Why acne, chin hair, and irregular cycles are more than an ovary problem [PODCAST]

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A condition named for the ovaries turns out to run through the muscle, the liver, and the pancreas. Insulin is the signal connecting them, and different organs hear it differently. Oluyemisi Famuyiwa, reproductive endocrinologist and founder of the Montgomery Fertility Center, returns to walk through it. This episode is based on her article “How insulin drives polyendocrine metabolic ovarian syndrome,” published on KevinMD. You will hear why the pancreas makes more insulin when muscle stops responding, and why the ovary and the liver are still listening when it does. You will hear what that does to androgen levels, and why acne, chin hair, and stubborn weight show up before irregular cycles. You will hear why body weight is a poor guide to who has PCOS, since lean patients carry the same elevated androgens and irregular cycles. And you will hear which tests she orders and why she works this across internal medicine and endocrinology. Press play for the reframe she leaves clinicians with: this is more than the ovary and more than insulin.

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast. Today we welcome back Oluyemisi Famuyiwa, reproductive endocrinologist, infertility specialist, and founder of the Montgomery Fertility Center. Today’s KevinMD article is “How insulin drives polyendocrine metabolic ovarian syndrome.” Oluyemisi, welcome back to the show.

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

Kevin Pho: All right. So this is the next article in a series of articles that you’re writing on KevinMD. Tell us what this one’s about.

Oluyemisi Famuyiwa: So this one, I thought I’d talk a little bit about how insulin plays a role, and it’s not the only role, in what we now call polyendocrine metabolic ovarian syndrome, and highlight the different effects that this could have on the disease entity itself and how it shows up in different women.

Kevin Pho: So polycystic ovarian syndrome, obviously, as you said, has been renamed recently, and I think on our last podcast we talked about some of the reasons behind that. So for our listeners who may not know, just give us a 30-second primer of why the name change. And then we’ll talk about your article itself today.

Oluyemisi Famuyiwa: I think the biggest reason they changed it is that when people emphasize polycystic ovary syndrome, it leads to a tunnel vision view of these women, who actually suffer from different entities. There are different organ systems involved. And when you narrow it down that narrowly, it leaves room for missing several things that may affect their long-term health, even beyond their reproductive years.

Kevin Pho: All right. So in particular, insulin. Tell us about the role.

Oluyemisi Famuyiwa: So we know that some women, not all, with polycystic ovary syndrome have a tendency to develop full-blown diabetes down the road. So then the question becomes, are they insulin resistant? You hear the word insulin resistance being handed out in social media and all that, but it’s actually more nuanced than that.

Insulin is not just about the blood glucose. It actually serves as a signal, and where that signal is heard can depend on which organ is listening closely. That’s the unique part. It’s not that there’s insulin resistance; the question is where it is being heard, where it is not being heard, and how that affects the disease entity.

Kevin Pho: So tell us the next step in the process. In terms of the insulin resistance, the signal being heard or not, how does that affect things downstream?

Oluyemisi Famuyiwa: Exactly. So what’s happening is that the role of insulin is to help you move glucose from your bloodstream into muscle when you need it, for instance. And so when your glucose level goes up, say you eat a high-carb meal, insulin goes up from the pancreas, and it’s going to carry some of this glucose and move it into muscle. Well, what happens is that in that channel where it goes into the muscle, through the receptor and post-receptor effect, there tend to be some downstream defects such that it can’t do that. It cannot respond to the glucose in the blood. That’s where the insulin resistance comes in.

But to understand the way insulin works, you have to understand that there’s something called a divergent pathway. There are more channels for insulin to produce its effect. Think of it as a river delta spreading out. That’s as many pathways as possible, and of these pathways, some are more enhanced in, say, muscle. Others are more enhanced in, say, reproductive organs.

So what happens is that if the muscle is resistant, if the key that the insulin uses, the doorway that it opens, is jammed and cannot pack that glucose in, the body is going to have a lot of glucose. But it still has a lot of insulin; it’s just not responding. The problem becomes that the pancreas thinks, “Wait, wait a minute. There’s too much glucose here. I need to make more insulin. This insulin is not enough.” So it dumps out more and more insulin.

The problem is that one of the pathways where insulin works in reproductive organs is at the level of the ovary. There’s a pathway of insulin that is still responsive to the insulin signal. So it’s not necessarily more responsive than before, but now you just have so much insulin, and that pathway, and some of it actually is also in the liver, results in growth. It produces growth, or it also produces androgens.

So what happens is that we know the brain controls the ovary. And one of the hormones from the brain, the LH, is responsible for the androgens that we make, the so-called male hormones. Insulin is like adding gasoline to the fire. It enhances the effects of androgen production. But at the level of the liver, it reduces the production of what we call sex hormone-binding globulin.

Why is that important? One of the ways to lower your androgen levels is to produce something called sex hormone-binding globulin, which latches onto your free androgens and effectively blunts them in the system. So if I want to drive your androgen levels up, a good way to do that is to force your ovaries to produce more androgens and then block the liver from making anything to help soak up these extra androgens.

Kevin Pho: So it sounds like this whole pathway starts when one of those paths, as you said, is blocked, right? Now, what are some of the reasons for that initial blockage? What are some risk factors? What are some reasons why this all starts?

Oluyemisi Famuyiwa: Which came first, the chicken or the egg? We know that there’s a vicious cycle, and once you start one vicious cycle, it just kind of propagates itself. We know that, for instance, when you have these so-called toxic fat cells floating around, free fatty acids, it may also enhance the blockage of glucose getting into the system.

So there’s a whole academic debate going on about which came first. We don’t know which came first in some areas. Some people suspect there’s a genetic defect at the level of the insulin receptor. Or could it be that you have inflammatory cytokines released from adipose tissue, or free fatty acids, that are causing this block? It’s very hard to pinpoint exactly what came first, but once you have the cycle going, it can propagate itself. So one of the things you can do is try to either unblock it or find a backdoor.

Kevin Pho: So it sounds like this change in the paradigm is going from polycystic ovarian syndrome to something more metabolic, more systemic.

Oluyemisi Famuyiwa: Systemic disease. Yes, yes.

Kevin Pho: Right. So from a practical standpoint, how does that change how you treat patients with this syndrome?

Oluyemisi Famuyiwa: So the first thing to do is not have a narrow vision of what’s going on in front of you. And you can’t even go by BMI. That’s a poor proxy of what’s going on with the patient. You may have to see what the presenting symptom is in this particular patient. Is it excess androgens? Do I need to target that? Is it metabolic disturbance? Do I need to target that with something like metformin that might create a backdoor for the glucose to get into the muscle? Is it exercise?

Now, with exercise, I don’t mean go be an Olympic athlete, but we do know that if you move your body a little bit, exercise is like a vitamin. It creates its own separate backdoor. Let’s say you have the GLUT4 glucose transporter that’s being jammed in insulin resistance. Exercise opens up a hatch door in the back through a cyclic AMP pathway. So you can still have the same correction, if you will, using exercise. So I tend to tell my patients, “Don’t think of exercise as work. Just think of it as a vitamin.” And that means that you don’t need to kill yourself out there. Go ahead and move. Do some movement. Walk around a little bit. Open that back door so that you can use up that glucose.

By categorizing it as a systemic illness, you can also look at things like whether there is anything going on with their pancreas, because the pancreas will always adjust for the poor insulin levels until it’s really bad. So you can’t really judge by that.

Now, one of the things we also look at is that we know this system can also affect the uterus. It can add gasoline to the fire of endometrial hyperplasia. Remember, the growth pathway is still open. And what else is it doing in terms of depression or other systems?

So what I do for my patients is try to listen to what the presenting problem is, and then try to work with my colleagues. I work with my internal medicine colleagues, I work with my endocrinology colleagues, because what we’re now seeing is that it’s multi-organ, and therefore it should be approached as a team effort.

Kevin Pho: So you mentioned metformin. Tell us, in this metaphor that we’re talking about today, you said that metformin can create a new pathway. Just give us maybe a 30-second pharmacology review of how metformin can do that. Also, from a primary care standpoint, when should one consider metformin in someone with polyendocrine metabolic ovarian syndrome?

Oluyemisi Famuyiwa: Now, again, you can’t just use fasting insulin or fasting glucose as a proxy. If you’re really, really concerned, you might want to get a two-hour glucose panel to really see it. Of course, some people may even argue that’s not accurate enough.

But metformin helps sensitize the body to insulin, so you might be able to correct some of this insensitivity before it gets worse. Metformin also helps at the level of the ovary. Metformin may help lower androgen production at the level of the ovary, because we know that the more androgens you have, the more it feeds into the vicious cycle as well. So you may be doing two things, working at the level of the liver, working at the level of the ovary, creating that balance.

Kevin Pho: So in my primary care setting, how do women typically present with this? What are some of the first symptoms that I should typically be looking out for?

Oluyemisi Famuyiwa: So women may present with acne, male-pattern baldness. Some of them may present and say, “Listen, doctor, I’ve tried everything. I just can’t lose this weight.” Or, “I’m noticing that I’m having to pluck more hair from my chin. What’s going on with me?” Later on they may start presenting with irregular cycles. Some of them may present with depression. We know there are mood disorders tied to these things. So when your antenna is raised, you can say, “Hang on a second. This is starting to fit a little pattern. Can we investigate a little more into this?”

Kevin Pho: And in terms of the diagnostic pathway, if I suspect this, what are some tests that we need to order?

Oluyemisi Famuyiwa: So I usually do a complete metabolic profile. I do look at free and total testosterone. I do look at levels such as androstenedione and 17-hydroxyprogesterone. I start out with a fasting insulin and glucose. I may escalate to other testing. I do look at a lipid panel as well, because we know that this entity may result in dyslipidemia. It may be involved.

So I do get that, and I can’t even tell you how many patients I see who do have this, and I tell them, “Oh my, we need to talk to your primary care doctor. We need to correct this path.” In addition to the reproductive hormones that I’m looking for, we do that on the second or third day of their period, but as you well know with PCO, their cycles may be irregular. So I don’t have to wait for a period. I do check those hormones as well.

Kevin Pho: In your article you also write that lean patients who don’t fit the usual picture can still experience polyendocrine metabolic ovarian syndrome as well, right?

Oluyemisi Famuyiwa: Exactly. So lean patients may have irregular cycles, may have elevated androgens. So they have hyperandrogenemia. They have irregular cycles. So we can’t just say, “Oh, it has to do with weight alone or BMI.” I think if our antenna is raised, no matter what the BMI of the patient is, if our level of suspicion is high, we can detect most of these patients earlier and save them the agony downstream.

Kevin Pho: We’re talking to Oluyemisi Famuyiwa, reproductive endocrinologist and infertility specialist. Today’s KevinMD article is “How insulin drives polyendocrine metabolic ovarian syndrome.” Oluyemisi, let’s end with your take-home messages to the KevinMD audience.

Oluyemisi Famuyiwa: Yes. I think the take-home message is that polycystic ovary syndrome, now PCOS, is more than just the ovaries. We shouldn’t just focus on the ovaries, because then we ignore other tissues that may be deleteriously affected. It’s more than just the ovary, and it’s more than just insulin.

Kevin Pho: Oluyemisi, great talking to you again. Thank you again for sharing your perspective and insight.

Oluyemisi Famuyiwa: Thank you.

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