Menopause: the stage of life nobody was advised about

On 17 July 2002 the hormone army was discharged. The Women’s Health Initiative, the largest randomised study of postmenopausal hormone therapy, had been stopped early, the results appeared in JAMA, and the message was: the risks outweigh the benefits. The use of sex hormones after the menopause subsequently fell in Europe by up to eighty per cent.

The consequence was not only a prescribing statistic. A gap of two decades opened up. A generation of doctors was trained in the conviction that hormones are dangerous. A generation of women received, in answer to the question of what was going on with their sleep, their cycle, their concentration and their mood, not an answer but an antidepressant, a sleeping tablet or the remark that it would pass.

These women are today between forty-five and sixty, and they stand in the pharmacy several times a year. Usually not because of the menopause.

What the study really showed

The WHI was not a study of menopausal symptoms. It was designed as a prevention study; it was meant to clarify whether hormones prevent chronic diseases. Accordingly it recruited women between fifty and seventy-nine, on average sixty-three years old – a large proportion therefore more than a decade past the menopause and without relevant symptoms. Oral conjugated equine estrogens were used, in the combined arm together with medroxyprogesterone acetate.

The result was subsequently transferred to a completely different group: to symptomatic women around fifty considering transdermal estradiol therapy. That was the error, and it has lasted longer than any hormone therapy.

In May 2024 Manson and colleagues presented in JAMA an overview of twenty years of the WHI. The core statement has two parts, and both belong together. Menopausal hormone therapy is not suitable for the prevention of chronic disease; nothing has changed there. For symptomatic women under sixty, or within ten years of the menopause, however, the risk-benefit balance is favourable. The risks observed in the study occurred predominantly in the older participants. This so-called timing hypothesis is today the central organising concept of the field.

For Switzerland, the Society of Gynaecology and Obstetrics published in 2025 Expert Letter No. 90 on systemic menopausal hormone therapy, prepared under the lead of the Bern gynaecological endocrinology department. It confirms hormone therapy as first-line therapy for the climacteric syndrome, provided there are no contraindications, while also holding that every use requires an indication. Both are important: no blanket rejection, but also no prescribing as a lifestyle measure.

The figure that is needed at the counter

The question actually asked is not about relative risks. It is: will I get breast cancer from this?

The most robust answer comes from the individual-data meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer, published in 2019 in the Lancet on the basis of 58 prospective studies. It converts the risk into absolute figures. Of a hundred women who never use hormone therapy, about 6.3 develop breast cancer between fifty and sixty-nine. After five years of estrogen plus daily progestogen from the age of fifty, it is around 8.3 – that is, about one additional case per fifty users. With estrogen plus intermittent progestogen the figure is 7.7, that is one additional case per seventy users; with estrogen alone it is 6.8, that is one per two hundred. With ten years of use these excess risks roughly double. Part of the excess persists for more than ten years after stopping.

And then comes the sentence that is worth more in the consultation than all the others put together: vaginally applied estrogens were associated with no increase in risk.

That matters, because the misunderstanding occurs on a mass scale. Women with genitourinary syndrome of menopause refuse local estrogen therapy because they believe it is the same as systemic hormone treatment. They instead treat for years with lubricants and moisturisers and wonder why the complaints increase. Because unlike hot flushes, which usually recede of their own accord over the course of years, the genitourinary syndrome is chronic and progressive. Without treatment it does not get better but worse, with consequences for sexuality, continence and the frequency of urinary tract infections.

Route and molecule also matter

The second area in which the field has moved since 2002 concerns not the whether but the how.

Oral estradiol is subject to the first-pass effect in the liver and influences the clotting factors there. Transdermally applied estradiol bypasses this route. Under transdermal use in low to medium dosage, the risk of venous thromboembolism is, according to the Swiss expert letter, lower or not raised. The highest risk exists in any case in the first months after the start of therapy and falls thereafter. For women beyond sixty, Swiss clinical standards recommend switching where possible to the transdermal form.

The choice of progestogen is not a side issue either. Under micronised progesterone and dydrogesterone the thromboembolic risk appears lower than under synthetic progestogens. What remains non-negotiable: anyone with a uterus needs endometrial protection under systemic estrogen therapy. Estrogen monotherapy with a preserved uterus is an error, not a saving.

The new substance class

For a few years there has for the first time been a purposely developed non-hormonal option. The physiology behind it is elegant: in the hypothalamus, the so-called KNDy neurons are stimulated by neurokinin B and inhibited by estrogen. If the estrogen falls away, stimulation predominates, the neurons hypertrophy, and the thermoregulatory centre is thrown into disarray. Blocking the neurokinin 3 receptor normalises the regulation.

Fezolinetant was the first representative and is approved in Switzerland. In the registration studies with a good thousand postmenopausal women, the number of hot flushes fell on average by six to seven a day, compared with about four under placebo, with a sustained effect over fifty-two weeks.

The substance does, however, have a safety history that must be known in the pharmacy. In January 2025 a Direct Healthcare Professional Communication was issued on drug-induced liver injury. After approval, serious cases with transaminase rises above ten times the upper limit of normal, in part with raised bilirubin and phosphatase, had been reported. Since then the rule is: liver function tests before starting therapy, no start with ALT or AST, or total bilirubin, at twice the upper limit of normal or above, monthly checks in the first three months and thereafter at clinical discretion. Treatment is stopped at a transaminase above five times the upper limit of normal, or above three times in combination with bilirubin above twice the limit or with symptoms. The authorities’ reasoning is remarkably open: because otherwise healthy women are being treated here for symptoms, a rare but serious risk shifts the risk-benefit balance considerably.

For dispensing this means three things. First, the warning symptoms of liver injury belong spoken aloud and not merely referred to the package leaflet: fatigue, itching, jaundice, dark urine, pale stool, nausea, loss of appetite, upper abdominal pain. Second, strong CYP1A2 inhibitors are to be checked, because they raise plasma levels. Third, the pharmacological side glance pays off: smoking induces CYP1A2, so stopping smoking during ongoing therapy potentially changes exposure. That is not a label warning, but a thought a pharmacy should have and a mail-order platform does not.

The second representative, elinzanetant, additionally blocks the NK1 receptor and was approved by Swissmedic under the Access Consortium procedure, in Switzerland earlier than in the EU. The daily dose is 120 milligrams, administered as two 60-milligram soft capsules once daily before bedtime. In the OASIS studies, alongside frequency and severity of vasomotor symptoms, sleep and quality of life also improved. In the EU the approval additionally covers vasomotor symptoms under adjuvant endocrine breast cancer therapy, a group for which there was previously virtually nothing and in which such complaints regularly lead to discontinuation of therapy. The Swiss approval names the postmenopausal indication; it is worth watching for any extensions.

Important for context: these substances do not replace hormone therapy. They are the option for women in whom hormones are contraindicated or who reject them, and they act exclusively on the vasomotor symptoms – not on bone, not on the genitourinary syndrome.

How it can be recognised

The menopause is defined retrospectively: as the time of the last menstrual period, established after twelve months of amenorrhoea. On average it falls around the age of fifty-one. Everything relevant happens before and after. The internationally used staging system STRAW+10 distinguishes the early from the late transition phase and the early from the late postmenopause.

On duration, one figure from the American SWAN cohort is worth citing, because it corrects the most frequent misinformation: in women with frequent vasomotor symptoms the median total duration was 7.4 years, of which 4.5 years after the last menstrual period. Those who start early have to deal with it for longer. “It will pass in a year or two” is therefore not comforting but wrong.

Early transition phase, often from the mid-forties. The cycle becomes irregular, typically shorter at first, with variations in cycle length of a week or more. Bleeding becomes heavier or longer. Premenstrual complaints worsen, breast tenderness increases. Added to this are difficulties falling asleep and above all staying asleep, frequently with nocturnal waking between two and four o’clock, irritability, mood swings, reduced resilience to stress and, where migraine already exists, a change in frequency or pattern. Hot flushes already occur in this phase in one woman in three.

Late transition phase, with phases of amenorrhoea of two months or more. Here the vasomotor symptoms reach their peak: hot flushes, night sweats, palpitations and racing heart without cardiac cause. Plus sleep disturbances with daytime tiredness, feelings of anxiety and panic episodes in women without psychiatric history, disturbances of concentration and word-finding, forgetfulness, new or intensified joint and muscle pain, dizziness, headaches and dry, sensitive skin. Loss of libido frequently begins in this phase.

Early postmenopause, roughly the first five years. The vasomotor symptoms persist or slowly subside. At the same time the genitourinary syndrome of menopause begins: vaginal dryness, burning, pain during intercourse, itching, frequent urinary tract infections, urgency and stress incontinence. Plus changes in body composition with an increase in visceral fat at unchanged weight, hair loss on the head alongside increased facial hair, brittle nails, dry eyes and an altered feeling in the mouth up to burning tongue. In this phase bone loss is at its fastest.

Late postmenopause. The vasomotor symptoms decrease but persist in some women. The genitourinary syndrome progresses without treatment. Added to this are the silent consequences: osteoporosis and fractures, shifts in the lipid profile and blood pressure, declining muscle mass and strength.

This list is deliberately long, because the typical customer does not come with “I have hot flushes” but with a single symptom from this list that she cannot place anywhere. The pharmacy’s counselling contribution consists not in a diagnosis but in one sentence: at your age this can be connected with the menopause, and there is assessment and treatment for it.

What else it can be

That is precisely why the differential diagnosis has to be borne in mind. Thyroid dysfunction produces an almost identical picture. Iron deficiency anaemia, often a consequence of heavier perimenopausal bleeding, explains fatigue, concentration problems and palpitations just as well. Depression, anxiety disorder, obstructive sleep apnoea, diabetes and adverse drug effects come into consideration. Night sweats alone, without hot flushes and with weight loss or fever, are not a menopausal symptom but a call for investigation.

Requiring immediate medical assessment are: any bleeding after amenorrhoea has already been established, very heavy or prolonged bleeding, intermenstrual bleeding, complaints before the age of forty suggesting premature ovarian insufficiency, as well as newly appearing breast changes.

With phytotherapy the scope is narrower than the shelf suggests. Preparations from Cimicifuga racemosa are the best-studied option for mild to moderate vasomotor complaints; note the long-standing official warning about rare liver injury and the caution in a history of hormone-dependent tumours. For extracts of rhapontic rhubarb and for sage in cases of sweating there are data justifying a trial. Isoflavone-containing preparations do not belong in the hands of women on endocrine breast cancer therapy. And St John’s wort, readily reached for in this age group to lift the mood, is a potent enzyme inducer with a correspondingly long interaction list. For the genitourinary syndrome, phytotherapy achieves nothing; here only local treatment helps.

Where the pharmacy actually closes the gap

The perimenopause begins years before the last menstrual period and rarely presents as a hot flush. It presents as difficulty staying asleep at three in the morning, as palpitations, as newly appearing joint pain, as irritability, as difficulty finding words, as a cycle that becomes shorter and heavier.

These women buy sleeping aids, St John’s wort, magnesium and iron preparations. They buy them in the pharmacy, often years before anyone utters the word perimenopause. The community pharmacy is thus in fact the first port of call for a stage of life for which there is no structured screening examination.

Not asked for two decades.

Four points are concretely relevant for action here. Heavy and prolonged bleeding in the perimenopause is a frequent cause of iron deficiency; anyone repeatedly dispensing iron should ask about the cycle and refer back where necessary. St John’s wort, readily bought precisely in this group to stabilise mood, is a potent enzyme inducer and reduces, among other things, the effectiveness of hormonal contraceptives. Because, thirdly: perimenopausal women are not automatically infertile and still need contraception, which is regularly overlooked. And fourthly, dispensing transdermal preparations calls for application advice worthy of the name, that is application sites and their rotation, drying time for gels, avoidance of skin contact with other people, as well as the note that micronised progesterone is taken in the evening because of its sedating effect.

Equally important is knowing when to refer back. Newly appearing bleeding after a phase of amenorrhoea, or persistent bleeding under continuous combined therapy, belongs investigated, not reassured away.

What remains

The scientific correction has taken place. The timing hypothesis is established, the route of administration differentiated, the absolute risks quantified, and with the neurokinin antagonists there is for the first time a targeted non-hormonal alternative.

What is missing is the translation. Between what an expert letter says and what a woman gets to hear in a sales conversation, twenty years of caution still lie. The sentence “you get breast cancer from that” is said more often than the figure 6.3 versus 8.3 per hundred women over twenty years. And the woman who has been buying lubricants for four years has in all probability never learned that there is an effective treatment for her problem whose risk profile in the largest available analysis was simply unremarkable.

Counselling here does not mean recommending a therapy. It means making possible a question that has not been asked for two decades.