Premature Menopause Overview

Premature Menopause

• Occurs when ovaries stop functioning before age 40.
• Leads to estrogen drop and early menopausal symptoms.
• Causes:
  • Genetic Factors:
    • Family history of early menopause increases risk.
    • Turner syndrome (missing or incomplete X chromosome) leads to ovarian dysfunction.
    • Fragile X syndrome carriers have a higher risk of premature menopause.
  • Autoimmune Diseases:
    • Immune system attacks ovaries, causing ovarian failure.
    • Diseases include:
      • Thyroid disorders (Hashimoto's thyroiditis)
      • Rheumatoid arthritis
      • Addison's disease
      • Type 1 diabetes
  • Medical Treatments:
    • Chemotherapy and radiation therapy can damage ovaries.
    • Surgical removal of ovaries (oophorectomy) causes immediate menopause.
    • Pelvic surgery can inadvertently damage ovaries.
  • Natural Aging:
    • Can be a factor, but premature menopause occurs before age 40.

Hormone Replacement Therapy (HRT)

• Types:

  • Combined E+P: Estrogen and Progesterone
    • For hysterectomized women.
    • Benefits: Relieves menopausal symptoms and prevents endometrial cancer.
    • Forms: Oral tablets, patches, combined regimens.
  • Estrogen only:
    • For women with a uterus.
    • Prevents endometrial overgrowth.
    • Can be administered sequentially or continuously.
      • Sequential Regimen: Alternates estrogen and estrogen-progestin, causing withdrawal bleeding.
      • Continuous Regimen: Preferred for elderly women who don't need monthly bleeding.

• Estrogen Preparations:

  • 17-beta estradiol: Poor oral absorption, used in parenteral formulations.
  • Micronized 17-beta estradiol: Bioidentical to premenopausal ovary product.
  • Conjugated equine estrogens (CEEs): Derived from mare urine.
  • Esterified estrogen:
  • Ethynyl Estradiol: Most potent estrogen, used in low doses in HRT.
  • Efficacy is similar across preparations.

• Estrogen Dosage Equivalents:

  • 0.625mg Conjugated equine estrogen
  • 1 mg micronized 17-beta estradiol
  • 0.05 mg/day transdermal 17-beta estradiol
  • 1.25 mg piperazine estrone sulfate
  • Estradiol gels and sprays are available in various strengths.

• Estrogen Mechanism of Action:

  • Oral
  • Spray
  • Patch
  • Vaginal ring
  • Gel

• Drug-Drug Interactions:

  • Estrogens metabolized by CYP3A enzymes.
  • CYP3A inhibitors increase estrogen levels.
  • CYP3A inducers decrease estrogen levels.
  • Increases TBG (thyroid-binding globulin), affecting T4 levels.

• Progestogen Preparations:

  • Progesterone: Naturally occurring hormone.
  • Progestogen: Synthetic or natural molecule with similar effects to progesterone.
  • Progestins: Synthetic progestogens.
  • Structural Classification:
    • Pregnanes: Medroxyprogesterone acetate, Nomegestrol acetate
    • Estranes: Norethindrone, norethindrone acetate, ethynodiol diacetate, norethynodrel
    • Gonanes: Levonorgestrel, desogestrel, Norgestimate, Gestodene

• Generational Classification:

  • Progestogens classified based on generations of development.

Progestogen Preparations for HRT

• Various progestogens used in HRT, each with different properties and side effect profiles.

Combined HRT Preparations

• Sequential Combined Formulations:

  • 1-2 mg oestradiol + 10mg dydrogesterone (Elleste, Femoston)
  • 1-2 mg oestradiol + 1mg norethisterone acetate
  • 1-2mg oestradiol + 1 mg norethisterone acetate

• Sequential Therapy: Estrogen and Progesterone Taken Separately

  • Oral oestradiol 1 -2 mg
  • Micronised progesterone (taken separately):
    • Utrogestan 200mg orally for 12 days
    • Provera 10mg orally for 12 days
    • Norethisterone 5mg orally for 12 days
    • Mirena intrauterine system

• Continuous Combined HRT:

  • 1-2 mg oestradiol + 100 mg progesterone (Femoston conti)
  • 1-2 mg oestradiol + 5mg dydrogesterone
  • 1-2 mg oestradiol + 0.5mg norethisterone acetate
  • 1-2 mg oestradiol + 2.5mg medroxyprogesterone acetate
  • 1-2 mg oestradiol + 5mg medroxyprogesterone acetate

• Estrogen and Progesterone can be taken separately with low dose of Progesterone.

Metabolism and Pharmacokinetics

• Oral progesterone: Undergoes hepatic first-pass metabolism.
• Plasma protein binding: Free or bound to albumin or other transport proteins.
• Bioavailability: Increased when micronized.
• Oral: Peak serum concentrations within 1-3 hours.
• Half-life: Varies based on progestogen type.

Adverse Effects

• Fluid retention
• Bloating
• Breast tenderness
• Headaches
• Mood changes
• Nausea
• Lowering dose or switching to different estrogen/progestogen can alleviate side effects.

Benefits vs Risk of HRT

• Cardiovascular Health:

  • Estrogen promotes vasodilatation, improving metabolic profile.
  • Protection from cardiovascular events, especially when used early after menopause.
  • Some RCTs (WHI) failed to show benefit in older women.
  • "Timing hypothesis": HRT may be beneficial early after menopause, reducing atherosclerosis and cardiovascular events in women under 60 years old, started < 10 years of menopause.
  • Blood pressure reduction with drosperinone.

• Breast Cancer Risk:

  • Risk varies based on formulation, timing, duration of HRT.
  • Estrogen stimulates breast tissue proliferation.
  • WHI showed increased risk with CEE+MPA.
  • Transdermal E reduced risk compared to oral E.
  • "Gap time hypothesis": Increased breast cancer risk when HRT started less than 5 years after menopause, particularly within 1 year.

• Endometrial Cancer (EC):

  • Women with unbalanced estrogen exposure are at increased risk.
  • Sequential E+P regimen showed decreased risk for EC when used < 5 years, increased risk when used longer.

• Venous Thromboembolism:

  • Increased risk with oral formulations due to higher liver concentration.
  • Increased production of coagulation and fibrinolysis factors.

• Bone Health:

  • HRT reduces bone loss in menopausal women.

Other Hormone-Sensitive Conditions

- HRT can be used to manage other conditions, like hot flashes, vaginal atrophy, and sleep disturbances.
- Non-hormonal therapies like SSRIs and SNRIs can also be effective for hot flashes.

SSRIs (Selective Serotonin Reuptake Inhibitors)

• Mechanism of Action: Increase serotonin levels, regulating mood and thermoregulation.
• Common SSRIs for Vasomotor Symptoms:
  • Paroxetine (FDA-approved for hot flashes)
  • Fluoxetine and Citalopram (off-label use)
• Effectiveness: Reduce hot flash frequency and intensity by 50-60%.
• Side Effects: Nausea, fatigue, sleep disturbances, sexual dysfunction.

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

• Mechanism of Action: Increase serotonin and norepinephrine levels, involved in mood regulation and thermoregulation.
• Common SNRIs for Vasomotor Symptoms:
  • Venlafaxine (most common)
  • Desvenlafaxine
• Effectiveness: Reduce hot flashes by 40-60%.
• Side Effects: Similar to SSRIs, including nausea, dry mouth, dizziness, increased blood pressure.

When to Use SNRIs/SSRIs

• When HRT is contraindicated due to cancer, cardiovascular disease, or thromboembolic disorders.
• For women who prefer not to use hormones.