Hot flushes and the brain

Berga: Hot flushes may not be quite as common as people think. In one recent study of about 6,000 women in the age range of 46 to 64, only about half reported hot flushes.⁴ I counsel my perimenopausal patients that they can’t rely on hot flushes as a sign of menopause. Hot flushes aren’t necessarily reliable for titrating dosage of hormone therapy either. That’s worth noting, because a lot of physicians have been taught that if hot flushes go away, the dose they’re prescribing is correct.

Schiff: Are you suggesting that the dose may be right for one part of the body and perhaps not enough for another part? What do we know about that?

Berga: What we know now is that the hypothalamus, which is where hot flushes originate, contains estrogen receptors that are predominantly alpha receptors [ER]. Elsewhere in the brain and in other important body sites, estrogen beta receptors [ERß] are more common. That being the case, I don’t think we can conclude logically that if the hypothalamus is receiving the right estrogen dose, the rest of the body and the rest of the brain are receiving the right dose. A reduction in hot flushes means that the hypothalamic ER have been occupied to the extent that hot flushes are relieved. Because ER are coupled with tissue-specific proteins called chaperones and coactivators, this does not mean that the dose will be appropriate for other tissues. Other tissues have different ratios of ER and ERß and different tissue-specific chaperones and coactivators.

Nachtigall: Your point about estrogen receptors is well taken, Dr. Berga. Their numbers and function are different at every site where they’re found. So when you stop a woman’s hot flushes, you’ve taken care of the receptors in her hypothalamus but not necessarily the receptors in her pelvic area. Maybe she needs less estrogen in the pelvic area, or maybe she needs more. One size clearly does not fit all situations. It may be that more estrogen is required after surgical menopause or early in natural menopause to control symptoms but less is needed later on. You have to know what you’re treating and what dose or combination is appropriate.

That’s why I never talk about long-term treatment with patients starting out on HRT. I think it’s a decision that you need to revisit regularly—at least once a year. When Dr. Susan Love wrote her hormone book for the layperson, she said that gynecologists want to put women on estrogen and keep them there forever.⁵ That is simply not so. No one writes a renewal for 10 years.

Schiff: That brings us back to the original question of continuance. Whether the goal is control of hot flushes or something else, you’re going to sit down with the patient at least once a year and review her needs and options, aren’t you?

Nachtigall: Absolutely. We know how important it is at the start of hormone therapy to explain to the patient just what HRT does and why she needs to take her pills or apply her patch exactly as prescribed. In our first study of adherence, best continuance with HRT was achieved when women really had a chance to talk about how they felt on it.⁶ Were their symptoms better? Were they worse? Was one symptom being traded for another? Was there someone to talk to when there were problems or questions—if not the doctor, then at least the nurse?

If you can’t spend as much time with a patient as you’d like at the first visit, you can at least provide her with good reading material, such as the NAMS [North American Menopause Society] publications for consumers on menopause.⁷ Then you can go over any questions she has at the follow-up visit or over the phone.

Schiff: Usually women become interested in HRT because they’re seeking relief for their hot flushes. There are other agents that we could use, such as SSRIs [selective serotonin reuptake inhibitors], and one that has been shown to be effective is venlafaxine. But it appears that estrogen provides the most rapid relief. Do hot flushes present any danger to women other than the discomfort they cause? I’ve heard it said that they may cause destruction of neurons, but that appears far-fetched to me.

Berga: I’ve heard that claim too, but there are no published data I know of suggesting there’s a bona fide connection between hot flushes and irreversible brain damage.

Nachtigall: But hot flushes do have an effect on brain tissue. In his lectures, Dr. Fred Naftolin [Yale University School of Medicine] shows a PET scan of a woman’s brain during a hot flush, demonstrating that blood circulation is decreased dramatically. Then he shows a scan of the same woman’s brain after estrogen therapy has controlled her hot flushes. Now everything looks normal. The implication is that if this happens over and over—for example, in a surgically menopausal patient who has 40 or 50 hot flushes per day—and if it goes on for months without treatment, the brain may be compromised in some way. Since there are no data on that, we can’t say it will happen, but it is a possibility.

Schiff: I think the idea that hot flushes could be dangerous emerged when SERMs [selective estrogen-receptor modulators] were introduced. Because SERMs have been reported to sometimes increase hot flushes, some suggested that could ultimately affect cognition.

Berga: Hot flushes probably don’t affect cognition, but the fact that something other than estrogen is occupying ER might not be good news in the long run for the neurons that serve that important function. If something causes a lot of hot flushes and makes them worse, it’s probably an ER antagonist in the brain. We know that cholinergic neurons are heavily invested with ER. Since those are the neurons that subserve memory and learning, use of an ERa antagonist might alter their functionality or long-term viability. We have to wonder what the long-term impact would be on important central nervous system (CNS) centers, but it’s not the hot flushes that we should worry about. They’re just a sign that something is happening to ER.

Schiff: That might be a problem particularly for women on tamoxifen for breast cancer prophylaxis. Do you tell your patients on tamoxifen that this is a potential concern?

Berga: I don’t, since it’s still just a theory. In our institution, patients are usually started on tamoxifen by our medical oncologists, and they do a good job of explaining the pros and cons. The emphasis is on fighting breast cancer. When you’ve got hard choices to make, as breast cancer patients do, your first concern is not whether you’re going to have dementia at 85.

Nachtigall: Women on tamoxifen often have severe hot flushes for the first year, along with extreme vaginal dryness and discomfort. But they will continue with tamoxifen because they have been told it’s their best bet for avoiding more breast cancer. That’s strong motivation for continuance, and it works.