Medical science has now explained hot flashes — and help may be on the way

Menopause is hot … still … again … and always, as anyone who has experienced it knows (Menopause is having a moment, and many say it’s about time – YouTube). But there may be good news on the way for women who suffer from its most common symptom, hot flashes or flushes, if new drugs that tackle the problem in a completely new way pan out.

I complained in this space back in 2016 that hot flashes were a medical mystery (Why do hot flashes remain a medical mystery? | Carolyn Brown). Fortunately for me, my hot flashes were manageable and lasted only about seven years before dissipating. For some women, they can last up to 15 years and can cause difficulty with everyday life and severe effects such as insomnia.

But there has been a scientific breakthrough since then, and we now understand why hot flashes happen. I’m going to explain it, but you might want to take a deep breath, because it’s not simple. It’s neuroendocrinology.

The reproductive cycle

The following is heavily simplified for everyday readers.

In medical terms, hot flashes are “vasomotor symptoms” — meaning they involve the blood vessels constricting and dilating. It was clear that these symptoms were tied to the drop in estrogen that happens with menopause as the ovaries stop producing this important hormone. Women who have to have their ovaries removed at a younger age than normal menopause often experience very severe vasomotor symptoms after the abrupt cut-off of estrogen.

For the following, I’ve leaned heavily on a very good review article published in the journal Neuroendocrinology in 2019 (Neurokinin 3 Receptor Antagonism: A Novel Treatment for Menopausal Hot Flushes (karger.com)).

Before menopause, women’s reproductive systems go through their regular monthly phases thanks to a complex process involving nerves, peptides and hormones, all acting in a delicate choreography. It starts in the hypothalamus of the brain, where specific nerves release a hormone, gonadotropin-releasing hormone. This hormone reaches the pituitary, a gland involved in growth, metabolism and reproduction, where, in turn, it stimulates the release of two other hormones, follicle-stimulating hormone and luteinizing hormone. In the first phase of the monthly cycle, the follicle-stimulating hormone controls the ovary’s production of eggs. The luteinizing hormone triggers the release of the eggs from the ovary.

These hormones also lead to the release of two other hormones — estradiol (the most potent form of estrogen) from the ovaries and testosterone from the ovaries, adrenal glands and other tissues. These hormones signal the original nerve in the hypothalamus to cease production, and hormone levels drop throughout the chain. Then the cycle starts again. This process controls women’s monthly changes in an extraordinary way without which none of us would be here.

Why menopause causes hot flashes

The big discovery is about two neuropeptides in the hypothalamus that are really key to this process — kisspeptin and neurokinin B. They are the link between estrogen and the release of gonadotropin-releasing hormone. When estrogen levels are high, these two neuropeptides lower the levels of gonadotropin-releasing hormone.

The thing is, the nerves in the hypothalamus that produce (“express”) these two peptides are in an area of the hypothalamus responsible for regulating body temperature. One of the messages from this part of the hypothalamus reduces body heat through dilating blood vessels on the skin and sweating. In hot flashes, this message is sent from the hypothalamus when it shouldn’t be.

This is a side effect of the drop in estrogen when the ovaries stop functioning in menopause. Researchers believe that the loss of estrogen means that the other hormones are not controlled and therefore increase, changing the way that the two key neuropeptides work, leading the hypothalamus to send mistaken messages to reduce body heat.

During the process, neurokinin B binds to a receptor called the neurokinin 3 receptor. If this receptor could be blocked, the hot flashes would cease.

The search for new drugs

And that’s exactly what some new drugs in development do, quite successfully, according to initial tests in women with hot flashes. Two drugs have been tested. One reduced hot flashes by 73% (45% lower than placebo), and the other, by 93% (46% lower than placebo). Unfortunately, further studies of the first drug have been halted because of concerns about risks versus benefits. Studies of the other are proceeding.

The hope is that drugs targeting the neurokinin 3 receptor can reduce hot flashes substantially with few side effects. Currently, the best treatment for hot flashes is estrogen replacement, but estrogen — especially used over many years — can increase the risks of heart disease and certain types of cancer in menopausal women. The new drugs would not increase estrogen and would therefore avoid these risks.

If you’re suffering from hot flashes right now, don’t get excited. Years of testing are needed to ensure that new drugs are safe and effective. As we have seen, one potential drug has already been shelved. It will take time, but women in their reproductive years today may have better alternatives to ease their menopausal years.

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