Sweet spot for HRT may reduce dementia risk by nearly a third, study says

(CNN) — Hormone replacement therapy may protect the female brain from Alzheimer’s disease and dementia — if hormones are taken in the 40s and 50s when menopausal symptoms begin, according to a recent meta-analysis.

The degree of protection appears to differ by hormone type, the report found.

The average age of menopause onset — defined as when a woman hasn’t had a period for 12 months in a row — is 51, although women can naturally enter this phase between the ages of 40 and 58, according to The Menopause Society. Symptoms such as hot flashes, night sweats, sleep and libido disturbances, heart palpitations, and vaginal pain can occur for years in advance, in what is called perimenopause.

“There’s a window of opportunity,” said lead study author Dr. Lisa Mosconi, director of the Alzheimer’s Prevention Program and the Women’s Brain Initiative at Weill Cornell Medicine in New York City. “Hormones work best for the brain when taken in midlife in presence of menopausal symptoms to support women through the menopause condition.”

In fact, the brain has a higher chance of being protected if hormone replacement is started soon after menopausal symptoms begin, according to the analysis recently published in the journal Frontiers in Aging Neuroscience.

Length of time also matters: As long as a woman began hormones while she was in menopause, there was a 26% reduced risk of dementia if hormones were taken for more than 10 years.

However, if a woman began estrogen-progesterone therapy after the age of 65 or more than 10 years after the start of menopause, dementia risk rose, said Mosconi, a neuroscientist who is also certified in holistic health care.

“While there is not a clear one-size-fits-all approach, in the right woman, at the right dose, and for the right duration of time, I believe that hormone replacement therapy can be one of our most powerful tools to reduce a woman’s risk for cognitive decline and to slow down Alzheimer’s pathology,” said Dr. Richard Isaacson, director of research at the Institute for Neurodegenerative Diseases in Florida. He was not involved in the study.

“I believe this may be especially true for women with one or more copies of the APOE4 genetic variant, which is present in about 25% of people,” Isaacson said via email. “It’s essential for neurologists and primary care physicians to work closely with gynecologists … and monitor treatment outcomes over time.”

Hormone type counts, too

There is more to the story, according to current science. Just how harmful or helpful hormone replacement therapy may be also depends on the type of hormones that are prescribed, especially at older ages.

Estrogen-only hormone therapy can be prescribed if the uterus has been removed via hysterectomy. If the uterus is intact, however, a woman should use a combination of estrogen and progesterone or risk the possibility of uterine cancer.

For women in their 40s, 50s and early 60s, both types of hormones protected brain health, Mosconi said: “If you look at the data in midlife, both estrogen-only and estrogen-progesterone therapy are brain protective, which is the good news.”

In fact, people using estrogen-only therapy in midlife had a 32% lower risk of dementia, while using estrogen and progesterone provided a 23% risk reduction when compared with using no hormone therapy, the analysis found.

Estrogen protects the brain in several ways, according to science. The hormone is a “master regulator” in the brain, playing a key role in glucose uptake. Estrogen regulates cellular power plants that provide the body energy required for metabolism. The hormone also supports plasticity in the brain, allowing it to rewire, reorganize and make new connections.

“Estrogen is involved in a gazillion different things,” Mosconi said. “It pushes your neurons and brain cells to work harder, faster and better; it supports the synthesis of neurotransmitters like serotonin, which is key for mood, sleep and appetite; and it’s just as important for the immune system, including immunity inside the brain. It’s an anti-inflammatory hormone that doubles as an antioxidant.”

The role of the uterus

There is good news for older women as well, but only if they don’t have a uterus and are using estrogen-only hormonal therapy, Mosconi said.

“If you start taking hormones after age 65 or more than 10 years after the final menstrual period, then estrogen-only therapy doesn’t have any effects. The overall effect is neutral,” she said.

However, there is up to a 30% increased risk of dementia for women starting estrogen-progestogen therapy after age 65 or more than 10 years after the final menstrual period. Just how significant that risk may be, Mosconi said, is not yet entirely clear.

“It was borderline significant,” Mosconi said. “Studies are quite mixed: There’s a lot of evidence for protective effects and then for negative effects, but on average, the data seem to point to an increased risk of dementia.”

Why? It is possible progesterone has an “antagonizing effect” that may change or blunt the neuroprotective properties of estrogen, the study said. Or it’s possible emerging signs of dementia in the older brain, such as amyloid plaques and tau tangles, may influence the risk. More research is needed.

“What I find interesting is that all of the studies we examined that found a negative association with the use of estrogen plus progesterone, the women were on a synthetic form of progesterone,” Mosconi said.

Synthetic vs. bioidentical

There are two ways to replace progesterone. One way is by taking bioidentical micronized progesterone, which has a molecular structure identical to what is made in the ovaries. The other is to take a synthetic form of progesterone called progestin, which is similar to hormones made in the ovary but “not the same thing,” Mosconi said.

“There is some evidence that bioidentical progesterone is safer, and that synthetic progestins are what’s driving the increased risk,” she said. “However, we need more studies on that.”

Many doctors today prescribe bioidentical estrogen and bioidentical progesterone that can be delivered via transdermal patches on the skin, which Mosconi says is a safer route of administration.

“If you take hormones through the skin, the effect is a little bit gentler, because the hormones don’t have to be processed by the liver,” Mosconi explained. “If you take something by mouth, those hormones need to be processed through the liver and that can increase the risk of some cardiovascular issues.”

There is good news on the horizon for older women, Mosconi said. Scientists are developing a new generation of hormone replacement called selective estrogen receptor modulator, or SERM.

“These preparations are specifically engineered to target one organ — the brain. It’s kind of genius because you really want an estrogen that goes straight to your brain and does not impact your reproductive organs and raise the risk of cancer,” she said.

There will be no need to take a SERM estrogen with a progesterone, Mosconi said.

“Estrogen stimulates cell growth, which is linked with an increased risk of uterine cancer,” she said. “But if you have an estrogen that doesn’t even go to your uterus, then you don’t need the progesterone.”

Until science delivers on its promise, women should discuss their hormonal symptoms with an expert in menopause, experts say. Every woman is different, and what may be best for one’s brain health may not be an optimal solution for another.

In addition, some women are not candidates for hormone replacement therapy, perhaps due to family history, heart conditions or clotting disorders. For those women, there are vetted nonhormonal options to consider.

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