Menopause and HRT: Balancing Benefit and Risk

Menopause is a hormone deficiency

Strip away the symptoms and menopause is a single endocrine event: the ovaries run out of follicles. The physiology of oestrogen and progesterone belongs to the Endocrine section, and it is worth reading there first; here we simply apply it. When the ovarian follicles are exhausted, oestrogen falls and the pituitary, no longer restrained by feedback, drives FSH sky-high — a rising FSH is the biochemical fingerprint of the menopause. Oestrogen is not just a reproductive hormone; it acts on receptors throughout the body, which is exactly why its withdrawal is felt everywhere. The vasomotor centre in the hypothalamus becomes unstable, producing the hallmark hot flushes and night sweats. The vulva, vagina and lower urinary tract, all oestrogen-dependent, thin and dry — the genitourinary syndrome of menopause, with dyspareunia and recurrent urinary infection. Mood and sleep suffer. And silently, over years, bone resorption outpaces formation, because oestrogen normally restrains the osteoclast — the long-term legacy is osteoporosis, a thread we pick up again below.

The core principle: replace oestrogen, protect the endometrium

If the problem is too little oestrogen, the treatment is oestrogen — and it is oestrogen that relieves the flushes, restores the tissues and preserves bone. But oestrogen given to the endometrium unopposed is a growth signal: it drives the lining to proliferate, and unchecked proliferation means endometrial hyperplasia and, over time, endometrial cancer. This single fact generates the central rule of HRT. A woman who still has her uterus must never receive oestrogen alone; she needs a progestogen added to oppose the oestrogen and keep the lining safe — this is combined HRT. A woman who has had a hysterectomy has no endometrium to protect and can take oestrogen-only HRT, sparing her the progestogen altogether. Everything else — which progestogen, which route, which regimen — is detail layered on top of this one load-bearing principle.

Regimens: sequential versus continuous-combined

How you schedule the progestogen depends on where the woman is in the transition. In perimenopause, when periods have not yet fully stopped, the progestogen is given cyclically — sequential (cyclical) HRT — so that a predictable monthly withdrawal bleed occurs, mimicking her own dwindling cycle; giving continuous progestogen here tends to cause erratic breakthrough bleeding. Once a woman is clearly postmenopausal (roughly a year past her last period), you switch to continuous-combined HRT, with oestrogen and progestogen every day and no scheduled bleed — the goal being a "period-free" regimen. A neat alternative for the progestogen component is the levonorgestrel intrauterine system (IUS): placed in the uterus, it delivers progestogen directly to the endometrium for local protection while also serving as contraception in the perimenopause, so a woman can take oestrogen by any route and let the coil handle the lining.

Why the route matters — the first-pass story

The single most important pharmacological choice in modern HRT is not the dose but the route. Swallow oestrogen and it is absorbed from the gut and carried straight to the liver, where first-pass metabolism exposes hepatic tissue to a high oestrogen load. The liver responds by increasing its output of clotting factors and other proteins, and this is the mechanism behind oral HRT's raised risk of venous thromboembolism (VTE) and stroke. Deliver the same oestrogen through the skin — a transdermal patch or gel — and it enters the systemic circulation directly, bypassing that first hepatic pass; the liver is never flooded, clotting-factor synthesis is not driven up, and at standard doses transdermal oestrogen carries little or no excess VTE or stroke risk. This is the pharmacology behind a clear clinical rule: for any woman at higher baseline risk — older, obese, a personal or family history of clot, migraine, or cardiovascular risk factors — choose the transdermal route. The first-pass principle links straight to the Cardiovascular and Haematology sections, where the coagulation cascade and stroke risk are taught in depth.

The progestogen component carries its own choices. Older synthetic progestogens (such as medroxyprogesterone acetate and norethisterone) appear to account for much of HRT's small breast-cancer signal and blunt some of oestrogen's favourable effects. Body-identical micronised progesterone and the closely related dydrogesterone are now preferred where possible, because they seem to carry a lower breast and cardiovascular risk. Beyond the standard oestrogen-plus-progestogen combinations sits tibolone, a single synthetic steroid whose metabolites have oestrogenic, progestogenic and androgenic activity all at once — it treats vasomotor symptoms and protects bone without a separate progestogen, and its androgenic action can help libido, though it is reserved for postmenopausal women. And when low sexual desire persists despite adequate oestrogen, a small dose of testosterone (an androgen borrowed from the Endocrine section) can be added specifically for libido.

The risks — the WHI legacy, now nuanced

The fear surrounding HRT traces to one trial, and understanding it defuses most of the fear. The Women's Health Initiative (WHI), published in 2002, tested oral combined HRT in a population whose average age was 63 — many of them well over a decade past menopause — and reported small increases in breast cancer, stroke and VTE. The headlines caused a global collapse in prescribing. Two decades of reanalysis have reshaped the picture without denying the real risks. The main hazards are genuine but small in absolute terms: VTE (driven by the oral route, minimal with transdermal), stroke (again an oral, dose-related effect), a small increase in breast cancer that rises with duration of use and is linked mainly to the progestogen component rather than oestrogen itself, and a raised risk of gallbladder disease (again largely with oral oestrogen). Crucially, oestrogen-only HRT in hysterectomized women showed little or no increase in breast cancer — reinforcing that the breast signal tracks the progestogen. These risks belong to the Oncology and Haematology sections, where hormone-driven cancers and thrombosis are taught in their own right.

Against those risks sit the benefits, which are large where they matter most. HRT is by far the most effective treatment for vasomotor symptoms, transforming quality of life; it reverses urogenital atrophy and restores mood and sleep; and it reduces the risk of osteoporotic fracture, a bone benefit that connects directly to the Endocrine chapters on osteoporosis and bisphosphonates. There is also the timing hypothesis: when HRT is started early — under 60, or within ten years of menopause — it appears to be cardiovascular-neutral or even protective, whereas starting it many years later (as in much of WHI) may confer no such benefit and more vascular risk. In other words, the same drug started in the right window behaves very differently from the same drug started too late. For most healthy, symptomatic women under 60 the benefit clearly outweighs the risk.

Contraindications and the local-oestrogen exception

Some situations forbid systemic oestrogen outright: a current or past oestrogen-dependent cancer (breast or endometrial), active or recent VTE or arterial thrombotic disease, and undiagnosed vaginal bleeding — which must always be investigated to exclude endometrial cancer before any hormone is given, never masked by it. But there is a critical exception for the woman whose only problem is urogenital: vaginal (local) oestrogen. Delivered as a cream, pessary or ring, low-dose vaginal oestrogen acts on the vulvovaginal and lower urinary tract tissues with minimal systemic absorption. Because so little reaches the circulation, it does not carry the systemic VTE or breast concerns, it can be used long-term, and — importantly — it does not require an accompanying progestogen even in a woman with a uterus. It is the treatment of choice for genitourinary atrophy, painful sex and recurrent urinary tract infection in the older woman, a use that ties back into the Genitourinary section on recurrent UTI. Many women who cannot or should not take systemic HRT can safely use vaginal oestrogen.

When hormones are off the table: non-hormonal options

Some women cannot take oestrogen — most often after a hormone-sensitive breast cancer — yet still suffer disabling flushes. Several non-hormonal drugs, borrowed largely from the Central Nervous System section, help. Certain SSRIs and SNRIs (such as venlafaxine or paroxetine) reduce vasomotor symptoms, though paroxetine's enzyme inhibition should be avoided in women on tamoxifen. Gabapentin can blunt flushes, particularly the night-time ones. Clonidine, a centrally acting alpha-2 agonist, has modest benefit. The newest and most mechanistically elegant option is fezolinetant, a neurokinin-3 (NK3) receptor antagonist: menopausal oestrogen loss disinhibits KNDy neurons in the hypothalamic thermoregulatory centre, and blocking their NK3 signalling calms the unstable vasomotor centre directly — a targeted, non-hormonal treatment for hot flushes. Alongside these, weight loss, reducing alcohol and caffeine, and cognitive behavioural therapy all have a genuine role.