The Menopause Brain

by Lisa Mosconi

women’s brains are hardwired to receive estrogen.

menostart as an alternative to menopause. This word seems apt for the many women who experience this life transition as a turning point, after which their interests, priorities, and attitudes shift in a positive way. A second adulthood, if you will, or a renaissance of sorts is entirely possible.

grandmother hypothesis proposes that ceasing reproduction around age fifty, and living to tell the tale, allowed older women to devote care and resources to their children’s children rather than birthing and nurturing new ones themselves.

Women’s Health Initiative (WHI). It was a federally financed examination of HRT started in the early nineties, extraordinary in both its scale and ambition: almost 160,000 postmenopausal women were enrolled in a multiyear comparison of estrogen pills with or without progesterone versus placebos. The goal was to provide conclusive evidence as to whether all this widescale prescribing of HRT was indeed a sound idea, with a particular focus on preventing heart disease. But on July 9, 2002, WHI investigators made the shocking announcement that they were pulling the plug on the trial three years earlier than planned. As it turned out, HRT was “too dangerous” to the participants’ health to proceed. The women on hormones had more heart trouble than their placebo-taking counterparts, instead of less. Their risk for stroke was on the rise, too, as was their risk for blood clots and breast cancer. Just as surprisingly, even their risk of dementia had gone up. Somehow HRT was doing precisely the opposite of what was intended and then some.

you possess a uterus, then you will receive both estrogen and a progestogen (a generic term including different types of progestogenic preparations).

However, the risk of breast cancer was increased only for women taking the estrogen-plus-progestin therapy.

Conjugated equine estrogens. The kind of estrogen used in the WHI trials is called conjugated equine estrogen, or CEE. CEEs are a concentrated formula manufactured from the urine of pregnant horses, which typically contains more than ten different forms of estrogen, mainly estrone, and smaller amounts of estradiol.

Estradiol. Today, estradiol itself is available, and is called micronized estradiol. It typically comes from yam whose molecules have been tweaked until they are atom-for-atom identical to our ovary-produced estradiol. For this reason, it is also referred to as bioidentical, or body-identical estrogen.

Although clinical trials have yet to examine transdermal estrogen thoroughly, observational data suggest that it is less risky as compared to oral estrogen delivery.

MPA (medroxyprogesterone acetate), and it has a problematic backstory of its own. Although MPA had the uterine cancer risk covered, there’s reason to believe it may have been a factor in the higher risk of breast cancer.

Currently, there is little evidence that the combination of bioidentical estrogen and progesterone increases the risk of breast cancer. As a side note, while estrogen can be given in different ways, progesterone is typically given orally.

fact, many scientific studies have clarified that HRT works best while our bodies are still receptive to estrogen. This receptivity occurs when a woman is in the thick of menopause, and may extend as long as symptoms persist, but not long after that period.

During this critical menopausal window, estrogen can improve and protect cellular health throughout the entire body. However, if given long afterward, estrogen may no longer have the power to strengthen or repair, but it may potentially cause detrimental effects.

dozens of studies since then have provided reassurance that for healthy women experiencing the symptoms of menopause, the benefits of taking hormones—given at lower doses and often via the transdermal route—generally outweigh the risks.

Scores of scientific studies have shown that HRT started at the right time can lessen the symptoms of menopause while also potentially protect against heart disease and other chronic conditions.

When estrogen is given to perimenopausal or recently postmenopausal mice, it spurs cell growth, supports brain function, and can even prevent the formation of Alzheimer’s plaques. But when given too long after menopause, HRT provides no benefit and may be harmful to the animals instead.

However, in actual numbers, taking HRT resulted in only 8 more cases of breast cancer in total. So another way to think about this is that for every 10,000 women taking hormones (i.e., that specific combination of oral CEE plus progestin), an additional 8 developed breast cancer.

Dr. JoAnn Pinkerton, executive director of the North American Menopause Society, “Most healthy women under age 60 or within ten years of having their last period can take hormone therapy without fear if taking estrogen alone or combined with progesterone.”

This is contingent upon there being no previous history of breast cancer, as the risk of cancer reoccurrence remains a concern.

Importantly, having a family history of any of the above conditions is not a contraindication, though it warrants medical review. To clarify this concept, hormones are not usually recommended if you personally have (or had) estrogen-dependent cancer—not because someone in your family has (or had) breast cancer.

VASOMOTOR SYMPTOMS

In clinical trials, both estrogen-alone and estrogen-plus-progesterone regimens reduced the number of hot flashes by about 75 percent while also reducing their intensity. Transdermal formulations seem to be as effective as oral options.

low-dose vaginal estrogen has not been linked with an increased risk of cancer.

While more rigorous research is needed, HRT seems to help with brain fog and forgetfulness, at least for some women.

we don’t know whether other HRT formulations might yield different results and that the women to test are the ones in the thick of menopause, not those decades past it.

Nonetheless, reexaminations of the fewer younger women (those fifty to fifty-nine) included in the WHI provided important evidence that HRT started in midlife may indeed help to reduce the risk of dementia. Results show that, as these women got older, those taking estrogen in midlife didn’t develop cognitive declines nearly as often as those given a placebo. Several observational studies report similar findings, prompting many clinicians to advocate for taking HRT during perimenopause or early menopause to sustain neurological health in older age.

PhytoSERM.

2022, in collaboration with Dr. Brinton, we launched an NIH-sponsored, randomized, placebo-controlled clinical trial (read, a very thorough clinical trial) to test PhytoSERM for support of brain energy and cognitive function in perimenopausal and early menopausal women. This launch shows exciting promise. With clinical validation, we are hoping this estrogenic formulation will prove valuable not only to address the symptoms of menopause but also to provide extra protection for our brains, shielding them against dementia in particular. The trial results should be available around 2025, which, judging by how fast time is flying, is right around the corner.

Several studies indicate that hormone therapy is viable for women who have genetic mutations or a family history of breast cancer, but do not personally have the cancer.