-dose ET; increased endometrial surveillance required

For Women WITHOUT a Uterus (after hysterectomy)

• Estrogen alone (ET) - progestin is unnecessary and adds risk

---

6. Route of Administration - Clinical Significance

Oral vs. Transdermal Estrogen

---

7. Benefits of MHT

7a. Vasomotor Symptoms

• Systemic ET is the most effective treatment available
• Reduces hot flash frequency and severity dramatically
• Perimenopausal women or those with surgical menopause may require higher doses

7b. Genitourinary Syndrome of Menopause (GSM)

• Affects at least 60% of menopausal women
• Includes vaginal dryness, dyspareunia, urinary symptoms
• Local vaginal estrogen (cream, tablet, ring) is effective and safe at low doses
• Unlike systemic HT, vaginal estrogen does not appear to significantly increase systemic estrogen levels
• Ospemifene (SERM, oral 60 mg/day) is another approved option
• Vaginal DHEA (prasterone) is also approved
• Vaginal lubricants/moisturizers are non-hormonal options

7c. Osteoporosis Prevention

• HT is FDA-approved for osteoporosis prevention
• Estrogen reduces bone turnover (antiresorptive mechanism)
• WHI trial: CE 0.625 mg/day produced a significant 34% reduction in hip fractures (mean follow-up 5.6 years)
• Most beneficial when started soon after menopause
• T-score guidance:
  • T-score ≤ -2.5: pharmacologic treatment indicated
  • Prior hip or vertebral fracture: treatment indicated
  • T-score -1 to -2.5 with high FRAX score: treatment may be indicated

7d. Cardiovascular Disease

• Timing hypothesis (WHI reanalysis): HT initiated in younger women (age <60 years) or within 10 years of menopause is associated with reduced cardiovascular risk; initiating in older women shows no benefit or possible harm
• Transdermal estrogen may have a more favorable cardiovascular profile than oral

7e. Sexual Function

• Estrogen improves vaginal atrophy-related dyspareunia
• In an RCT, transdermal (but not oral) estradiol was associated with significant improvement in sexual function vs. placebo
• Testosterone: Low-dose testosterone (off-label) has evidence for female sexual interest/arousal disorder (FSIAD)

---

8. Risks of MHT - The WHI Evidence

8a. Breast Cancer

• Combined EPT (CEE + MPA): Modest but significant increased risk of breast cancer (HR ~1.26 in WHI); risk increased with >5 years of use
• Estrogen alone (CEE without progestin): In the estrogen-only arm (women without a uterus), a decreased risk of breast cancer was observed
• Progesterone type matters: Micronized progesterone may carry lower breast cancer risk than synthetic progestins (observational data)
• Key point from Berek & Novak: HT risk differs depending on formulation, dose, route, and duration

8b. Endometrial Cancer

• Unopposed estrogen significantly increases risk of endometrial hyperplasia and carcinoma
• Progestin added to estrogen neutralizes this risk
• TSEC (CE/BZA) avoids progestin while still protecting the endometrium

8c. Venous Thromboembolism (VTE)

• Oral ET/EPT increases VTE risk
• Transdermal ET does not appear to increase VTE risk (observational studies)
• HT remains contraindicated in women with active or high-risk thromboembolic disease

8d. Stroke

• Oral HT is associated with modestly increased ischemic stroke risk
• Transdermal ET may carry a lower stroke risk

8e. Coronary Heart Disease (CHD)

• WHI showed increased CHD events in women starting HT >10 years after menopause
• "Timing hypothesis" (Critical/Opportune Window): HT started in early menopause may be cardioprotective; started late (>60 years), it may be harmful
• HT is contraindicated in women with established CVD

8f. Dementia/Cognitive Function

• WHI Memory Study (WHIMS): Women ≥65 randomized to EPT had a twofold increased risk of probable dementia
• Estrogen-alone arm: increased risk was not statistically significant
• HT should NOT be used to prevent or treat dementia

8g. Gallbladder Disease

• Oral estrogen increases gallbladder disease risk
• Transdermal estrogen may not carry this risk

---

9. Contraindications

Absolute Contraindications

• Known or suspected breast cancer
• Known or suspected endometrial cancer
• Undiagnosed abnormal vaginal bleeding
• Cardiovascular disease: CHD, cerebrovascular disease, thromboembolic disorders
• Active liver disease
• Active gallbladder disease

Relative Contraindications

• High-risk states for any of the above
• Women with relative contraindications may still be offered HT if alternative treatments for severe VMS are ineffective, after thorough risk-benefit discussion and shared decision-making

---

10. The "Timing Hypothesis" and Patient Selection

• Women <60 years of age or within 10 years of menopause: Benefits of HT are highly likely to outweigh risks for bothersome VMS
• Women ≥60 years or >10 years post-menopause: Risks increase; initiation is generally not recommended unless there are compelling indications
• HT should be used at the lowest effective dose for the shortest necessary duration
• The need for continued HT should be reassessed at least annually
• Long-term use may be appropriate for women with persistent symptoms after thorough shared decision-making

---

11. Discontinuation of HT

• Cessation of ET should be done gradually (dose tapering), not abruptly
• Abrupt stopping causes return of disruptive VMS in ~50% of HT users
• Dose and dosing interval should be reduced slowly over months to years
• Very few controlled trials exist on the optimal way to discontinue HT; most guidance is based on clinical experience

---

12. "Bioidentical" Hormones

• "Bioidentical" = hormones structurally identical to ovarian hormones (estradiol, progesterone)
• FDA-approved oral and transdermal estradiol products are available in a wide range of doses
• Oral micronized progesterone (Prometrium) is FDA-approved
• Custom-compounded "bioidentical" preparations: associated with potentially significant risk and no known additional benefit
• Women requesting "natural" HT should be prescribed FDA-approved formulations containing estradiol and micronized progesterone
• All nonoral ET formulations (patches, sprays, gels, vaginal ring) contain natural estradiol

---

13. Non-Estrogen Alternatives for VMS

---

14. Osteoporosis Pharmacotherapy Summary (Non-HT)

---

15. Clinical Approach Summary

Patient with menopausal symptoms
        ↓
Assess: VMS severity, GSM, osteoporosis risk, CVD risk, breast/endometrial cancer risk
        ↓
Contraindications? (CVD, breast/endometrial cancer, abnormal bleeding, liver/gallbladder disease)
     YES → Non-hormonal alternatives
      NO ↓
Age <60 or within 10 years of menopause?
     YES → HT benefits likely outweigh risks → initiate at lowest effective dose
      NO → Higher risk; individualize; timing hypothesis applies
        ↓
Uterus intact?
     YES → EPT (estrogen + progestin) or CE/BZA (TSEC)
      NO → ET alone
        ↓
Route preference? 
  Oral: convenient, may raise SHBG/clotting factors
  Transdermal: preferred in women with VTE risk, thyroid disease, or libido concerns
        ↓
Reassess annually; use lowest effective dose; taper when discontinuing

---

Recent Evidence Update (PubMed 2023-2025)

• A 2023 systematic review (PMID 37449718) highlighted important pharmacological interactions with MHT, including effects on anticoagulants, antihypertensives, and antidepressants.
• A 2024 meta-analysis (PMID 38385734) assessed MHT eligibility criteria in breast cancer survivors, supporting individualized decision-making for non-ER-positive cancer survivors.

---