Preventing memory loss

Schiff: Women fear breast cancer when they’re in their 50s, but as they get into their 70s or 80s they may become more concerned about losing their mental acuity. Dr. Berga, what’s your assessment of HRT’s effect on memory skills?

Berga: This is possibly the most difficult topic to study properly. You don’t see much memory loss that can be detected on simple tests until the late 70s. Testing for cognitive change is difficult. Even though a woman might report loss of memory or verbal fluency, she usually does well when you test her. The verbal or memory loss women sense they’re experiencing just doesn’t show up.

Schiff: Are you saying that there may be HRT effects on memory but that they take a long time to show up clinically?

Berga: There’s only one study with curves that demonstrate benefits of therapy for cognition, but those curves don’t start to segregate until after age 80.⁸ So a 3-year study of younger women isn’t likely to show differences, no matter what product you use. That was apparent in a recent study of memory in women in their 60s published in Fertility and Sterility.⁹ Predictably, there were few differences between hormone users and nonusers. The problem was that the subjects were 20 years too young.

On the other hand, studying older women whose dementia is well advanced is also unlikely to tell us much. A study by Mulnard and co-workers published in JAMA in 2000 is a case in point.¹⁰

Nachtigall: That’s right. There were MRIs of the women in that study showing their brains were damaged beyond repair. No therapy was going to help them.

Berga: Dead neurons don’t come back. It’s like trying to rescue the osteoporotic woman with vertebral compression fractures. You might be able to stop further compression fractures, but you’re not going to restore vertebrae that are already crushed. The dementia study was equally pointless in the sense that, realistically, you couldn’t expect to see improvements. Unfortunately, this study has been interpreted as providing evidence that estrogen has no potential for improving cognition or for protecting neurons, but it was not designed to study those issues.

Schiff: But if protective effects don’t show up clinically until women are older, how do you find evidence of that?

Berga: We’re focusing on biologic measures rather than clinical outcomes right now. Specifically, we’re looking at what brain parts respond to estrogen and how they respond. We chose serotonergic neurons to start with because they’re so involved in both mood and cognition. In the first part of our study, we determined what happens to serotonergic receptors when you give estrogen versus what happens when you give estrogen plus progestin in cyclic fashion.¹¹ We’re doing the second part of that study now to look at effects with a continuous combined regimen.

Schiff: Were these older women?

Berga: No. They were early menopausal women. Because we were measuring biologic changes, we didn’t want to study older brains that would already have undergone too much change.

Schiff: Did you get any definite answers?

Berga: Yes. For one thing, we looked at serotonergic binding in the cortical centers. In particular, we looked at the anterior cingulate cortex, which is at the medial edge of the temporal lobes bilaterally. It’s an integration station for limbic and cortical input and an important center for responding appropriately to social context. In women, it probably subserves functions like maternal behavior or social congruence, such as matching your words and the tone of your voice to your facial expressions. This center exhibited a huge amount of serotonergic binding after we gave estrogen. We also looked at the prefrontal dorsolateral cortex. That’s the “mistake” center.

Schiff: How does that work?

Berga: Let’s say I used the wrong verb in a sentence. That brain part will light up and flash the message, “You used the wrong word. Find the right one and substitute it.” It’s a very important part of the brain for monitoring output, and it was also heavily invested with serotonergic binding after we gave estrogen. This is a very integrated interpretation, drawing on more than our own studies, but it allows us to correlate what our biologic findings might mean in terms of clinical effects.

Nachtigall: Studying biologic effects is very important, and you can do that in younger postmenopausal women. At one point we wanted to study cognition in over-80 women living independently, but we found it was very hard to recruit them.

Berga: The ideal trial would be to randomize women at the time of menopause and look at them 35 years later, but there are things we can learn in the meantime by studying biologic changes.

Schiff: At what age do women start to complain of decreased memory for words, or going to the supermarket and forgetting what they came for?

Berga: For words, that starts very early—in the perimenopause.

Nachtigall: I agree. That’s one of the first things women in their late 40s complain of, even while they’re still having menstrual periods. Almost always they talk about forgetting names. They say, “I can see the face but I can’t recall the name, and I used to be good at names.” I hear that every day.

Schiff: Do they improve when you start them on hormones?

Nachtigall: I haven’t done a formal study of that, and as Dr. Berga said it’s difficult to study. But my clinical impression is that they do improve if you start them early. There’s less response in women who start HRT 5 years or more after the menopause than in women who start right away. I think this may have something to do with effects on ER, as Dr. Berga suggested earlier. Memory loss may have nothing to do with hot flushes per se, but hot flushes may be a marker for other effects on the neurons. Perhaps if you treat early you can save those neurons and if you don’t treat early you can’t.

Berga: I think there’s also a lot of variability in risk for neuron loss just as there is for bone loss. Women differ in their risk for osteoporosis because they arrive at menopause with different bone densities. In the same way, women arrive at menopause with different brain reserves. If we could do a large population-based study of verbal fluency we might find that a certain percentage of women, say 10%, had severe dysnomia as a consequence of menopause. We could then take those dysnomic individuals and see if estrogen would improve them. But those studies have not been done.

Schiff: Studies of older women with Alzheimer’s disease have shown that estrogen has little or no effect on their cognition. On the other hand, I think we’ve all observed that early postmenopausal women given estrogens have an improvement in memory, at least for certain things. But whether they improve because their brain function is better or because they are sleeping better or can focus better after a reduction in hot flushes is difficult to say. Then there are all the women between those two extremes that we know even less about. How do you decide whether HRT is appropriate for brain function, Dr. Berga, or is it always appropriate?

Berga: I would say that a brain that’s in distress is a brain that clearly should get HRT, just as a skeletal system beset by severe osteoporosis clearly needs treatment. Deciding on therapy is easy when women have hot flushes or serious sleep disturbances. It’s more difficult with patients who are relatively asymptomatic. If a woman is feeling fairly good and we start her on something that doesn’t make her feel any worse but may not make her feel any better, there’s no strong motivation for continuance.