Use of menopausal hormone therapy (MHT) is not associated with an increased risk of developing dementia

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Use of menopausal hormone therapy (MHT, also known as hormone replacement therapy, HRT) is not associated with an increased risk of developing dementia, regardless of hormone type, dose, or duration, concludes a large UK study published by The BMJ today.

Within the subgroup of women with a specific diagnosis for Alzheimer’s disease, a slight increasing risk association was found with use of oestrogen-progestogen treatments, but measurable only for long-term usage (5 years or more).

The researchers say this study “brings clarity to previously inconsistent findings and should reassure women in need of menopausal hormonal therapy.”

MHT is used to relieve menopausal symptoms such as hot flushes, sleep disturbance, mood swings, memory losses and depression.

Treatments include tablets containing oestrogen only, or a combination of oestrogen and progestogen, as well as patches, gels and creams.

Some menopausal symptoms are similar to early signs of dementia. Laboratory studies and small trials have suggested a beneficial link between oestrogen and age related brain decline. However, the largest trial of MHT, the Women’s Health Initiative Memory Study, found an increased risk of developing dementia among users of oestrogen-progestogen treatments.

A recent large observational study in Finland flagged an increased risk of developing Alzheimer’s disease among users of both oestrogen-only and oestrogen-progestogen treatments, but the study had some methodological weaknesses.

To address this uncertainty, researchers at the Universities of Nottingham, Oxford and Southampton set out to investigate the risks of developing dementia for women using any of the menopausal hormone therapy treatments commonly prescribed within the UK National Health Service.

They used two UK primary care databases (QResearch and CPRD) to analyse MHT prescriptions for the 118,501 women aged 55 and older diagnosed with dementia between 1998 and 2020 (cases), and 497,416 women matched by age and general practice, but with no records for dementia (controls).

All information from MHT prescriptions issued more than three years before the case diagnosis was used, including hormone type, dose, and method of administration.

Other relevant factors, such as family history, smoking, alcohol consumption, pre-existing conditions (comorbidities), and other prescribed drugs were taken into account in the analysis.

Overall, 16,291 (14%) cases and 68,726 (14%) controls had been exposed to menopausal hormone therapy in the period up to three years before diagnosis.

After adjusting for the full range of potentially confounding factors, the researchers found no overall associations between use of hormone therapy and risk of dementia, regardless of hormone type, application, dose, or duration of treatment.

Within the subgroup of younger than 80 years who had been taking oestrogen-only therapy for 10 years or more, they found a slightly decreased risk of dementia.

However, an analysis of cases with a specific diagnosis of Alzheimer’s disease showed a slight increase in risk associated with oestrogen-progestogen therapy. This rose gradually with each year of exposure, reaching an average 11% increased risk for use of between 5 and 9 years and an average 19% for use of 10 years or more – equivalent to, respectively, five and seven extra cases per 10,000 woman years.

This is an observational study, so cannot establish cause, and the researchers acknowledge some limitations, such as incomplete recording of menopausal symptoms, particularly for women registered after their menopause, that may have affected their results.

However, the study used a large data sample from primary care records and was designed not only to assess overall risk for women exposed to different types of long term hormone therapy but also to explore the differences between component hormones, offering new, more reliable estimates for doctors and their patients.

The researchers say this study provides the most detailed estimates of risk for individual treatments, and their results are in line with existing concerns in guidelines about long term exposures to combined hormone therapy treatments.

“The findings will be helpful to policy makers, doctors, and patients when making choices about hormone therapy,” they conclude.

Overall, these observations do not change the recommendation that menopausal hormone therapy should not be used to prevent dementia, say US researchers in a linked opinion article. At the same time, it is helpful for providers to put dementia findings in context for patients, they add.

“The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason,” they conclude.


Formulations and Route of Menopause HT

Various formulations and routes are available to allow for an individualized approach to menopause care including estrogens, progestogens, and tissue selective estrogen complex (TSEC). Table 1 summarizes indications and contraindications for different formulations of HT.

Estrogen Therapy

Estrogen therapy alone is used for post-menopausal women who have undergone a hysterectomy (16). Estrogen formulations include human estrogens (17B-estradiol (E2), estrone (E1) and estriol (E3)), animal-derived estrogens (oCEE), and synthetic estrogens (ethinyl estradiol (EE)). The only FDA -approved, formulation of human estrogens is E2, which is the primary estrogen produced by the ovaries and most biologically active (16). oCEE is comprised of a mixture of estrogens derived from natural sources, such as the urine of pregnant mares (16).

Routes

Estrogens are well absorbed through the gastrointestinal (GI) tract, skin and mucus membranes. Formulations are available as oral preparations, transdermal patches, sprays, gels, topical emulsion preparations, vaginal preparations, in combination with progesterone, and in a TSEC (16, 18). Table 2 includes a comprehensive list of menopause HT available in the United States.

Oral Estrogen Therapy

In the US, oral estrogen therapy in the most widely used formulation. Estradiol is converted to estrone during first pass metabolism such that estrone is the major hormone found in the circulation (16). Risks of oral estrogens largely stem from first pass metabolism through the liver and include increased production of coagulation factors and various inflammatory markers, hypertriglyceridemia, and elevated risk of venous thromboembolism (VTE), and gallstones (16).

Transdermal and Topical Estrogens

Transdermal and topical estrogens bypass first pass metabolism so can be dosed lower than oral estrogen. Because of the avoidance of the first pass metabolism, they have less impact on triglycerides, coagulation factors and gallbladder disease (16, 18). Absorption varies based on how the patches and gels are applied. Transdermal therapy may not significantly increase VTE risk, in contrast to oral therapy, as seen in the Estrogen and Thromboembolism risk trial (19).

A single nested case-control study showed stroke risk was not increased with transdermal HT, while it was with oral HT. KEEPS, the only randomized control trial (RCT) comparing oral and transdermal estrogen, was too small to allow a comparative analysis of risks of stroke, VTE, or other clinical events (16, 20).

Transdermal estrogen patches have a higher likelihood of causing skin irritation compared to other topical or oral formulations. Topical formulations including gels, sprays and emulsions may lead to a small amount of estradiol transferred if skin-to-skin contact is made within two hours of administration (16).

Vaginal Estrogen Therapy

Low-dose vaginal estrogen therapy use is FDA approved to treat moderate-to-severe vaginal dryness and dyspareunia caused by GSM (13). It comes in multiple forms that are used vaginally including a cream, ring, tablet or capsule. Its primary mechanism is to locally treat postmenopausal vulvovaginal changes. It does not cause an increase in estrogen levels systemically above what is expected for a postmenopausal woman.

Estrogen acetate vaginal rings (Femring) are the only vaginal estrogen used to treat vasomotor symptoms with systemic absorption (16). Apart from estrogen acetate vaginal rings, progesterone is not necessary for use with vaginal estrogen formulations given minimal absorption and low risk of endometrial cancer (16).

Progestogen Therapy

Progestogen therapy is primarily used to avoid an increased risk of endometrial cancer for a woman on systemic estrogen, as unopposed estrogen thickens the uterine lining and increases risk of endometrial cancer. Progestogens protect against this endometrial thickening by decreasing estrogen receptors in target tissues and by inhibiting the luteinizing hormone surge that results in increased estrogen production from ovaries (16, 21).

Progestogens aid in the conversion of estradiol to estrone in the endometrium by increasing 17B-hydroxysteroid dehydrogenase activity. Estrone’s weaker estrogen activity results in less endometrial stimulation (16).

Progestogen options include micronized progesterone and synthetic progestins, such as MPA or norenthindrone. Micronized progesterone is bioidentical to the hormone made endogenously and has efficient oral absorption. It can also be given vaginally, as was done in ELITE (10). Compared to natural progesterone, synthetic progestins have 10-100- fold greater activity (16).

Progestogens come in oral and transdermal forms. The most commonly used and widely studied formulation of progestogens in the United States (US) is the oral progestin MPA. Oral progesterone has mild sedating effects, micronized progesterone significantly decreases VMS and helps with sleep (22).

Transdermal progesterones do not provide adequate endometrial protection so should not be used in combination therapy. The side effects of progestogen therapy include swelling and breast pain (more common with MPA), acne and hirsutism (more common with norethindrone), dizziness or fatigue, or adverse mood effects (23, 24).

Combination Formulations

FDA-approved combined estrogen-progestogen formulations provide adequate dosing of progestogen for endometrial protection, and include continuous-cyclic estrogen- progestogen, continuous combined estrogen-progestogen therapy, and intermittent combined estrogen-progestogen therapy (16). Continuous- cyclic estrogen-progestogen therapy includes daily estrogen dosing with progestogen added cyclically for 12 to 14 days per month or in long cycle formulations, every 2 to 6 months for 14 days.

Up to 80% of women on regimens that dose progestogens monthly have uterine bleeding with progestogen withdrawal. Those on the long cycle have less frequent withdrawal bleeding, though the uterine bleeding tends to be longer and heavier (16). Continuous-combined estrogen-progestogen therapy, the most commonly used formulation in North America, provides women estrogen and progestogen every day.

These formulations prevent withdrawal bleeding that occurs with cyclic formulations (16). Lastly, intermittent-combined estrogen-progestogen includes daily estrogen with cycles of progestogen for 3 days and off progestogen for 3 days. Trials have shown intermittent progestogen dosing results in 80% amenorrhea rates after 1 year (16, 25).

While various options of combined estrogen progestogen therapy (EPT) are available, no evidence supports one regimen over the other. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial showed that, among women with a uterus on estrogen therapy alone, a 34% increased risk of endometrial hyperplasia, was observed, while those on combined therapy had a risk of 1% (23). Continuous- combined EPT showed no increased risk and possible protection against endometrial cancer compared to the general population (26).

Uterine bleeding with use of EPT oftentimes results from withdrawal bleeding after progestogen cessation or breakthrough bleeding. Forty percent of women on continuous- combined EPT will have break through bleeding in the first 3-6 months (27). Breakthrough bleeding occurs more frequently in women who begin HT within 1 year of menopause.

Ultimately, most women on continuous EPT obtain amenorrhea (16). If women continue to bleed beyond 6 months of initiation of HT, they will need to undergo evaluation with an ultrasound and/or endometrial biopsy (28).

Tissue Selective Estrogen Complex (TSEC)


TSECs pairs a selective estrogen-receptor modulator with estrogen. The FDA approved medication marketed as DuaVee combines 20 mg bazedoxifene, a selective estrogen-receptor modulator, with 0.45 mg oCEE for use in postmenopausal women with a uterus. It is used for moderate to severe VMS and for prevention of osteoporosis.

Compared to placebo, TSEC had a similar profile in that it did not increase breast tenderness, breast density, or endometrial thickness; avoiding these conditions may be indications to use this therapy over other formulations. Amenorrhea occurs in more than 83% of users (29–32). It has not been studied regarding its ability to provide breast cancer risk reduction.

reference link : https://www.frontiersin.org/articles/10.3389/fendo.2021.564781/full


Original Research: Open access.
“Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases” by Yana Vinogradova et al. BMJ

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