PCOS, Anovulation and Infertility

Podcast Transcript

Erica Newlin, MD:

Welcome to OB/GYN Time, a Cleveland Clinic podcast covering all things obstetrics and gynecology. These podcast episodes are intended to help you better understand your health, leaving you feeling empowered to live your best. We hope you enjoy today's episode.

Hi everyone, I'm your host, Erica Newlin, MD. Welcome to our third episode of OB/GYN Time. During this season, we are focusing on topics related to infertility. On this episode, I'd like to welcome back Jenna Rehmer, MD, who will be talking with us about PCOS and infertility. Dr. Rehmer, to those listeners that missed you in the last episode, can you tell us about your role in the Cleveland Clinic and a little about your background?

Jenna Rehmer, MD:

Yeah, of course. Thanks so much, Dr. Newlin, for having me back again. It's always an honor to be here, and to be able to talk about fertility this season. I am an REI Physician. So, REI stands for Reproductive Endocrinology and Infertility. REIs our double boarded in both OB/GYN and REI. So, we spent the first four years of our training focusing on OB/GYN and then transitioned to a three-year fellowship in REI. So now my practice focuses almost solely on getting women pregnant, or issues related to fertility, and the hormonal implications of some other diseases as well too, such as our topic here today, which is PCOS.

Erica Newlin, MD:

Let's talk about ovulation and a normal cycle. What's the ovary doing each month?

Jenna Rehmer, MD:

Yeah. So, every month there is a little group or a little cohort of follicles that kind of rise to the surface in the ovary. And these contain eggs, and each one of them is available to be stimulated to grow. Our brain sends down a signal from a little gland inside the brain. And that signal is called FSH or Follicle Stimulating Hormone. It sends it down and the ovary responds typically by just growing a single follicle or a single egg out of that little group or cohort that presented itself. This will grow large for a couple of weeks. In the most classic cycle, which is the textbook cycle of 28 days, it typically grows for about the first 13 to 14 days. As it's growing, the egg inside of it is maturing, and it's putting out the hormone estrogen.

Estrogen has two roles. One is that it acts on the lining of the uterus and tells that lining to start to grow thick and to prepare itself for a possible embryo to come along and implant. And its other job is to send a signal back to the brain, to let the brain know that hey, that signal you sent down, that FSH, it's doing its job, it's working, I'm growing a follicle and responding just like you told me to. Once that estrogen reaches a certain level, kind of a critical threshold, it then triggers the brain to send a different signal down called LH.

LH is the luteinizing hormone, and it is the signal for ovulation. So many women who are focusing on fertility may be testing for LH in their urine in the mornings on the sticks to look for the ovulatory surge. This signal causes that follicle to rupture open and to spill its egg out or otherwise known as ovulation. Once ovulation occurs from that follicle, that follicle continues to produce hormones, and it starts producing a new hormone of the cycle called progesterone. That progesterone starts to rise a few days after ovulation. And its job is to help stabilize the lining of the uterus and to prepare it even more so for pregnancy to come along and implant.

That follicle that ruptured open and is producing progesterone can only survive for a set amount of time, it typically only puts out hormones for around 12 to 14 days. So, after that timeframe, if pregnancy has not occurred, and the pregnancy is not producing progesterone, then the progesterone goes away in the female body. And so, what we see at that point is that the lining, which was previously being stabilized by progesterone, will start to kind of become disorganized and begin to shed and that's when the period comes. So, this is the classic 28-day cycle, 14 days to prepare, ovulation occurs, 14 more days to allow for pregnancy to set up. And if it doesn't, the period comes again. And you start the process all over.

Erica Newlin, MD:

Yeah. And you mentioned that's the textbook's normal but there can be some variation between people.

Jenna Rehmer, MD:

Yeah, we see a range and what is quote, unquote, normal. And most classically, it kind of ranges. There's different text that quote different things and different studies that have shown different variations of normal, but I normally like to think somewhere between 25 to 34 days can be normal. It's not true for everyone. So, someone might have a 26-day cycle, but ovulate really late in that cycle, like not till day 18. And that's not normal. Whereas if somebody has a 26-day cycle, but they ovulate on day 12, that can be very normal. So, there's more to it than just the number of days that make it regular. But we typically start with a range of somewhere between 25 to 34 days.

Erica Newlin, MD:

Great. And when Dr. Hur was here, she really mentioned the value of that menstrual diary.

Jenna Rehmer, MD:

Yes.

Erica Newlin, MD:

And keeping track of things.

Jenna Rehmer, MD:

Yeah, absolutely. I think especially in a patient who is considering fertility or wanting to start to become more proactive about their fertility, seeking, you know, either using an app or a calendar or just writing things down on a piece of paper in a journal or phone can be really helpful for tracking, it's hard to look, you know, look back retrospectively and like remember, Oh, when did I get my period? But if we keep track of it, it makes it a lot easier. And then when you come to see your OB/GYN, or a fertility doc, if you're fertility seeking, it gives you an opportunity to really kind of digest and dig into those cycles and find out what, whether or not they're normal.

Erica Newlin, MD:

What kind of cycles might make you suspicious of polycystic ovarian syndrome?

Jenna Rehmer, MD:

The most classic cycle in a patient who has PCOS is that they don't ovulate regularly. And ovulation is what drives the period coming and what drives the lining to shed each month. So, if you don't ovulate, you typically won't get a period. Now, sometimes women who don't ovulate get what we call anovulatory bleeding and anovulatory just means not ovulating bleeding. So, it's bleeding related to not ovulating. And that can still happen, but it's not as classic of a period. So oftentimes women will describe it as like two or three days of like a weird spotting, that goes away and like a week later, it comes back and they have a few more days of spotting, and then it goes away. And then they may go for like two months with no bleeding. And then all of a sudden, they have a very heavy period, like way heavier than what they classically see.

So that's concerning for what we call oligomenorrhea, which is a fancy term you might see out there if you're looking at PCOS online, or reading up on it, and it just means that periods are spaced out further than what is classical. So, in PCOS patients, we normally see periods that are greater than 35 days apart. 

Erica Newlin, MD:

And then we went through the regular cycle of an ovary and what it looks like each month, what would you see in a polycystic ovary?

Jenna Rehmer, MD:

Yeah, so a polycystic ovary can do a couple of different variations. One is that it doesn't respond as well to the hormonal signal that causes a follicle to grow. And so, you may see on ultrasound, that there are a whole bunch of really small follicles, classically more of those than in a woman who doesn't have PCOS. And we'll talk more about that in a moment. But you may find that there are no follicles growing. So rather than seeing a single dominant follicle preparing to ovulate, they may have no growth of anything happening. Alternatively, they may have follicles that grew but never ovulated. So, they had a follicle that responded to the stimulation to grow and perhaps the egg in it was preparing to become mature and to get ready to ovulate. But then the signal that forced ovulation never was quite sufficient to cause ovulation to happen in these women.

Erica Newlin, MD:

So, when we're talking about the term polycystic ovaries, is it less about cysts than those follicles?

Jenna Rehmer, MD:

Yeah, so this is a very common question I get and what I tell patients is that a follicle is a cyst. So, a cyst is just a medical term for any fluid filled containing structure. So, a follicle is a cyst because it is a structure that on ultrasound when we look at it, it is circular and round and it contains fluid in the center and it shows up on ultrasound as looking as if it has fluids, so we call them cyst, we call them follicles. The names are interchangeable. All follicles are cysts, not all cysts, though, are follicles. So, a cyst can be very benign, nothing to worry about like a follicle, or it can be other things that are more concerning. In our prior episode we talked about endometriomas. Endometriomas are a cyst of the ovary that's caused by a disease called endometriosis. So, this is another type of cyst. So, this is where the word cyst doesn't mean as much to me as knowing what type of cyst that it is.

Erica Newlin, MD:

I hate the term polycystic ovary. I feel like it's very confusing.

Jenna Rehmer, MD:

It's one of the first things I tell my patients when I'm telling them about the disease process. I say somebody, you know, 30, 40 years ago came up with this name based upon what they were seeing on ultrasound. But in reality, the ovary's not the bad actor here. And so, the ovary is just showing symptoms and signs of this overall systemic disease of polycystic ovarian syndrome. And I really wish we could come up with a new name for it.

Erica Newlin, MD:

And let's talk about how it is diagnosed and what you'd see.

Jenna Rehmer, MD:

So, in order to diagnose PCOS, you have to have two out of three things. So, they're the three things that allow us to make a diagnosis. The first one is what we've already been talking about, which is irregular cycles. So, patients have to have the majority of their cycles being greater than or equal to 35 days in length, or less than eight periods a year. And that's how they get diagnosed with oligomenorrhea. So that's the first criterion. The second one is on ultrasound; we see signs of polycystic ovaries. So, we see ovaries that contain polycystic. Poly just means an increased number of, and the cysts are these follicles, so women with PCOS have a higher number of egg follicles in their ovaries than other women. These little egg houses on average, typically number less than 12 in each ovary. So, if we see greater than 12 in each ovary, then we're concerned about polycystic ovarian syndrome.

The third diagnostic criteria that is part of making the diagnosis of PCOS is signs of what we call hyperandrogenism, which is a fancy way of saying on lab work or blood work, we see signs of increased testosterone. So, in women, the ovaries make testosterone, and we convert it to estrogen and polycystic ovarian syndrome. The ovaries are larger in these women than women who don't have PCOS, they often produce a higher rate of testosterone. And sometimes we can see that with signs or symptoms on physical appearance like increased cystic acne or adult acne. Sometimes they may have an increase in facial hair along their upper lip or chin, sometimes on their belly area. And sometimes even at extremes we see things like male pattern balding. When levels are getting that high, though, we start to like to think about, could there be other causes other than just PCOS?

Erica Newlin, MD:

And you just mentioned three very specific criteria. But it seems like a lot of people fall on that anovulatory spectrum but may not fit the criteria for PCOS.

Jenna Rehmer, MD:

Hmm. So, there can be other causes of not ovulating. So, we have to rule out these other things too. So that's a very important part of making the diagnosis is we have to make sure that other causes of not ovulating have been excluded. So, these things include things like checking thyroid level, thyroid is known both in the hyperthyroid and the hypo, so both high and low states to cause issues with the regulation of the period. So, we want to rule that out. We often also check another hormone level that's secreted from the brain called prolactin, we want to make sure that that's not a bad factor causing issues with the regularity of cycles. And then we also know that other things that cause insulin resistance in the body such as obesity and diabetes can also contribute to not ovulating regularly.

Erica Newlin, MD:

And on that topic, as gynecologists we focus a lot on the ovulatory aspects of PCOS. But I think there's been more and more attention paid to the metabolic aspects. Can you discuss that briefly?

Jenna Rehmer, MD:

Yeah, and this is why I hate the name PCOS, because PCOS really kind of points the finger at the ovary as being the problem when in reality, the underlying issue with PCOS, at least what we think to be the biggest bad actor is insulin resistance. So, women can have PCOS and... Well, let me back up. When we hear the term insulin resistance, I think most classically, patients start to think about diabetes, but patients can have PCOS and not have diabetes, but they do run together. So, you're at a higher risk of developing diabetes over your lifetime if you're known to have PCOS because of the underlying insulin resistance. That insulin resistance is felt throughout all cells of the body. And the way that the ovary responds to that resistance is by not growing follicles and not ovulating as well. So, things that we can do to help improve insulin resistance, also, in the long run, improve fertility by improving ovulation. So that's often part of my conversation with patients who have PCOS, is that we're gonna work towards improving overall insulin resistance in the body to help improve fertility and ovulation.

Erica Newlin, MD:

And what do you recommend?

Jenna Rehmer, MD:

Yeah, it depends. So, there's a couple of different what we call classic presentations or phenotypes of PCOS. So, some women who have PCOS, present with a very normal BMI, they may be athletes, they've, you know, worked out their whole life, and they've maintained kind of a normal body composition of fatty tissue. And so, we know that there's insulin resistance in their body because of PCOS. But they've kind of already optimized weight and these types of things, and oftentimes, like altering that, working out more diet in these types of patients, don't tend to show a significant improvement. And so that's were doing things like being on certain supplements or using medications to help with ovulation, which we'll go into more detail about can help improve their fertility.

And other patients who have PCOS, what we kind of see is a more classical picture of PCOS is that the insulin resistance has started to impact other areas of their body as well. And one of those areas is the way the body stores and holds on to fatty tissue. So, in PCOS, when there is insulin resistance, it tells the body I'm starving for energy and I need to save energy, I need to store energy. And as it does so, it builds up this fatty tissue in the body, the fatty tissue in the body contributes even more to insulin resistance. So, it's kind of a Catch-22, the more insulin resistant we are, the fattier tissue we store, the fattier tissue we store, the more insulin resistant we become. And so, I often counsel my patients who have PCOS, that weight comes on easier, and it's way harder to get off.

And so, this is where working with a team of individuals who are experts in weight loss management can be really helpful because most patients who present to us who are overweight, have done lots of interventions already to help to try to lose that weight with diet and exercise. And sometimes we need a little bit more of a boost and a helping hand in that journey to help overcome that inertia threshold that is needed to be able to get that weight to start to peel off.

Erica Newlin, MD:

Yeah, I think it's helpful for people with PCOS to know and to hear that it will be harder to lose weight.

Jenna Rehmer, MD:

It is.

Erica Newlin, MD:

Yeah.

Jenna Rehmer, MD:

Yeah, absolutely. And there are things that we can do that when diet and exercise are not enough, we have medications that can help improve the insulin resistance and to help with the weight loss to kind of get that journey started. And then diet and exercise really come into play to help maintain things once we get down to the weight, we're, we're desiring.

Erica Newlin, MD:

Yeah. What about traditional diabetic medications in patients with PCOS that might not have diabetes?

Jenna Rehmer, MD:

Yeah. So most classically, like if you, you know, look back in the literature 20 or 30 years and even today, some practitioners will still prescribe Metformin as a kind of first line drug. So, Metformin is used in patients with diabetes, to help improve their insulin resistance, and has been used for many years in PCOS as well. And it was originally thought to help significantly improve ovulation. Now, there are studies that have been published more recently that have shown that Metformin alone by itself without other ovulation induction drugs or other interventions, does not significantly improve the overall pregnancy rate. So, I don't recommend starting Metformin by itself if you do not have some sort of insulin resistance at baseline. So that is doing things like testing your glucose levels, a hemoglobin A1c, checking for issues related to that.

So, if there is insulin resistance that can be seen on laboratory testing, so it's severe enough, it's always there in PCOS but if it is severe enough that we're seeing it on glucose levels in your blood, then we would recommend starting Metformin to help improve that. Additionally, Metformin has kind of been more recently used as a weight loss drug. And so, in patients without insulin resistance, it can be helpful without diabetes, without insulin resistance, that are just obese, it can be very helpful with the overall weight loss journey. And so, we will often prescribe Metformin to our patients who are both struggling with PCOS and weight loss, kind of as an overall like help in general. So not only are we working on it for the weight loss aspect, but it also helps the underlying insulin resistance and we're just kind of using it to head down the right path overall.

Erica Newlin, MD:

There is a lot on social media about different supplements and natural medications for PCOS. How many of these scientifically been shown to help?

Jenna Rehmer, MD:

Yeah, there's a lot out there and I always caution my fertility patients that they're a vulnerable population. So, fertility patients are often high anxiety. So, if we look at studies about the stress level in patients who have a diagnosis of infertility, there are studies that have been shown that women with a diagnosis of infertility have the same level of stress as a woman with a new diagnosis of breast cancer. So, I think that we can all empathize with how stressful it would be to have a diagnosis of breast cancer. But correlating that to the same level of stress for a woman who has infertility doesn't always come as easily. So, I think first pausing and recognizing that these women have a higher stress level than their peers is important. And when you add that in, it creates vulnerability.

So, vulnerability for this patient population comes in that they will do anything they think is going to significantly improve their chances of becoming pregnant. And sometimes that means that individuals who are marketing and selling certain drugs or supplements or the fix-it, can take advantage of you. And so just to know that that happens, this is where I recommend checking with your OB/GYN or your REI physician to really talk about where's the evidence? What do we know about these different supplements and how they're helpful is really important because we want to make sure you're doing the right thing and not just all the things.

So, for PCOS specifically, there is one supplement that I put my patients on, which is inositol. Specifically, there's two inositol, Myo-inositol, and D-chiro-inositol. These inositols are a part of the insulin signaling pathway. So, they're involved in insulins signal within the cells. And they are known to be in deficient levels in women who have PCOS. And when we supplement them and give them back, we see an improvement in that insulin signaling pathway. So, there are formulations out there that have the exact correct ratio that you need, you need to get 2000 milligrams of Myo-inositol for every 50 milligrams of D-chiro-inositol, and that's the daily dose we recommend. And so, we recommend that women start that, and they continue it daily until they get a positive pregnancy test.

Erica Newlin, MD:

And then people with PCOS can get pregnant naturally, correct?

Jenna Rehmer, MD:

Yeah, absolutely. That's definitely a big misconception that I hear. I don't hear it as frequently anymore. I think that patients are really empowered to be their own advocate these days, and they do a lot of research and looking up sources and things like that online. But I think that there definitely used to be a misperception that if you had PCOS, you couldn't get pregnant. And although it's harder to get pregnant if you don't ovulate, when you do ovulate, your chance of fertility is very similar to women who don't have PCOS. So as long as that ovary is kicking out an egg, and you're getting periods, whether it's by us helping stimulate ovulation, or your body's insulin resistance has improved and you're ovulating on your own spontaneously. Whichever mechanism it is, if you're ovulating, your chance of fertility is really good.

Erica Newlin, MD:

Can you touch on when someone with PCOS should seek care if they're trying to get pregnant?

Jenna Rehmer, MD:

Yeah, I would say that if they have a known history of PCOS, and they're actively trying to conceive and their cycles are irregular, they should seek care either with their OB/GYN or an REI fertility specialist early in the journey, because otherwise, you can spend months trying and not really ovulating. And that just builds to the frustration and the stress that's behind all of it. And the sooner we get you ovulating, the sooner we'll get you pregnant, and we have a lot of things we can do to help with that. Alternatively, if they're ovulating regularly, and they're consistently picking up on an ovulatory surge, period is coming, you know, less than 35 days apart consistently every single month, I would recommend that if they are over the age of 35, that they come see us within six months of regular cycles, if they've not had a pregnancy.

If they're under the age of 35, they can give it up to a year of trying before coming to see us, although there may be other things within their health that we can help optimize in the meantime. So, if there is, you know, concerns about weight, concerns about other issues with insulin resistance, such as like pre-diabetes or diabetes, these are conversations that can be helpful to have while you're still in the trying process or before you've contemplated trying.

Erica Newlin, MD:

What medications are available to people to help them ovulate?

Jenna Rehmer, MD:

So, there's two main drugs out there that are used frequently to help patients ovulate who don't. One is the most, I think probably well-known and that is Clomid. Clomid has been around for many, many years, many decades actually, and it is FDA approved for ovulation induction. The other drug is called Letrozole or Femara. And it is, I think, gaining in its popularity or well-known status over time, and it has been around on the market less in length than Clomid has and was originally not marketed as an ovulation drug. So, it doesn't have FDA approval for ovulation induction. However, it works really, really well and has been used for a long time for that purpose. It tends to have less side effects than Clomid does, and overall, less risk. There's also been some studies where they've compared Clomid head-to-head against Letrozole, in trials specifically in women who have PCOS, and letrozole has been shown to come out way ahead as far as the ability to get pregnant and stay pregnant compared to Clomid.

Erica Newlin, MD:

So, you would say for most patients with PCOS, Letrozole would be your first line?

Jenna Rehmer, MD:

It's for sure my first line in PCOS and because of the reduced side effects, and overall similar pregnancy rates in patients even without PCOS, it's kind of become my favorite of the two overall.

Erica Newlin, MD:

You briefly mentioned side effects, what are the side effects?

Jenna Rehmer, MD:

So with Clomid, side effects can include things like hot flashes, night sweats, mood changes, because it works at the level of the brain to tell your brain that estrogen is not available, essentially blocks the signal of estrogen at the brain, which forces the brain to send a stronger ovulatory signal, that FSH hormone, that LH hormone, those signals are stronger when the brain doesn't think estrogen is available, because it's trying to get that ovary to ramp up and make a follicle. But because it blocks estrogen at the level of the brain, people almost feel like they have menopausal like symptoms. So, it is really common to hear hot flashes and night sweats mood changes.

It also has a few risks as well too. They both come with risk, but Clomid has a slightly higher risk. So, the most important risk I counsel my patients on is that Clomid can often produce two eggs or two follicles to grow and sometimes even a third. So, there is a significantly higher risk of twins and even triplets in patients who use Clomid compared to not using an ovulation med or using Letrozole. The Clomid twin rate is about 10 percent, whereas the general baseline population rate is only 1 percent. So, we're increasing the number of twins by tenfold in women who are using Clomid.

Erica Newlin, MD:

And I think a lot of people hear that and are like, great two babies.

Jenna Rehmer, MD:

But in real life, we know that they come with a lot of complications. And especially in the fertility world, some of the biggest risks are that they have a higher rate of miscarriage. They have a higher rate of preterm birth and preterm delivery. So that can lead to complications in the baby if they're born early and end up in the NICU. These complications can be lifelong, and they can sometimes when really preterm even end in loss of the life of the infant. So, these things all come with risk, and so we have to carefully weigh the pros and cons.

So, for me when I know there's another drug out there, like Letrozole, which does still have side effects, but significantly fewer hot flashes, less night sweats, and the twin risk is only 4 percent. But the pregnancy rates are the same that, then to me, it's a no-brainer. I have the same chance of getting you pregnant. If you have PCOS, even a higher chance of getting pregnant on Letrozole and less side effects and less risk of having twins which comes with lots of complications. So Letrozole is my drug of choice for that reason.

Erica Newlin, MD:

Perfect. Well, thanks so much. Anything else you'd like to add or anything I didn't ask about?

Jenna Rehmer, MD:

No, this was awesome. Thanks so much, Dr. Newlin.

Erica Newlin, MD:

Great. Thank you. Thank you for listening to this episode of OB/GYN Time. We hope you enjoyed the podcast. To make sure you never miss an episode, subscribe wherever you get your podcast or visit clevelandclinic.org/OBGYNtime.