Menopause and hormone replacement therapy

Overview

The menopause is the last menstrual period. It happens when the ovaries run out of responsive follicles and stop making oestrogen in cycles. It is a retrospective diagnosis, made after 12 months without a period.

It matters for the exam because it ties together physiology (hormone changes), disease (osteoporosis, cardiovascular disease, postmenopausal bleeding) and pharmacology (HRT and its risks).

Definitions

• Median age: 51-52 years; 95% of women reach it between 45 and 55. This has not changed for many decades even though life expectancy has.

Physiology

• Oocytes are lost from fetal life onwards; only a few hundred ever ovulate, the rest undergo atresia.
• As follicle numbers fall, inhibin B falls first. Less inhibin lets FSH rise, which drives the remaining follicles harder for a while.
• Cycles become irregular, with anovulatory cycles and unpredictable progesterone: periods may be scanty, or irregular, prolonged and heavy.
• When follicles are exhausted, oestradiol falls and FSH and LH stay high (FSH more than LH). Loss of the menstrual cycle is permanent.
• The ovarian stroma goes on making some androgen; androgens in women decline steadily with age rather than suddenly.
• After the menopause the main oestrogen is oestrone, made in fat by aromatisation of adrenal androstenedione. This explains why obese postmenopausal women have more endometrial hyperplasia and cancer.

Diagnosis

• Over 45 with typical symptoms and irregular or absent periods: diagnose clinically. Blood tests add little, because hormone levels swing during the perimenopause.
• Under 40 (suspected POI): needs blood tests: two raised FSH levels (over 30 IU/L) at least 6 weeks apart, with low oestradiol.
• Always consider pregnancy.
• After hysterectomy there are no periods to follow, so rely on symptoms.
• A very low AMH in a woman with still-regular cycles suggests menopause within a few years.

Premature ovarian insufficiency (POI)

• About 1% of women under 40 and 0.1% under 30.
• Presents with primary or secondary amenorrhoea and menopausal symptoms. Ovarian activity can return unpredictably, so pregnancy is still possible and contraception should be discussed.

• Management by a specialist team: HRT or the combined pill until about the usual age of menopause (51), for symptoms, bone and heart protection. In these women HRT replaces what they should have had, so it does not carry the age-related risks of HRT at 60.
• Fertility: donor egg IVF is the only realistic option; egg or embryo freezing before cancer treatment where possible.

Iatrogenic menopause

• Surgical menopause (both ovaries removed for endometriosis, cancer or BRCA risk) causes sudden and often severe symptoms because hormones fall overnight.
• GnRH agonists cause a reversible "medical menopause"; add-back HRT protects bone.

Effects of oestrogen loss

Vasomotor symptoms

• Up to 80% of women; may last up to 7 years or longer.
• Thought to arise from loss of oestrogen's control of the hypothalamic temperature centre (neurokinin B pathway).
• Worse with high BMI; triggered by alcohol, caffeine, spicy food, smoking.

Genitourinary syndrome

• Thin, dry, pale vaginal epithelium; loss of glycogen and lactobacilli raises vaginal pH, so infections and UTIs increase.
• The urethra and trigone share oestrogen sensitivity with the lower vagina, giving urgency and frequency.

Bone

• Peak bone mass is reached at 20-30 years.
• Oestrogen restrains osteoclasts. After the menopause bone loss accelerates (especially trabecular bone of the spine) until about 60, then continues more slowly.
• Osteoporosis is about 4 times commoner in women than men; fractures of the wrist, spine and hip rise after 60.
• Risk factors: family history of hip fracture, smoking, excess alcohol, long-term steroids, POI or a medically induced menopause, immobility, malabsorption or liver disease, thyroid or parathyroid disease.

Cardiovascular

• Oestrogen protects vessel walls. After the menopause: more abdominal (android) fat, higher LDL and triglycerides, lower HDL, and stiffer vessels.
• Cardiovascular disease becomes the leading cause of death in women over 60.

Management

General and non-hormonal

• Lifestyle: exercise, weight control, stopping smoking, less alcohol, calcium and vitamin D.
• CBT helps vasomotor and mood symptoms.
• Non-hormonal drugs for flushes when HRT is unwanted or contraindicated (for example after breast cancer): SSRIs/SNRIs (venlafaxine, paroxetine, fluoxetine, citalopram), clonidine, gabapentin. Neurokinin-3 receptor antagonists are a newer class.
• Vaginal moisturisers and lubricants.
• Bone: bisphosphonates, raloxifene (oestrogen-like on bone, blocks oestrogen at breast and endometrium), denosumab, teriparatide.
• Herbal products (black cohosh, red clover, "natural" hormones) are poorly regulated and poorly studied.

Hormone replacement therapy (HRT)

Components

• Oestrogen: oestradiol (most physiological), oestradiol valerate, conjugated equine oestrogens, oestriol (vaginal).
• Progestogen: norethisterone, levonorgestrel (including the LNG-IUS), dydrogesterone, medroxyprogesterone, micronised progesterone, drospirenone.
• Testosterone: for low sexual desire not helped by standard HRT (specialist use).

Choosing the regimen

Route

Benefits of HRT

• Vasomotor symptoms: over 90% improve within about 6 weeks; better sleep, mood and concentration.
• Bone: prevents bone loss and fractures of hip and spine; strongly advised in POI and early menopause.
• Genitourinary: less dryness and dyspareunia, fewer UTIs.
• Cardiovascular: likely protective if started early in the menopause ("window of opportunity"); harmful effects more likely if started after about 65.

Risks of HRT

• No link with cervical or vulval cancer. Vaginal oestrogen does not raise breast cancer risk.
• For most symptomatic women under 60, benefits outweigh risks.
• There is no fixed maximum duration; review the balance at least yearly.

Contraindications

Side effects

• Oestrogen: breast tenderness, nausea, leg cramps, headache.
• Progestogen: fluid retention, breast tenderness, mood swings, acne, headache. Switching to an LNG-IUS or a different progestogen often helps.
• Bleeding outside the expected pattern on HRT needs investigation (see the abnormal uterine bleeding chapter).

Quick revision

• Menopause = last period; diagnose after 12 months; median 51-52.
• POI under 40 (FSH over 30 IU/L twice, 6 weeks apart); early menopause 40-45.
• Inhibin falls first → FSH rises; then oestradiol falls.
• Postmenopausal oestrogen = oestrone from fat.
• Effects: flushes → urogenital atrophy → osteoporosis and CVD.
• HRT: oestrogen alone only without a uterus; otherwise add progestogen.
• Transdermal: no added VTE risk.
• Combined HRT: small duration-related breast cancer rise.
• Absolute CIs: pregnancy, breast or endometrial cancer, active liver disease, active VTE/thrombophilia, uncontrolled BP.

Written by The House Job from standard references (Gynaecology by Ten Teachers; Guyton and Hall Textbook of Medical Physiology).

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