Why PCOS may start in the brain, not the ovary [PODCAST]

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A hormone doctors use to estimate how many eggs remain may also be acting on the brain. Oluyemisi Famuyiwa is a reproductive endocrinologist and infertility specialist. This episode is based on her article “The brain signal that drives polycystic ovary syndrome,” published on KevinMD. You will hear why anti-Müllerian hormone, or AMH, runs high in polycystic ovary syndrome, now renamed polyendocrine metabolic ovarian syndrome, and why new guidance lets doctors use age-adjusted AMH in the diagnosis. She explains the 2016 discovery of AMH receptors in the hypothalamus, and how a revved-up GnRH rhythm tips the pituitary toward LH and the ovaries toward androgens. She describes mouse studies in which blocking the AMH signal reversed the pathology, and early work on fezolinetant, a menopause drug with liver toxicity. Press play to hear why she hopes this condition may one day be treated at the level of the brain, and tailored to each patient.

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A note from Dr. Famuyiwa: When discussing AMH, I said it “doesn’t tell us anything about the quantity.” I meant quality. AMH is, of course, used as a marker of ovarian reserve/follicle quantity.

Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today, we welcome back Yemi Famuyiwa, reproductive endocrinologist and infertility specialist. Today’s KevinMD article is “The brain signal that drives polycystic ovary syndrome.” Yemi, welcome back to the show.

Oluyemisi Famuyiwa: Thank you. Thank you for having me.

Kevin Pho: All right. What’s your latest article about?

Oluyemisi Famuyiwa: Well, my latest article is about another effect of AMH that we don’t usually talk about and that most people are not aware of.

Kevin Pho: And AMH is anti-Müllerian hormone, right?

Oluyemisi Famuyiwa: Anti-Müllerian hormone. OK. Most people are aware of AMH as a literal dipstick to figure out whether the ovaries still have any follicles or eggs left in them. And most people, and probably most doctors too, are not aware that it has a secondary function in the brain. So I thought that was very exciting and interesting to talk about and to delve into a little bit.

Kevin Pho: All right. So bring us all to the same page. Give us a little bit of a physiology lesson in terms of what anti-Müllerian hormone is and what it does in the body.

Oluyemisi Famuyiwa: Yes. I won’t take you all the way back to the genesis, but the name means it inhibits the Müllerian structures, the female parts. So in a fetus, it’s what helps make sure that you develop male organs or female organs, because in men it makes the uterus and all that regress. But we also know that it is produced by the small follicles that are still left in the ovary. So we use it as a sort of backward feedback loop to count how many follicles, and thereby how many eggs, you still have left. It doesn’t tell us anything about the quantity. So the more follicles you have, the higher your AMH levels, right? So in the past, we’ve used it as a sort of gauge, a dipstick to look at the ovary. That’s what most people are aware of.

Kevin Pho: When do you typically order an anti-Müllerian hormone level?

Oluyemisi Famuyiwa: I usually just get it when I do my hormonal testing. It doesn’t really fluctuate with the menstrual cycle that much. It can be temporarily suppressed by birth control pills, only because the more follicles you have, the more AMH you have, and the fewer follicles you have, the less AMH you have. And I would normally check it in most of my patients. The funny thing, though, is that in PCO patients, it can be elevated for a separate reason.

Kevin Pho: All right. Tell us more about that. Polycystic ovary syndrome, and it has a new name now, right?

Oluyemisi Famuyiwa: Yes, PMOS. It’s taken me a while to go from polycystic ovarian syndrome to polyendocrine metabolic ovarian syndrome. It’s a tongue twister.

So in PMOS, it’s not pathognomonic, but in PCO, you tend to have a lot of immature follicles that are blunted in their growth, right? Normally, you have a small follicle growing in the ovary, it gets big enough, the brain causes ovulation, and it goes out. Well, in the ovary of PCO patients, some of these follicles are blocked from going from that medium size to the size where they’re big. So in PCO patients, you have those intermediate-sized follicles, and they back up. When you look in the ovaries, you might see them as small follicles, and that’s where most people thought the name came from, because you see them as round little holes.

So now, because those follicles are blocked, they back up. Think of a conveyor belt. You’re moving eggs: They’re small, they get big, they ovulate. But somebody puts a brake on the conveyor belt. Now all these follicles are blocked over here. They can’t go anywhere, but they’re producing AMH. So your AMH levels in this condition tend to be higher than you would normally see, as a function of those small follicles being there.

Kevin Pho: Now, in terms of diagnosis and treatment, is it pathognomonic? Is it a screening test? What’s the relationship as it relates to PMOS?

Oluyemisi Famuyiwa: As it relates to PMOS, there’s new guidance. They can’t give us a real number to say, “Oh, beyond this number, it is PCO, and below that number, it isn’t.” That’s because the assay may vary from region to region, and AMH may be higher in younger women than in older women, right? So you can look at it on an age spectrum and say, OK, if you are, say, forty-four and you have an AMH of five, that is very high for a forty-five-year-old. That might be someone with PCO. But if you are, say, twenty-six or thirty, your AMH might be ten or something like that. So that’s where the new data says we can now introduce AMH into our algorithm when we’re making the diagnosis, age adjusted.

Kevin Pho: So in your article, you talk about how AMH is changing the paradigm, right? The fact that AMH is being influenced by the brain. So tell us more about that.

Oluyemisi Famuyiwa: Yes. So here’s the key thing. The question is, is it the chicken or the egg? We know AMH is high because the follicles are blocked, right? The unique thing is that there was a study in Nature Communications in 2016 where they located AMH receptors in animal brains, in mouse studies, and then they looked in the human brain, and they found that in the arcuate nucleus, in the hypothalamus, there are receptors for AMH. And these receptors can be affected by rising levels of AMH, right? So it’s really interesting.

Now, to understand why we’re so excited about this, you have to understand the way the brain works in PMOS patients. The brain sends a signal from the hypothalamus to your pituitary gland. That signal is called GnRH, gonadotropin-releasing hormone. It goes to the pituitary and causes the pituitary to release FSH and LH, which go to the ovary. FSH and LH are what control follicular growth, and then when you have an LH surge, you ovulate. Everything has to work on a nice rhythm.

The thing with GnRH is that it has a tonal pattern to its release, right? It doesn’t release in a constant manner. So if you’re a musician and you put on a metronome, your GnRH has to work like a tick-tock, tick-tock, tick-tock. And when it does that, you produce more FSH relative to LH, OK? In PCO, that tonality has been revved up. It’s like somebody cranked up the frequency. So instead of tick-tock, tick-tock, you’re going tick-tock-tick-tock-tick-tock-tick-tock. And when you release GnRH in that fashion, a funny thing happens at the level of the pituitary: Instead of producing more FSH relative to LH, you produce more LH relative to FSH. So we’ve known for years that PCO patients have elevated LH, but it’s really interesting to take it all the way back to the brain.

Now, the funny part is that when your LH is high, your ovaries produce more androgens than they should, and more androgens also tend to block the progression of the same follicles that we’re talking about. The interesting thing is that when they found AMH receptors in the brain, they did animal studies where they proved that if you gave AMH to the brain, you could actually take this metronome up to a higher level. So the curious question is whether AMH, the lowly AMH that we’ve been worried about for the ovaries, may be doing something in the brain that we don’t fully understand. And this AMH may actually be part of what is instigating or maintaining this phenomenon we now call polyendocrine metabolic ovarian syndrome, right? So AMH may be central to maintaining this vicious loop.

Kevin Pho: So you mentioned that AMH can be measured in various age groups of patients, with age-adjusted interpretations. So what does this mean for future treatment of PMOS, and what can clinicians tell patients now as it relates to AMH?

Oluyemisi Famuyiwa: Yes, and that is the exciting thing about this, right? Now, these are all still investigational, right? There are other aspects of PMOS that you can also work on. But they went further. There was another study where they said, “OK, if the AMH going to the brain is causing it to fire abnormally, how about we give a blocking antibody to prevent that signal?” So they did that in mice, and they found that in PCO-induced mice, they were able to reverse the pathology. They were able to bring down the tonality of LH and resume the estrous cycle. There’s no human data yet, so they’re still investigating it. And if that works, we may have something that would also help us treat PMOS at the neuroendocrine level.

The other thing they’re investigating: We know that the metronome is out of whack in PCO patients, so how about we block the metronome? You could block the AMH receptor that’s affecting the metronome. You could also block the metronome from being activated. You could block neurokinin B, which is part of the kisspeptin, neurokinin B, and dynorphin system. Neurokinin B is the accelerator that pushes it hard. So if you give something that antagonizes that, can you slow it down? That has been studied, and there’s a medication currently approved for menopausal patients, called fezolinetant, that they’re now studying to ask, “Well, can we use this to slow down this activity?” It’s investigational. There are other things. The downside to this medication is that it does have liver toxicity, and that’s why you’re not seeing any widespread adoption of it. But we’re on the right path. All these things are coming up in the pipeline.

Kevin Pho: As far as you know, is anything specifically targeting AMH in the brain? You mentioned that one investigational drug. Are there more things coming down the pipeline, or are we still very early in the research process?

Oluyemisi Famuyiwa: I think we’re still early in the research process. I don’t think we’ll see it. Clinically, if you see it, it will be more in clinical trials, right? They would want to establish safety parameters before they give it to the general population.

Kevin Pho: We’re talking to Yemi Famuyiwa, reproductive endocrinologist and infertility specialist. Today’s KevinMD article is “The brain signal that drives polycystic ovary syndrome.” Yemi, as always, let’s end with your take-home messages to the KevinMD audience.

Oluyemisi Famuyiwa: I think the take-home message is that I’m very excited about all these new things coming out, and that we may be able to finally treat this condition at different levels. We also have to target it, because not every PMOS patient behaves the same. If all this pans out, we can now tailor treatment to the specific abnormality for each of these diverse patients. So that’s exciting.

Kevin Pho: Yemi, as always, thank you so much for sharing your perspective and insight, and thanks again for coming back on the show.

Oluyemisi Famuyiwa: Thank you so much, Kevin. My pleasure.

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