Debunking the Timing Hypothesis: Does Menopausal Hormone Therapy Really Protect Against Dementia, Depression and Cardiovascular Disease?

Part 5 of The Menopause Files

It’s been over a year since I wrote the last installment of The Menopause Files. In that time, enthusiasm (misplaced enthusiasm, IMHO) for hormone replacement therapy - now rebranded ‘menopausal hormone therapy’ or MHT - has only grown. Every week, I see female clients in their mid-to-late forties who have been prescribed some form of hormonal therapy for concerns such as weight gain, low mood, and mild cognitive issues like difficulty with word finding. As noted in Menopausal hormone therapy: Overpromising and underdelivering? (Part 2 of The Menopause Files), these complaints are not alleviated by MHT. So why do doctors - especially those who brand themselves as ‘holistic’ or ‘integrative’ - continue to prescribe hormones for conditions for which there’s no proven benefit?

In some cases, the answer is simple: greed. Many ‘integrative’ doctors charge appointment fees that are far above Medicare or private insurance rebate rates, and if they’re subjecting patients to completely useless blood and/or saliva tests, supposedly to optimise hormone dosage, they’ll generate multiple repeat visits. Some even sell compounded hormone preparations to their patients. Ka-ching, ka-ching.

What about the well-meaning practitioners who aren’t intentionally fleecing their patients? Most of these cases can be explained by ignorance. Unaware of the vast sums of money spent by the pharmaceutical company Wyeth (acquired by Pfizer in 2009) to smear the Women’s Health Initiative trial that led to a precipitous decline in prescriptions for hormone replacement therapy, these doctors have apparently been suckered by claims spawned by the Wyeth-funded campaign.

Prominent among these claims is the critical period or timing hypothesis. That is, critics of the Women’s Health Initiative study argue that the negative results that led to its premature termination - namely increased risk of coronary heart disease, stroke, pulmonary embolism and breast cancer - and the subsequent finding that women who took combined HRT had double the risk of developing probable dementia, apply only to women who started hormone therapy well after they had gone through menopause. Conversely, they assert, women who commence taking hormones within a few years of menopause are not subject to these risks... and in fact, observational studies (i.e., non-randomised trials) suggest that they will benefit, with a reduced risk of Alzheimer’s disease and cardiovascular disease, along with decreased all-cause mortality.

Another claim of the new crop of menopausal hormone therapy spruikers, is that the negative effects of hormone therapy that were found in the Women’s Health Initiative study, were due to the types of hormones used - namely, conjugated equine (horse-derived) estrogen and progestin (synthetic progesterone), both taken orally. According to this argument, transdermal estradiol - that is, an estrogen preparation that has the same chemical formula as the type of estrogen made by women’s ovaries¹, but is delivered via a patch, cream, gel or lotion - and bioidentical progesterone, which are used in present-day menopausal hormone therapy, do not have the drawbacks of earlier HRT drug regimens.

Photo by Melany @ tuinfosalud.com on Unsplash

In fact, these enthusiasts claim that by maintaining estrogen and progesterone at levels comparable to those in premenopausal women, bioidentical hormone therapy may protect women from the increased risk of diseases whose incidence climbs dramatically after menopause, especially cardiovascular disease, stroke, dementia and cancer. And many also tout hormone therapy for mood disorders that a lot of women suffer as they go through the menopause transition.

Sounds pretty appealing, doesn’t it? Who wouldn’t want to prevent those nasty diseases, if they could? And there’s some biological plausibility to these claims. After all, every cell in the body - including the brain - has receptors for estrogen, and the hormone does appear to play a major role in facilitating the lower rate of cardiovascular disease that premenopausal women enjoy, compared to men of the same age - protection that evaporates after women go through menopause.

But if there’s one thing we should have learned from the history of drug trials, it’s that plausible mechanisms don’t always translate into beneficial clinical outcomes. That is to say, just because something should work, based on its mechanism of action, doesn’t mean it will work, in the sense of delivering a net benefit to health. So let’s examine the evidence for these two claims.

Firstly, does menopausal hormone therapy, whether oral or transdermal, protect women against dementia when they start taking it within the “critical window” - that is, ten years or less after going through natural menopause?

Dementia, Alzheimer’s disease and cognitive decline

As Barbara Mintzes and Adriane Fugh-Berman point out in a commentary published in the BMJ Drugs and Therapeutics Bulletin in December 2024, the Women’s Health Initiative study that the MHT enthusiasts love to hate on, did in fact enrol almost 9000 women aged 50-59. 1326 of these women were included in the Women’s Health Initiative Study of Younger Women (whimsically abbreviated ‘WHIMSY’). After an average follow-up period of 14 years, WHIMSY found no overall difference in cognition between women who had been randomised to receive hormone therapy (oral conjugated equine estrogen, with or without medroxyprogesterone acetate) and placebo recipients. However, women who had taken estrogen-only hormone therapy performed slightly worse in tests of verbal fluency.

Were the disappointing results seen in WHIMSY the consequence of using the older formulation of menopausal hormone therapy, namely conjugated equine estrogen, taken orally? To answer this question, the Kronos Early Estrogen Prevention Study (KEEPS) randomised women within three years of natural menopause to receive either oral conjugated equine estrogens or transdermal 17β-estradiol, or placebo. Both estrogen therapy groups also received oral micronised progesterone (200  mg/d) for the first 12 days each month, in place of the synthetic progestin used in the Women’s Health Initiative. After four years of follow-up there were no effects of either form of estrogen therapy on cognition, for better or for worse.

A systematic review of placebo-controlled randomised trials on menopausal hormone therapy with either oral or transdermal estrogen plus progesterone or a progestin, in spontaneously menopausal women under the age of 60 identified nine such trials which evaluated cognitive outcomes in a total of 2452 women. No benefits of either type of estrogen therapy on cognition were identified.

And an as-yet-unpublished systematic review and meta-analysis identified ten studies enrolling a total of 213,678 participants who commenced taking hormone therapy (either oral or transdermal estrogen), with or without synthetic or bioidentical progesterone, within five years of menopause. Of the ten studies, three were randomised controlled trials, three were nationwide nested case-control studies and the remaining four were prospectively gathered cohorts from population databases. Outcomes assessed included dementia diagnoses (including Alzheimer’s disease), cognitive decline and mild cognitive impairment.

Meta-analysis found no increased risk of all-cause dementia in women who began taking menopausal hormone therapy between the ages of 45 and 60, but a 14 per cent higher risk of developing Alzheimer’s disease in women with a uterus and 12 per cent higher risk in those without. Longer duration of use conferred higher risk. No protection against cognitive decline or mild cognitive impairment was found.

In summary, menopausal hormone therapy with either oral or transdermal estrogen, has not been found to improve cognitive outcomes, reduce cognitive decline, or prevent dementia, and may in fact increase the risk of Alzheimer’s disease, especially with prolonged use.

Cardiovascular disease

The systematic review of nine randomised controlled trials of menopausal hormone therapy referred to in the previous section, also identified three trials which evaluated outcomes related to cardiovascular disease, in women who commenced therapy within ten years of naturally-occurring menopause. Of these, the Women’s Health Initiative identified no cardiovascular benefit of taking oral conjugated equine estrogen plus medroxyprogesterone acetate in women aged 50-59, and a protective effect of conjugated equine estrogen alone on some cardiovascular outcomes (coronary heart disease, coronary revascularisation, and a composite measure of cardiovascular death plus coronary revascularisation), but an increased risk of stroke.

The other two trials found no benefit of either oral or transdermal estrogen therapy plus micronised progesterone or medroxyprogesterone acetate (in women with a uterus), on cardiovascular disease.

In summary, women with a uterus derive no benefit of menopausal hormone therapy when it comes to preventing cardiovascular disease; the observed benefit for women without a uterus may be attributable to offsetting of the negative cardiovascular effects of oophorectomy (surgical removal of the ovaries).

Cancer

In women aged 50-59 at enrolment in the Women’s Health Initiative, there was a 36 per cent higher risk of invasive breast cancer at 20-year follow-up in those randomised to conjugated equine estrogen plus medroxyprogesterone acetate. Women taking estrogen alone did not have an increased risk, but the authors of the study speculated that this might have been because those with a longer time between undergoing oophorectomy and commencing estrogen therapy, were protected from invasive breast cancer.

There was no difference in the risk of endometrial or colon cancers in women taking hormones vs placebo.

In summary, women who commenced taking conjugated equine estrogen plus medroxyprogesterone acetate under the age of 60 had an increased risk of invasive breast cancer. No randomised controlled trials have examined the risk of cancer in women using transdermal estrogen.

Depression and low mood

Nine randomised controlled trials enrolling a total of 1280 women between the ages of 40 and 60 have evaluated the effects of oral conjugated equine estrogen, oral 17β-estradiol, or transdermal 17β-estradiol on depression and other mood states.

Of these, six found that hormone therapy improved some aspect of mood, while three found no effect on any mood endpoint. Of the five studies that specifically examined depression, two found that hormone therapy improved depression scores, while three reported no difference in depression scores between women assigned to hormone therapy vs those who received placebo.

Transdermal estrogen did not outperform either oral conjugated equine estrogen or oral 17β-estradiol, and three out of the four studies of transdermal 17β-estradiol therapy found no difference between hormone and placebo groups.

Studies that differentiated between mood symptoms related or unrelated to sleep disruption from vasomotor symptoms (hot flushes/flashes and night sweats), found that only women whose sleep quality was improved by menopausal hormone therapy experienced better mood.

In summary, evidence from randomised controlled trials does not support the claim that menopausal hormone therapy improves mood or prevents depression, except to the extent that it relieves vasomotor symptoms that interfere with sleep and quality of life.

The bottom line

Menopausal hormone therapy is approved for only two indications: relief of vasomotor symptoms (hot flushes/flashes and night sweats), and mitigation of loss of bone mineral density. For women with medical contraindications to hormone therapy (e.g. personal or family history of breast cancer, or thromboembolic disease), or those who just don’t want take drugs to manage this perfectly natural and normal life-stage, there are highly effective Lifestyle Medicine approaches to relieving vasomotor symptoms, improving body composition and bone density, reducing the risk of cardiovascular disease and relieving depression and improving psychological well-being, which I discussed at length in Drug-free treatments for perimenopausal symptoms (Part 3 of The Menopause Files).

And if you want to ditch Substack and get my posts straight from the source - as well as commenting and viewing any content that Substack won’t let you see without using their privacy-invading facial recognition app - just

For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.

1. Although it is not exactly the same as the estradiol produced by the ovaries, as Dr Jen Gunter points out.