We know ovulation is important for reproduction, but did you know that it’s a critical indicator of general health?
In this episode, Lara Briden delves into the physiological role of ovulation outside of reproduction and takes us through the many health benefits women gain from quality ovulatory cycling. Lara shares how oestrogen helps regulate metabolic flexibility, why the brain loves oestrogen, and the importance of progesterone for immunity, neurological health and inflammation. Lara also goes into why shutting down ovulation with hormonal birth control is detrimental to women's wellbeing as well as how to differentiate between PCOS and hypothalamic amenorrhoea.
Covered in this episode
[00:49] Welcoming Lara Briden
[01:09] Why women ovulate
[02:47] Benefits of oestrogen and progesterone
[08:33] Do men have hormonal cycles?
[09:45] Benefits of ovulation
[13:51] Obstacles to ovulation
[18:11] Birth control
[23:20] Using bioidentical hormones
[25:33] Do we need to have a period?
[28:03] PCOS diagnosis
[33:46] PCOS and anovulatory cycles
[37:32] Clinical testing to differentiate between PCOS and hypothalamic amenorrhea
[42:52] BMI in anovulatory amenorrhea
[46:08] Progression towards ovulation
[49:13] Managing PCOS
[51:57] What Lara will be discussing at the 2020 BioCeuticals Symposium
[54:33] Lara’s closing thoughts on female health
Mark: Hi, everyone, and welcome. Today we're talking with Lara Briden. She's a Sydney naturopath with more than 20 years experience in women's health and a strong science background. She first worked as a biologist before qualifying from the Canadian College of Naturopathic Medicine. Hi, Lara. How are you going?
Lara: I'm good, Mark. Thanks for having me.
Mark: It's a pleasure to have you here. You've done so many of the FX Medicines, just delightful to talk with. We're going to cover an area today which I am not a personally experienced expert in, and that's about ovulation and the importance of ovulation beyond reproduction, just for general health. Can we start there? Why do women ovulate and does it do them good or is it just a burden upon women that nature is forever trying to have a next generation and put a pregnancy in place?
Lara: Yeah, let's talk about that. And I'm going to try to be part of a bit of a paradigm shift around this because, of course, the traditional view is that ovulation is only to make baby and that we don't need it in the rest of our lives. Now, of course, from an evolutionary perspective, ovulation is to make a baby. I'm an evolutionary biologist by training originally.
Lara: So I do see most things through that lens. So, clearly, it's for reproduction, but the way our body is, you know, our body is calibrated it's expecting to have those ovulatory cycles or a pregnancy, one or the other. And the reason ovulation is important even if we don't make a baby is that ovulation is how we make hormones.
Lara: So, the analogy I would give is having testicles and making sperm, you know, is how men make testosterone. But testosterone is not just for making a baby, clearly, you know, testosterone has other benefits…
Lara: …for men and for women as well. But another case for women are oestradiol and our progesterone have benefits. Like wide ranging benefits. And I could list a few of those for you if you like.
Lara: Let's talk about oestrogen first because it is my favourite hormone of all hormones, actually. And did you know, from an evolutionary perspective, that oestrogen was actually the ancestor of all the other steroid hormones? So we know like some of the most primitive animals have oestrogen and that probably cortisol, testosterone, all the other hormones descended from oestrogen.
Lara: So it's very powerful hormone. It's very potent even in small doses as I'm sure you know.
Mark: I do know picomolar versus nanomolar.
Mark: You don't need much oestrogen to have an enormous effect, do you?
Lara: Exactly. It's like a tablespoon in a, you know, Olympic size swimming pool kind of thing, you can get an effect from it. And so, some of the benefits include, and I'm going to start with some of the lesser known ones. So, oestrogen is really important for metabolism. It's anabolic, so it helps to promote healthy muscle mass, which is why a lot of the women strength training community, you know, train with their menstrual cycle, track their menstrual cycle, do some of their more strong power lifts and training during the high oestrogen times of the cycle because that's when we can do that, that's when we can build muscle.
And oestrogen also helps to promote something called metabolic flexibility, which you may have discussed with some of your other guests. That's about helping the cells, in particular, the mitochondria be able to switch between using glucose for energy and using ketones for energy. It's quite an important part of metabolism, healthy metabolism. And so, here's just to give menopause as an example, when we lose oestrogen at menopause, we become more vulnerable to insulin resistance, and that's losing that metabolic superpower that oestrogen gives us.
Mark: That's a take I never knew. So I had no idea that it had that job.
Lara: Yeah. And so there's, of course, there's many others. For oestrogen, it builds bone, it's good for skin, the brain loves oestrogen. Like, not to overstate it, but I saw some quote from a scientist, like, to the brain, oestrogen is like chocolate. Loves it. It's a mood enhancer which is why we get this little euphoria kind of, some of us, you know, before ovulation, we can actually feel quite a bit more outgoing.
It's an appetite suppressant, which from an evolutionary perspective is interesting too. So during that pre-ovulatory phase when oestrogen is high, we're more outgoing, we're more willing to leave the house. We're not interested in eating. I've got other things on my mind. So, that's just a very tiny snapshot of oestrogen.
Progesterone, it's quite different. It's the hormone we make after ovulation. So it's the hormone to prepare for pregnancy, and hold the pregnancy. It's very good for the foetus, obviously, and the uterine lining. It does all of that, but it also is, from a clinical perspective, it's important to understand that progesterone is an immune modulator, a beneficial immune modulator. It has quite strong anti-inflammatory effects.
Now, just to use perimenopause as the example, because we use menopause as the example for oestrogen because we mostly lose the oestrogen with menopause, we lose progesterone before we lose oestrogen. So we lose...What happens in perimenopause, those years leading up to menopause is that we lose progesterone first because we start having cycles where we don't ovulate. And just to tie back to the immune modulating benefits of progesterone, of course, I know you know this as a clinician, women in their 40s are more vulnerable to flare ups of autoimmune disease, particularly Hashimoto's.
Lara: And I am quite convinced that some of that risk is from losing progesterone and making us more vulnerable to autoimmune. The other time we have an autoimmune flare is postpartum, which is when we get this massive drop in progesterone as well. So the immune system is quite sensitive to progesterone.
Progesterone is also, as you know, converts to a calming neurosteroid called allopregnanolone. It has a GABA effect in the brain. So if we're responding to progesterone normally, and that's not everyone, but the normal response to progesterone is that it's quite calming, it's almost drug-like, actually. It makes us sleepier, stimulates appetite. Yeah, it has lots of good properties as well. So just to give you an example of why I love both these hormones so much.
Mark: Yeah. And they're on each side of the cycle. Then the oestrogen on the anabolic side of, you know, the precursors to it are the DHEA and the testosterone and so, the muscle building. And on the other side, the catabolic side, the cortisol side of the equation, the progesterone is being used increasingly in medicine as a neuroprotective anti-inflammatory in place of cortisone.
Mark: And so, closed head injuries and the like are now being, progesterone is becoming a line of first attack to try and minimise inflammation damage and to try and get control. And it's of interest to me, as I understand it, the oestrogen triggers the ovulatory response, the progesterone follows, and then is maintaining that kind of high level of progesterone awaiting pregnancy.
Mark: It seems like you should have plenty of progesterone and oestrogen all the damn time. You shouldn't have a two-week period where you're waiting for it.
Lara: It's interesting... I mean, they're such great hormones, but the way our body works, yeah, we have them cyclically. So, that's the reality.
Mark: You may know the answer to this. Do men have cycles of testosterone and oestrogen? I mean, we all have all of the hormones. Do males have any cycle whatsoever or are we just the dummies that sit with, you know, kind of constant levels of steroid hormones the whole time?
Lara: Well, they're not constant, because there's a diurnal cycle.
Lara: So there's a, I've lost the third word. There's a 90-minute cycle from steroid to hormone. So that's another word for that. That's an even shorter cycle. And then there's the diurnal, the daily circadian.
Lara: And so, of course, men, you get a big, like much higher levels of testosterone in the morning. I have heard arguments that testosterone may vary longer term as well. It seems like it does vary seasonally.
Mark: It does, seasonally. Yes, I do, actually, I do know that. But there's no clear menstrual cycle to men or is there?
Mark: I think sometimes there is a moon cycle. Men maybe not aware of it, but in our hospital setting, the males and the females went off at the full moon equally and everybody tried to get away from them.
Lara: I wouldn't totally discount that maybe there's some more subtle thing going on, but no, there's no pronounced monthly cycle like there is for women. Yeah.
Mark: In general then, oestrogen has important factors to it as in the life cycle from puberty up to menopause, there's a clear period of oestrogenising and progestronising and when it disappears, we see what happens with the loss of those hormones.
Mark: In the meantime, though, what over that, say, 30, 40 year span, what is the benefit? What does ovulation, specifically and the oestrogen peaks do for us, or for you?
Lara: Yeah. Perfect question. So I'm going to quote my colleague, Professor Jerilynn Prior who helped me with my book, "Period Repair Manual." She's a reproductive endocrinologist from Canada, a scientist. She's published dozens of papers on this topic as well as being a clinician. And she has a quote, she's at the University of British Columbia and runs something there called the Centre for Ovulation Research.
Lara: She has a quote which I love, which I give all the time, which is that, women benefit from 35 to 40 years, exactly what you said, of ovulatory cycles, not just for fertility but to help to prevent cardiovascular disease, osteoporosis, dementia, and breast cancer.
Lara: And she includes breast cancer in there because she argues that progesterone, which is very different than the progestins and hormonal birth control, we'll come to that soon, but progesterone has arguably some breast cancer-preventing effects.
Mark: There has to be. Right.
Lara: So she makes some pretty bold statements about that. And building on that, I can just speak about our ovulatory cycles as each and every month that we can have them as building metabolic reserve, kind of building up that metabolic flexibility, for future, like even to carry us through after we lose our hormones with menopause. I kind of tend to think of it like each and every ovulatory cycle is like a deposit to the bank account of long-term health.
Lara: We’re building up healthy muscles, healthy bones, healthy insulin sensitivity, healthy brain. And that takes time to kind of build that over the decade.
Mark: There's a good reason to that, isn't it? The investment in women has to be high so that their health is good. While babies take 12 years to develop, they're not like horses where you drop a foal and then if it's not walking quickly, you leave anyway. So, women need to be healthier than men need to be. Men are expendable, really, when you think about it. But women have to be there to raise the child. And there are positive benefits that have to occur for that to work for that to work out well.
Lara: Absolutely. And if you, for a future podcast, you can get me back and I'll share all my thoughts on menopause through an evolutionary lens, because I'm currently writing my second book on that. But I'll just quickly say, there's evidence in the literature, the anthropological literature that menopause evolved hand in hand with longevity, that early human societies really did depend on their grandmothers…
Lara: …you know, literally and figuratively because women in that age group are such amazing providers. So, not just for their own...like obviously, their own children are grown by that point, but they provide for the whole tribe. And so, yes, I think investing in our long-term health, even past menopause is, I want to say, a big part of what we need to do.
Mark: That goes against the common thinking of who needs anybody to go past the age of 50. You know, the reason that menopause happens is that nature has no interest once you're not ovulating, it seems utter rubbish in any evolutionary biology view.
Lara: That's completely wrong.
Lara: We’ll save that for another interview.
Mark: Okay. Alright.
Lara: You have to get me back when I have my menopause book out, I can talk, you know, at great length on that topic, but there's more evidence that our ancestors, many of them succumb to infection and injury, of course, but those who did survive that, there's growing evidence that we lived into our 70s. That was not unusual.
Mark: Coming back again, ovulation, how does it make for a healthier woman? And are there tricks that we need to know about that? I mean, we have that graph that goes low oestrogen, low progesterone, big peak at ovulation, high in the second half of the cycle, and that's all. There's more detail than that, isn't there?
Lara: Right. Let's move into reasons why women don't ovulate, because that's huge.
Lara: That’s not a small issue. I think clinicians are seeing that all the time and there's different reasons for that, which we'll explore, but I mean, it needs to be talked about because, as we've just said, I mean, the conventional view has been, we don't need to ovulate. So I don't think it's being treated and addressed the way it deserves.
Mark: What are the obstacles then?
Lara: Well, as you know, as a doctor, of course, you know, there's dozens of potential obstacles. So a clinician's job would be to rule out some of the more obscure things like high prolactin or thyroid issue or different… put it this way, one of the things I talk about in my book, "Period Repair Manual" is that our period, which means therefore our ovulatory menstrual cycle is the report of the month...our monthly report card, a report card of health. So ovulation is hard to do and if we're able to do it, especially month after month, then that is a sign that everything is working with health, right?
Mark: Okay. Meaning it's metabolically costly and so you have to be well to ovulate well and to menstruate well.
Lara: Yeah. It's a sign of health. And that's not just me saying that, actually, that's now the ACOG or the American College of Obstetricians And Gynecologists came out with a statement a couple of years ago, which made me cry when I read it. I was amazed to see it, which was that menstruation is a vital sign of health.
Lara: So, yes, so potentially there's lots of different things that have to be going right for ovulation to occur. And sometimes a bit of detective work is required, but at the end of the day, it's usually not that complicated. At the end of the day, it's often one of three things which I think we have time to cover today. So, one is hormonal birth control, which obviously is sitting there for a minute.
Lara: Those are drugs that shut down ovulation, so obviously, I have a lot to say about that. Numbers two and three are PCOS, polycystic ovary syndrome.
Mark: Which we see more, and more, and more.
Lara: Yes. Yes.
Mark: I mean, is it really increasing or is it just we're noticing that more and more?
Lara: It's both.
Mark: It's both? Okay.
Lara: Yeah. It's both. So is that PCOS, which we'll hopefully have time to cover. And then the third thing which has to be mentioned is hypothalamic amenorrhea, which is losing your ovulation due to under-eating, which is also becoming more and more because of the clean eating movement and low carb and things like that. Keto diets can put young women into hypothalamic amenorrhea. Not all young women, but some. And just to be clear, from an evolutionary perspective, hypothalamic amenorrhea is not a malfunction, right?
Mark: It's a function, yes.
Lara: Like it's the body doing exactly what it's designed to do, which is to say, "Oh dear, there's definitely not enough food to make a baby. So I'm not even going to attempt it.”
Lara: Because humans, unlike some animals, we cannot pause or terminate a pregnancy just physiologically, right? Like we have to, once we're going, you know, we're potentially all in. So there's this protective mechanism to ensure that we don't embark on a pregnancy when there isn't enough food.
Lara: So there's that. And we'll circle back to PCOS and hypothalamic amenorrhea, but I'll just say at this point, for anyone who might, for whatever reason, I'm sure they wouldn't, but if they don't listen to the whole interview, they need to hear this now. There's a big problem with misdiagnosis between misdiagnosing hypothalamic amenorrhea as PCOS. So, little red flag, little alerts to that. That's definitely something as a clinician to have your eye on.
Yeah, so, we're in a paradigm where it's only 60 years old, which is actually not very long in terms of medical history, where we've decided that it's okay to routinely shut down ovulatory cycles with contraceptive drugs and replace those cycles and the hormones they make with contraceptive drugs, which are not oestradiol and progesterone. Like let's just say categorically are not, although I know there are a few types of combined pill that use oestradiol, bioidentical oestradiol, but the progestin is always...progestin, not a progesterone. And some of them like levonorgestrel are more similar to testosterone than they are to progesterone.
Lara: So those drugs do not have the same benefits that we were just speaking about in terms of the beneficial immune modulating or beneficial effects on the brain. No progestins convert to allopregnanolone, that beneficial neurosteroid, none.
Lara: Which is why...And keep in mind, when you take those drugs, you've also shut off your own progesterone. So not only are you taking a protestin, you're not making any progesterone. So, now, I don't think we should be surprised that we're seeing research coming out that women on hormonal birth control have altered brain structure compared to women who cycle naturally or that hormonal birth controls associated with an increased risk of anxiety and depression. Or that this latest research out of Canada showed, I'm just going to see if I can get this right, say this carefully. What they found, it's a small study, but they found that women who took the pill as a teenager went on to have, I think, triple the risk of depression later in life, even once they stopped taking the drugs. Because that's a critical window of development of the brain, right? So you've been taking something, a drug that alters the brain. You've been also robbing the brain of progesterone during those years.
Mark: And their brains are structurally different, did you say or?
Lara: Well, no. So what this last research study that I quoted, and I can get you that for the show notes, if you'd like.
Lara: And it's preliminary study, so...I mean, I don't want to read too much into it, but what they found was that, that one, they didn't look at brain structure. They just found that women who took the pill as a teenager went on to have an increased risk of depression later in life as an adult, even when they weren't taking it.
Mark: Was there a dose response to that? Meaning if they took it for longer or the higher dose ones, was there any association with worse or longer depression or was it just if you took the pill you were in that risk area?
Lara: Yeah. From memory, they didn't have that kind of detail that they were able to pick that up. That's a very good question though. That would be one of the next questions to ask, I think, is how dose-dependent that was. But keep in mind, the dose dependence in terms of your dose of these drugs, but also, there's also kind of an all or nothing thing like if you shut down ovulation...
Mark: Yes, you're shutting down ovulation.
Lara: You've shut down ovulation, like there's no progesterone.
Lara: Not all types of hormonal birth control shut down ovulation. I mean, obviously, the combined pill does, the Nuva Ring does, Depo injection does. The progestin-only like implants and progestin-only pills mostly do, they don't officially completely shut it down, but effectively they do, although you can still get some oestrogen moving, like cycling a little bit, not cycling, but kind of some oestrogen present.
Lara: But the only one that...the hormonal IUD is different in that it does not routinely shut down ovulation. It usually does in the first year, especially in younger women when the dose is higher, the dose that's levonorgestrel is the drug in the hormonal IUD and then...But many women can start to ovulate. I've talked to women who were able to track their cycles, like with temperatures, having ovulatory cycles on the hormonal IUD even though they're not bleeding. So, think about this. I need to say this.
With the hormonal IUD, weirdly, you're potentially able to cycle, as in have a menstrual cycle, but not bleed as opposed to on the pill, you have a pill withdrawal bleed, which means nothing, but you don't cycle. The menstrual cycle is shut down, ovulation is shut down, but you still have these like ridiculous, stupid monthly bleeds, which no one needs to do. So, with the pill you bleed, but don't cycle. With the hormonal IUD, you can cycle but not bleed.
Mark: Okay. Either way, you're not going to get pregnant in both circumstances.
Lara: Correct. Yeah. Obviously, those methods all prevent pregnancy. They have that in common, yes.
Mark: …it has been a big thing throughout kind of integrative medicine that body identical stuff or bioidentical was important.
Mark: And always the answer was, of course it's not important, it's just progesterone-like activity to do a job without any understanding of the benefits of the hormones they were closing off.
Lara: Yeah. Yes.
Mark: So, what can you do for hormonal birth control? Can you even do it with bioidentical hormones? Is that possible?
Lara: Okay. It's a really good question. My understanding is you need 200 milligrams of progesterone or micronised progesterone to suppress ovulation.
Lara: So, I mean, in theory, you could do that. I'm not, you know, it's not approved for use that way…
Lara: …and I don't know anyone who prescribes it for that purpose. But just back to your point, I mean, yes.
Mark: You could do it.
Lara: So many decades, they're like, "Oh, no, there's nothing different about progesterone or bioidentical progesterone. No different." And now suddenly, like since the last four or five years, "Oh, yeah. It's actually really quite different."
Lara: It’s much safer for the breast and cardiovascular risk, all these things. It's like, "Oh, that's way better now,” which makes me smile, that’s a topic for another day too. But I think it's quite interesting that the change from the term biodentical to body identical, which mean the same thing.
Mark: I know. It's hilarious because once medicine has fought an enemy, you never call your enemy your friend.
Mark: So you give a different name even if it's the identical thing and then everybody gets comfortable with it.
Lara: I know. So I just spoke with a...on Twitter, I was just speaking with someone who was trying to reclaim the term bioidentical because, really, it's a perfectly good term…
Mark: I know.
Lara: …and we shouldn't have to. Yeah.
Mark: So in theory, it's a possibility to do it, but it's not a common practice and we don't have the data to really rely on for effective birth control by using bioidentical hormones yet?
Lara: Correct. Yeah.
Mark: All right. To finish off the hormonal birth control, my understanding of it was always that what you're aiming to do is suppress ovulation and trick the body into having a period without there ever being a period. And the period is the same look as a menstrual cycle, but it isn't the natural body dropping away things, it's the trick of the end of the pill and then everyone worked out, “Oh we can stay on the pill for 6, 12, 18 months continuously. You don't need the period.” Is that true or not?
Lara: You don't need a monthly pill bleed.
Lara: There’s no medical reason to have a monthly pill bleed. It's mimicking a natural cycle, but for what purpose?
Lara: The timing of a natural cycle is about ovulation.
Lara: So if you're not ovulating, there's no reason to have that monthly bleed, which a lot of women have felt pretty annoyed about it once they find out they didn't need to be having that monthly bleed all these years or decades on the pill.
Lara: And also, you know what happens, because there's no medical reason to have a monthly pill bleed, we get these crazy statements being made by very smart people, which just blows me away, saying, "Okay, therefore there's no reason to have a period. Women don't need periods,” when they're actually just talking about pill bleeds. But if you really start to look at do we need hormones?
Lara: And, you know, and ovulation is how we make hormones, then yes, we need ovulatory cycles.
Lara: It’s quite a different question. Yeah.
Mark: There is also...I attended a conference now 20 years ago and the etiological question is why do women have periods? So that they live longer. In fact, having a menstrual cycle reduces the amount of iron in the body, that the normal iron for women is lower than men. Iron is proinflammatory, aggressively anti-inflammatory with infections and that men live a shorter time because their iron levels are higher and women are smart, they get rid of iron every month, keep the iron at a lower level, which is associated with better longevity, which lets them look after children. And so, the evolutionary biologists at this conference was saying “the reason women bleed is to live long enough to raise healthy children.” And there was no allowance for live long enough and be healthy themselves for the rest of their lives. It was all about raising children at that stage.
Lara: Yeah. Interesting angle. I mean, certainly it probably does help us to have to lose iron every month.
Mark: It does
Lara: I doubt that it's a causative reason why they evolved it, but still, it's an interesting, you know, angle on that.
Mark: All right. So let's move on. The birth control is one issue, but the one that we as practitioners see all the time is the repeated diagnosis, you have PCOS and thinking of PCOS as an auto immune, kind of inflammatory, the sugars and the insulin levels are all over the place, hair growth is abnormal. What's going on in PCOS and is there any reason that we're seeing more of it now or are we just putting everything into the PCOS basket?
Lara: It's both, as I said earlier. So, okay, so PCOS, I'll say a couple things about it and then I'll define it. You know, PCOS is over-diagnosed in that it's, you know, mistakenly diagnosed by ultrasound, which you simply can't do because the polycystic ovaries finding means essentially nothing, especially with the more modern ultrasound where they're just have a higher resolution and see more follicles.
Lara: The follicle, I mean, they're so-called cysts, like they're not cysts, right? I mean, ovarian cysts are something quite different. They're just counting follicles, which are eggs, which are normal for the ovary. So, there's definitely an over-diagnosis problem. At the same time, arguably, there's an under diagnosis problem because there's a lot of women out there who are having an ovulatory cycle and have insulin resistance and have not been told they have PCOS. So I think what it means is a redefinition and how...My definition for PCOS, which I think is quite helpful, I'd love to see it used out there, is that it is essentially the condition of androgen excess in women when all other causes of androgen excess have been ruled out.
So it's a diagnosis of exclusion and that way it's an umbrella diagnosis, like it's basically anyone who has demonstratively like higher androgens, whether on blood tests or with symptoms, as in hirsutism…
Lara: …when you've ruled out like adrenal hyperplasia and high prolactin and other things, right? So then you're left with, okay, they have high androgens and that can end up being, I suspect it's quite heterogeneous. So you have someone then who are in that group who, under that diagnostic umbrella, who insulin resistance is the main driver of high androgens, whereas other women, it's maybe something else going on. There seems to be this definitely back and forth between high androgens and insulin resistance in that high androgen's worsen insulin resistance in women, which is something I've really only come to understand fairly recently, that, in men, you know, testosterone essentially, if I've got this right, is it's particularly helpful for preventing insulin resistance and preventing abdominal weight gain. But for women it's the opposite. If you give a woman testosterone, she usually gains weight around the middle and develops, can work, you know, be more likely to develop insulin resistance.
Mark: I did not know that. I thought that it worked the other way around, that there was an insulin resistance problem that ended up with a failure of the aromatase and the conversion of testosterone to oestrogen.
Lara: Yeah. It's bi-directional.
Lara: So, definitely there by several mechanisms, insulin resistance in vulnerable women can increase androgens and the other direction having high androgens can worsen insulin resistance. So it's sort of chicken and the egg. I think what I've seen, I think in many cases maybe it is the testosterone coming first.
Lara: And some of that's in-utero. I think there is something definitely going on with environmental toxin exposure and epigenetics in-utero and kind of miscalibration of the HPO access. So, higher levels of LH stimulating more testosterone and potentially feeding into the bi-directional cycle that way. It’s elective, it's heterogeneous, so you probably come at that place from a few different places, if that makes sense. You end up with high androgens from a few different drivers.
Mark: We have a whole generation, don't we? Of people whose mothers were exposed to xenooestrogens, lots of the pesticides, plasticisers, so we're dealing with only the first and then the second generation and we do know that genetically, that manipulation of those hormones in grandmothers and mothers can percolate down.
Mark: I wonder if that...Are you saying that in the early years of life of a woman with this kind of androgenisation, that it may be the mother, in fact, and the pregnancy, even that early that sets the stage for what happens later?
Lara: Yes. And it's actually, it's not just me saying that. There is some research in-utero toxin exposure to, I think BPA, but PCBs and things too. I mean, I have to kind of look at the current research, but definitely.
Mark: I come from the really old school. We had organic chlorine pesticides, the dieldrin, heptachlor, chlordane, all of that group. Every house in Australia had it under the house. So sometimes yearly, and even though it lasted 20 years…
Mark: …and those definitely had an effects on fertility on the oestrogen receptors, they were strong binders of it. And there's a whole disaster that I think has played out over that time that we think of now as infertility and difficulties with pregnancy. I think the IVF kind of phenomenon has grown a little bit on what we did 50, 60, 70 years ago that we're still just seeing the repair of now.
Lara: Possiblly. There’s the whole sperm side of things too, right?.
Mark: Yes, but we're not dealing with that today because we're dealing with oestrogen and ovulation.
Lara: No. That's not our topic today. No, no. So, PCOS, yeah, it's real. Its main symptoms are high androgens. I mean, by definition, androgens have to be there to qualify for the diagnosis, but often, not always, but often there are anovulatory cycles as part of it.
Lara: And it's also, just to point out, restoring ovulation is one of the most important things to do for PCOS. I mean, obviously, because you want to restore ovulation, but also because both oestradiol and progesterone have natural anti-androgen effects.
Lara: So progesterone, in particular, helps to suppress LH, luteinising hormone, which helps to normalise that, keep LH low, so it doesn't overstimulate the androgens in the ovaries. So there's also some of your...I mean, well I know all your listeners are clinicians, so I'll say, there's a treatment developed by professor Jerilynn Prior, who I mentioned earlier, she has something called cyclic progesterone therapy for PCOS where she uses oral micronised progesterone, the real stuff, the real progesterone, not a progestin.
Mark: Right. The good stuff.
Lara: Yeah, the good stuff. And she does that two weeks on, two weeks off. And I've used that with a few of my patients too, and that, it does... Well, at first you get like a couple of withdrawal bleeds from just the progesterone.
Mark: So it doesn't matter about the timing to when you start that, are you trying to see where the menstrual cycle is and go two weeks off for the follicular phase and trying to hit the luteal?
Lara: Yeah. Well, how I've done it, which is slightly different, you have to, your listeners can go and look at Professor Prior's protocol. She's written it in a few places, but, what I have tended to do is if they're having no cycles at all, do two weeks on, two weeks off…
Mark: You’ve got to pick somewhere.
Lara: …and then when they do start to have periods, and it might be withdrawal bleeds at first, but then it starts to track cycles and look for signs of ovulation and then, yeah, maybe I would then come in with the progesterone to the final estimated two weeks of the cycle after it. Essentially, it's preferably after ovulation if you can confirm that ovulation happened by tracking temperatures.
Mark: And some people know, they feel it, don't they? Ovulation is, about half the women that I ask say, "Ah, I know when I ovulate. I can feel it."
Lara: Yeah. And you see the fertile mucus, which seeing the egg white cervical fluid or egg white cervical mucus, which looks like raw egg white is...That happens when you get the oestrogen surge.
Lara: So that's a pretty good indication that ovulation is about to happen, but it's not a guarantee because with PCOS, you can actually get actually quite a lot of fertile...just a lot of unopposed oestrogen and therefore fertile mucus and that doesn't mean ovulation. So, that's something to keep in mind.
Mark: So you go for the ovulatory cycle, you go the two weeks on, two weeks off, two weeks on, two weeks off. And how does that reestablish ovulation? Is it just the body gets back there or what's the mechanism?
Lara: Yeah. The main mechanism is that progesterone suppresses LH.
Lara: So, with PCOS, you have chronically elevated LH usually and that's a key part of the HPO signalling, right? So that's...the signalling is just not working, but the chronically high LH is stimulating too much testosterone rather than oestradiol and then you're not able to kind of prime and get that LH surge.
Lara: So, by pushing down on LH, and that's how a lot of the natural treatments for PCOS work, then you can hopefully break out of that trap.
Mark: So, the pathologists do report the FSH, LH ratios, and so, you're trying to get the LH down so that you are not having the stimulus for the testosterone production. Is that a fair summary?
Lara: Yes, exactly. And so you're able to ovulate too. Let's talk about LH, FSH testing, because this is one of the other clinical pearls that I'd like to offer everyone because this is actually quite a good way to differentiate between PCOS and hypothalamic amenorrhea.
Lara: So, there's a lot of overlap between the two conditions in that the overlap is both PCOS and hypothalamic amenorrhea can have irregular periods or lack of periods. Both PCOS and hypothalamic amenorrhea can have polycystic ovaries. I'm just pausing so everyone can take that in. You can see polycystic ovaries on ultrasound with hypothalamic amenorrhea, so that's why you need to ask your patients like, are you under eating?
Lara: Because it doesn't mean anything.
Mark: Right. Oh, okay, so this is the measurement issue.
Lara: Yeah, Mark, it's just an ovary, like a polycystic ovary, I guess, depending on how it's being defined is really, if you think about it, it's just an ovary that doesn't have a dominant follicle.
Lara: So it's an ovary that isn't ovulating.
Mark: They're all bubbling away, but nothing bubbles to the very top.
Lara: Yeah, the follicles’ in there, but nothing's happening. And what the research shows. I mean, truthfully, any woman, even a perfect woman with perfectly normal hormones who's mostly having ovulatory cycles can have the occasional cycle where nothing happens. And that's why, the statistic I've seen is that, a population of normal women, women with normal hormones, not PCOS, one in four of them will have polycystic ovaries at a given time. So it really does not mean anything. And also just conversely, not seeing polycystic ovaries cannot rule out PCOS because PCOS is a condition of high androgens. And if they've got signs of high androgens, it doesn't matter if they have polycystic ovaries or not. The only other criteria is to rule out other causes and then you're left with, the exclusion diagnosis of high androgen PCOS, basically.
So, yeah, so in terms of differentiating, what I do clinically, and like so many things clinically, there's always going to be exceptions to this rule, but let's just say most of the time, women with PCOS had a higher LH to FSH ratio and women with hypothalamic amenorrhea have a low LH to FSH ratios and that's extremely low LH if they're really under eating. And it does depend on where you are in the cycle. Because any kind of cycle, which there can be with PCOS, that you could still be having some cycle, so you don't want to make the mistake of accidentally testing the LH surge and thinking that’s elevated, right?
Like ideally, if it's been a cycle, you want to do it on day two and try to get like standardise that and it's pretty interesting because LH is the signal, I mean, both FSH and LH are the signals, but LH comes, it's those, what they call LH pulsatility which is coming down from the hypothalamus pulsatility which is pulsing at the rate, like if you under eat, it has to be pulsing at just the right rate, right? So if you under eat, it pulses too slowly and you don't get...There's no signal to the ovaries. If you've got insulin resistance, LH, it's pulsing too quickly. You have high LH pulsatility and elevated LH and you also cannot get ovulation because it is too much, right?
Lara: So there's a sweet spot with LH and it's in ratio to FSH because, as you know, both LH and FSH increase with age. So we can't have an absolute number. We have to just look at that.
Mark: Right. They vary, you know, the day before, or two days before ovulation and two days after. They're all over the place for short periods of time…
Mark: …and then they seem to be relatively stable once you're mid luteal or mid follicular. There seems to be more stability there in most people who are ovulating. Is that the case for people with PCOS or hypothalamic amenorrhea?
Lara: Well, in terms of the stability, I mean, certainly LH has a big surge just before ovulation, so there's that. But it should be generally, LH should be quite flat. I mean, FSH obviously goes up. Well, they both kind of go up at the beginning of the cycle and then, yeah, they're suppressed somewhat. FSH will be kind of lower and then a bit higher again to ovulation and then lower. I think it's something like that.
Lara: So I generally do day two, there's possibly other ways to do it, but I just find that's the best. Day two or random day and if you have to do a random day, which you'd have to do if they've had no period at all, then you do have to at least take care to think about when did their period, if they ended up getting a period after that testing...
Mark: Yeah. When was it?
Lara: ... just to retrospectively understand where you were in this relative to a possible ovulation with that test. Yeah.
Mark: The approaches to each of them, PCOS versus hypothalamic anovulatory cycles has got to be almost. They are very different approaches to management, aren't they?
Lara: Yeah, they're very different.
Mark: Is the anovulatory cycle, which is hypothalamic, is it always related to underweight and is there a kind of cut-off point in terms of BMI? Are we talking about 14 or 15 or something with BMI where reliably, the body will shut down and say “no more ovulatory cycles?”
Lara: No. So the current research, my understanding of it anyway, so we used to go a lot by BMI. Now it's about energy, relative energy status.
Lara: So the current term in sports medicine is relative energy deficiency in sport but it's the same idea. So are you eating enough to keep up with your base metabolic rate plus activity? And it's really just about the amount of food coming in. And the problem with BMI, like and, of course, as you know BMI really varies between people and between races.
Mark: I know. Highly muscular people can have high BMIs and none of the fat that the rest of us have.
Lara: Well, with my patients, I do measure LH. If I see a low, a really quite a low, it could be half FSH sometimes like LH is half the level of FSH. If I see that, plus a low insulin, low fasting insulin, plus a clinical history of some kind of dietary restriction and other things ruled out, then that's what it is.
Lara: And I'll have patients say, "Well, I don't want to eat more. I'm already a BMI of 20." It's like, "I'm sorry, like until your LH comes up, you need to eat more."
Lara: And it's a lot more, it's like possibly at least 2,500 calories a day, if not more. And it takes months. Like it takes possibly minimum four months, sometimes quite a few more months to get your period back because of what I described in my book as the 100 days to ovulation.
So, the whole, you may know this, but like the ovarian follicle starts its journey to ovulation 100 days before it actually gets there. Similar to how sperm starts, spermatogenesis takes 100 days. That's why we always say preconception, three months, right? So you've got this healthy crop of sperm and eggs coming up. So, same when you're trying to restore ovulation, like those follicles need to have the, well, the signals, receiving the signals from the pituitary, but also have just the whole environment like good, you know, not inflammation, just generally being nourished.
Mark: So, it's not eggs ready to pop all the time, it's, they develop, they mature and it takes, is that right? About 100 days. So, from stimulus, they progressively move towards ovulation.
Mark: Not, they're just sitting there waiting for the signal on day one and say, "Okay, off we go."
Lara: No. They get recruited, like batches of them get recruited to start growing. Of course, most of them are never going to make it there, right? Like only one's going going to make it to the finish line. Most of them just end up, they partially grow and then they get suppressed and reabsorbed and that's the end.
Mark: They get picked up by ultrasound on the way and called polycystic ovarian syndrome.
Lara: Yeah. They're viewed on ultrasound, but they never get to actually pop out their egg. Yeah.
Mark: They're the losers.
Lara: Yeah. Oh, yeah. They lost the race to ovulation, I call it the triathlon, ovulation triathlon. Yeah.
Mark: So we should stop thinking of it as establish, just wait. We should see the LH becoming a marker that we pay attention to and it's a progression over three or four months towards ovulation rather than, can we trick ovulation into happening next month?
Lara: Correct. Can you build towards ovulation? This is in the case of hypothalamic amenorrhea, a bit different with PCOS, which we'll come to it in a minute, but yeah, it takes a while and so, it's good for patients to know that, have expectations and also in the meantime, they might start seeing signs of oestrogen. So, as their follicles get recruited, they're going to start pumping out a bit of oestrogen and they'll start to see some fertile, like not fertile mucus necessarily, but even just more vaginal discharge, more.
Mark: Breast tenderness.
Lara: More stuff happening like a bit of breast swelling. They'll feel it. They'll just feel a little bit more hormonal, which is a good sign that they're making some oestrogen.
Mark: And the basis of this is to bring the energy from diet up to meet the energy needs of the body with a little to spare.
Lara: The hypothalamus is sitting there, it's just like a switch, right? It's going, it's like constantly asking, "Is there enough food to make a baby? Is there enough food to make a baby?"
Mark: Yeah, okay.
Lara: It’s like, "Oh, yeah, yeah. There's enough food to make a baby." Okay, now we're sending up the correct LH signals via the pituitary and even once those start going in the case of hypothalamic amenorrhea, it's still going to take 100 days to get there, right?
Mark: Okay. Alright.
Lara: Like you don't want to start signalling, but it might take a few months for the hypothalamus to be convinced…
Mark: That the threat is over.
Lara: There's a phrase I like called ovarian set points, which I learned from this book on evolutionary biology that different women with different genetic backgrounds have a different switch calibration, if you will. And also, younger women, younger women are a lot more likely to lose their periods to under eating than older women. It's just to do with gynaecological age. They just more vulnerable, like their hypothalamus is just not going to take the risk whereas the woman in her 40s or like 30s or 40s could probably...like, for example, could probably get away with a keto diet and not lose her periods, for example.
Mark: So I mean, that fits with clinical practice. We see people who are terribly under, you know, true anorexia or bulimia. We see that it can take years and years for the hypothalamus to be convinced that the starvation is not going to happen again…
Lara: Yeah, yeah.
Mark: …and it can maintain set points that seem entirely unreasonable for the woman but seem to be the best that the body can manage to prevent the threat of maybe starvation and dead.
Lara: Yeah. Exactly. It's got its own wisdom. So you just try to work with that. Trust the body. Trust the body is one of my mantras, especially women's health with the period. For a lot of things, not every single thing, but for a lot of things, your body will come through for you. It’s okay, like just give it a chance to do what it needs to do.
Mark: Is that something we can get through today or is this a whole other?
Lara: It is. You know, I'll be very brief because I'm conscious of our time, so I'll just say, in my work and in my book, I break PCOS down into functional subtypes. I don't really see how else to do it because, as I said earlier, there's different drivers.
Lara: The main, most common one being insulin resistance. In that case, reversing insulin resistance is the number one thing to do. But there's also a whole subset of women who have mainly elevated adrenal androgens. So it's not officially called adrenal PCOS, which is really quite different, clinically. They don't need to be go on a...They often don't have insulin resistance, so they don't need all the insulin lowering treatments that might otherwise work.
Lara: So, all that said, I'm going to mention inositol because it's so great for PCOS and also, I don't know if you know this, but the humble supplement, inositol made it into the international, the 2018 international guidelines for PCOS treatment, which means it's full-fledged evidence-based medicine for PCOS.
Lara: Yeah. It helps with… inositol works as an intracellular hormone signal amplifier. That's kind of more in layman's terms, but it, you know, it's, I've forgotten some of the more technical terms, but basically it helps amplify the signal of FSH, which is good in the case of PCOS of insulin, which is good. It also, just as an aside, helps to amplify the signal of TSH. So that's why it can also be helpful for thyroid conditions, the kinase to do with the kinase system, intracellular, some of your more biochemically minded people probably know.
Mark: What kind of doses of inositol? Are we talking about gram doses or multi-gram doses?
Lara: Yeah. Minimum 3 grams, maybe up to 6 grams. But fortunately, it's an inexpensive supplement so you can do that. It's also very safe. I always feel like I'm doing an infomercial for inositol when I talk about it because...And it's safe. And you can take it with pregnancy even if you're pregnant. So, yeah.
Mark: Is that a generic thing? Does that matter whether...That's primarily for insulin resistance, along with PCOS, that part of the diagnosis rather than any other form of the PCOS?
Lara: Yeah. That's a good question. Yes, I would generally, even given all my different subtypes, I'd often give it for the insulin resistant type, but I would potentially give it for any type because it helps with that amplify the FSH part of the signalling.
Mark: Our listeners are going to be able to hear you more at the Bioceutical Symposium in just a short period from now.
Mark: And this looks like a very, pardon the expression, ripe area that looking at birth control, fertility, they're the big issues on the agenda of, you know, if a species becomes infertile because of the stupid things that they do, however they do it, you’ve got a limited life span in this world and these sound like, great, you know, great sub divisions of what we just had evolve. You've got polycystic ovaries and your fat, therefore, X, that used to be. You're underweight and that's why you lost your periods. This seems to be putting the data between what happens and it's not underweight, it's not meeting the energy needs. It's a subtle difference, but it's an important one isn't it?
Lara: It's underfed.
Mark: For the needs of the person. Yeah.
Lara: Yeah, for her needs, her body size, her metabolic rate, her exercise level, activity level. So I'm also at the symposium. I'm going to be... I think all of us are, I'm doing like a workshop as well, so I'll do the presentation and then in the workshop, I'm going to do kind of a deep dive into PCOS versus hypothalamic amenorrhea. I'm going to present a couple of cases so people...And, of course, in that session, people can ask questions and...
Mark: Quiz you and open up every last wound and detail. I know. I love the symposium. It does provide that opportunity to really go deep and for it to be clinician-relevant. The best part of it is clinicians asking questions. They ask different questions than researchers do.
Lara: Yeah. Exactly.
Mark: So I will be looking forward to seeing you there. I'm dusting to follow that up and to go through the rest of the distance. What we've covered is just the surface of PCOS, hypothalamic anovulatory cycles or lack of ovulatory cycles.
Mark: That’s not enough for us to get the full picture of why women need to ovulate and to stay healthy. And so, it'll be delightful to see you at the symposium and then we will follow it up with another of the podcasts on the other side of that if that's okay with you.
Lara: Sure. Yes, it's great to talk to you. Before we came on air, we were just observing, realising we were in clinical practice just probably a few kilometres from each other in Sydney for almost 20 years.
Mark: I know.
Lara: And I don't think we've met, although I knew you from your patients, but probably vice versa that. Yeah, we'll get to finally meet in person, will be great.
Mark: All right, Lara. I'm looking forward to the symposium. I'm looking forward to us talking again on the other side of that. Fabulous to talk with you and to learn a lot about what, for most males, me included, is a mystery. We don't understand ovulation. We don't understand menstruation. And I don't think that's just being a helpless male. It's complex and it is nature providing the next generation and those things have to be thought through.
Lara: I want to finish with one other thing though, because this is one of my little messages to the world, one of my mission statements is to kind of plant the idea that female health, women's health, exactly what we've been talking about, periods, menstrual cycles, are not that complicated. You know, like I know and I totally hear what you're saying, like they're portrayed as quite mysterious a lot of us feel they're quite mysterious, but they're not. So, at the end of the day, you know, I feel like women may hear that, that it's actually not that complicated. You kind of bring it back to, "Am I ovulating?” You know, “is there inflammation?” Some of the basic questions that it helps women to reclaim their cycle as something normal and logical.
Mark: And not to over-medicalise it then turn to drugs that are poor mimics of the natural hormones that we've had throughout ovulation.
Lara: Exactly. Yeah. Not to shut it all down just because it feels too hard.
Mark: Lara, thank you so much for our discussion today. I'll see you soon.
Lara: Thanks, Mark.
Mark: This is FX Omics, and I'm Dr. Mark Donohoe.