Knocked Up Podcast - Progesterone: the Pro-Pregnancy Hormone
Progesterone is often called the “pregnancy hormone”, but what does that actually mean for your body and your fertility?
Progesterone is often called the “pregnancy hormone”, but what does that actually mean for your body and your fertility? In this episode of Knocked Up, CREI fertility specialist Dr Raelia Lew unpacks how progesterone works, why timing is everything, and how this hormone helps prepare the uterus for implantation and early pregnancy.
We discuss what “low progesterone” really means (and what it often does not), how levels differ in natural cycles versus IVF, and why cycle length can tell us more than a single blood test.
TRANSCRIPT
Jordi Morrison: Okay. Hello and welcome to Knocked Up, the podcast about fertility and women's health. You were joined as always by me, Jordi Morrison and Dr. Raelia Lew, C -R -E -I, fertility specialist. Welcome, Raelia.
Dr. Raelia Lew: Hi, Jordi.
Jordi Morrison: Hi, Raelia. Today's topic is that we're talking about a hormone today.
Dr. Raelia Lew: Yeah, we thought we'd talk about the hormone progesterone.
Jordi Morrison: Yeah, we hear a lot about progesterone. I can't say I understand it, so I'm really looking forward to this episode. I want to start off with what makes progesterone so unique and essential to women.
Dr. Raelia Lew: Well, progesterone is a steroid hormone, so it's one of the families, one of the, sorry, I'll say that again. Progesterone is a steroid hormone. It's one of the family of steroid hormones, and it is the steroid hormone of pregnancy. So it is named progesterone because the jest in it is gestation or pregnancy. You can think of it as the pro -pregnancy hormone. It's the hormone that the body makes to encourage the mother to allow the baby to take hold and the pregnancy to take off and to be supported actually. So it's a really important hormone. And progesterone function is also all about timing and feedback. And so progesterone as a drug, as a medication, is often used as a form of contraception paradoxically because the timing of progesterone exposure to the womb is very important and so it can be used in one context to support pregnancy and in another context to prevent pregnancy.
Jordi Morrison: So interesting, is progesterone one of the hormones that the levels change throughout the menstrual cycle?
Dr. Raelia Lew: It is. So in a natural menstrual cycle, the menstrual cycle is so fascinating and interesting. There is a series of hormone exposures that the body produces. And it's almost like an orchestra playing a melody. The hormone pattern has to present in a certain fashion in order to open the fertile window and to sustain a pregnancy. So the first part of the menstrual cycle we think of as the menstrual period, it's really also the end of the previous menstrual cycle. And what brings on a period is really the hormones of the cycle falling to a baseline level in the absence of a pregnancy. A lot of women think of period or the definition of a period as just menstrual bleeding. And so many of us sometimes confused when we're on contraception like the pill. You know, we feel when we have a withdrawal bleed that it's a period. But actually, when you have a period on the pill, it's just because you're taking the sugar tablets, which means that the level of hormone in your body falls compared to when you were taking the active tablet of the pill. And that kind of mimics what happens in the body when the hormones come down after someone has had an ovulation cycle where they haven't got pregnant. The patterns of hormones in the cycle can sometimes have burned certain terminologies like you might have heard of the terminology estrogen dominant. And that's because the first part of the menstrual cycle is dominated by the hormone estrogen. What happens is as eggs start to ripen in the ovary, and there's a bit of competition that happens in the ovary between different follicles, which are the structures that eggs are in, in a natural cycle, estrogen is made by those follicles predominantly, and that has a role of growing a nice thick endometrial lining, which is a cushiony lining of the womb, getting ready for an embryo to implant. And in the context of assisted reproduction, we like that lining to get to at least seven millimeters in size, if we can, in thickness. And sometimes it goes well beyond that. And then what happens is as the estrogen levels peak, as a dominant follicle takes hold and suppresses through other factors. It's very complicated. There's lots of different hormones and vasoactive peptides made by the follicle, not just estrogen. But as the estrogen level piece, the brain picks up on that level. It's like a sensor in the hypothalamus. And it causes a cascade reaction where we have an ovulation search of two hormones, luthanizing hormone, LH, and also follicle stimulating hormone. And that's what people pick up when they do an ovulation predictor kit to see that ovulation is going to happen. They're actually picking up that LH usually, surge. And some very sensitive digital kits also can tell you that estrogen is getting to a peak. And that can be something that couples who are trying to conceive use as a sign that they should be trying naturally at that time because they're going to ovulate soon. And then what happens is ovulation occurs, usually about 40 hours or so after that surge is detected. And then when ovulation happens, the eggs released from the follicle and the follicle switches gears and it changes the product that it's producing from estrogen to progesterone and the cells of the ovary start to make progesterone hormone and is that sequential exposure of firstly estrogen and then progesterone to the cells of the endometrium the lining of the womb that makes the metrum potentially receptive when an embryo arrives in the womb. So that egg that was released from the follicle, if it meets sperm, fertilizes and forms an embryo, we want that embryo to have a home and the progesterone makes the uterus receptive. And one really cool fact is that it takes usually about five to seven days for the embryo to make it down the fallopian tube because the egg is released in the female pelvis the sperm has to swim up the female genital tract and find the egg usually they meet when the fallopian tube picks up the egg somewhere in the fallopian tube and it takes roughly five to seven days for that embryo to get to the inside of the womb where the endometrium is And during that five to seven days, the embryo develops. It goes from being a single -celled embryo to a cleavage embryo where it's got a few cells. And it keeps developing, dividing, dividing to the point where it becomes a blastocysts embryo when it's got about 200 odd cells. And it arrives in the womb at the stage where a blastocyst can implant. And it's just amazing. Nature is so clever that that corresponds to the same period of time, that progesterone exposure to the lining of the womb opens the window of endometrial receptivity. So it's all about timing and collaboration and synchronization. And so we want the womb to be receptive by the time the embryo arrives. Now, if there's too much progesterone too early, then that window of receptivity, it's not perpetual, it's limited. So it closes again. And so it's really only a short window of receptivity of a matter of days.
Jordi Morrison: And so too much progesterone means that that window of receptivity is shut and those endometrial cells are no longer receptive to that implantation phase of an embryo?
Dr. Raelia Lew: That is the principle of most contraception. Most forms of contraception involve giving progesterone at the beginning of a cycle and onwards so that if an embryo does make it to the womb, it can't implant because there's no receptive endometrium. So that's how the pill works. In one sense the pill has a few mechanisms it also prevents ovulation but the mini pill works that way the marina iud works that way the implanton rod works that way and deproprovera and a lot of progesterone medications one aspect of their function is preventing endometrial receptivity we also know that if progesterone rises too early in an IVF cycle We have low success rates. And so we check that also to make sure we have receptivity. Doorbell just right. Okay.
Jordi Morrison: So you sort of answered this, but I'll ask it, and you just give a quick snippet. You've briefly touched on this, and I think it was in relation to the lining, but what role does progesterone explicitly play in preparing the uterus for The, it's really,
Dr. Raelia Lew: it is about the lining. Hold on, mate, I'll just start that here. It is about the lining. So it affects the cells of the endometrium. The word that we use is decidualization. And it desist those cells. So it basically makes them into welcoming cells that the embryo can implant in. So the embryo by this stage is a blastocyst. It has an inner cell mask that's going to become the baby itself, and it has an outer cell layer that we call the troughectaderm, and the troughectaderm is going to become ultimately the baby's placenta, but its job is to invade and implant into the maternal lining. It's an amazing situation. I mean, the placenta is its own organ, its fetus derived, so it's baby derived. It's got the baby's DNA, not the mother's DNA. But his job is to implant into the lining of the womb and draw a blood supply that comes from the mother. So the mother's interface of the placenta is the lining of the womb, and that is the progesterone primed endometrium that becomes the decidua. And then the baby's side of that placental interface comes from the trophectaderm, and they basically have a situation where the baby's allowed to really plug in to the mother. And it's also, it should be, a structure that ultimately once birth occurs, separates completely from the mother and is expelled from the mother's body. And unlike when we have something like a kidney transplant, which has to be exactly matched in certain types, we have this process of tolerance, immune tolerance, that allows the mother to accept the implanting tissue of the baby, whose DNA is 50% derived from her partner or the sperm source if it's a donor, so a perfect genetic stranger. And we accept it. It's unbelievable.
Jordi Morrison: It's unbelievable. Our bodies are just so clever, aren't they?
Dr. Raelia Lew: Yeah. And so there are definitely immune issues sometimes that crop up that do affect implantation. Absolutely. We don't always understand them fully in medicine. We know they exist. We don't always understand them fully. And there will be a proportion of women who have recurrent implantation failure, both naturally and in IVF, where immune factors do play a role, because every system of our body is subject to, Unfortunately, disease and dysfunction, and this is no different when it comes to fertility.
Jordi Morrison: Yeah, sure. Where was I? Okay. So how do progesterone levels typically differ between natural cycles and then when stimulated for fertility treatment?
Dr. Raelia Lew: In a natural cycle, one follicle will be dominant, usually, and you'll ovulate one egg. And then you'll have one corpus luteum which is what the follicle becomes when it switches gears and starts making progesterone so think of it like one follicle equals one dose of this hormone and that's what the body needs in a natural cycle to open the receptivity window if you get pregnant in a natural cycle what happens is the baby makes a different hormone and that hormone is called HCG or human corionic gonadotrophin. So big word HCG. Sometimes we just call it pregnancy hormone. And that hormone actually tells the body to keep making progesterine and to make more. So the corpus luteum responds to that. So it's almost like progesterine in a natural cycle has a different pattern if you get pregnant to if you don't get pregnant. If you don't get pregnant, maybe you're not trying or maybe you were trying but an embryo did not implant and so there was no HCG signal or if an embryo tried to implant made a little bit of HCG signal and then the embryo made a mistake and stopped growing. What we see is that the progesterine peaks and then it falls and when it falls it is that fall, that drop that triggers the period. In a stimulated IVF cycle where we're trying to get many eggs to grow, we will always, always, always have much more progesterone produced by the corpus lutei or corpore lutei of the many follicles than we would in a natural cycle. And so the levels are much higher at the peak. We also see those levels sometimes rise too early. And it's just a function of how follicles are stimulated. And working together, they make progesterone potentially slightly earlier and too much. And so what that can do is it can actually open and then close the window of receptivity at a time before the embryo is ready to implant. And so by the time the embryo gets to the womb, its lining is hostile and not receptive. That's why we often do a blood test on the day that we give a trigger in IVF and we do that to measure the progesterone if we're planning to do a fresh embryo transfer or we might just decide from the outset that we're not going to do a fresh embryo transfer. So if I have a patient and they have heaps of follicles and I think they're going to have a high response. I won't do an embryo transfer. That's for multiple reasons. One of them is completely separate to prevent hypostimulation syndrome, which we've talked about in other episodes, but also because the lining of the uterus is, you know, in one way of thinking about it, overcooked. It's had too much progesterone too early, and it's not going to be receptive. So it's not going to offer the best chance of pregnancy for the best embryo for that cycle and so we'll freeze that embryo and put it back on another day. Another important point to make is that in a natural cycle, when the receptivity window opens, because it is just one follicle making that progesterone, and it's just one dose of progesterone, the receptivity window does not close as quickly. So what that means is that if it takes a blastocyst six days to get to the implanting phase or seven days to get to the implanting phase in nature, that's totally fine. The lining's still receptive. In a stimulated cycle, we tend to, if we're going to do a fresh embryo transfer, only do it on day five. Even though blastocystists might quite happily make it to the implanting stage on day six, the lining in a stimulated cycle is no longer receptive and we see lower pregnancy rates with fresh day six embryo transfers in a significant sense compared to if we freeze those embryos and put them back in another month. So in general, what we'll do is if a blastocyst is ready on day five of a stimulated cycle and we think everything else is suitable for a transfer, we'll proceed. But if a blastocyst is a little slower and it doesn't get there till day six, we'll freeze and put that embryo back in a different cycle.
Jordi Morrison: Yeah, sure. Are there any key lives? Okay, we often talk about lifestyle or health factors. Can these influence natural progesterone production?
Dr. Raelia Lew: Well, certainly age can. And so as we get older, our follicles aren't as competent. And so sometimes we don't make as much progesterone later in life as we might of earlier in life that can occasionally happen as long as we have the right building blocks and we're ovulating i mean the thing about ovulation is if we are nutritionally compromised one of the things the body does is stop us from ovulating so you'll only really ovulate naturally if your body feels that you are pregnancy ready and so not not really i wouldn't say i mean Cholesterol is a building block that we use to make steroid hormones. So even though we sometimes try to avoid eating foods high in cholesterol, a little bit is important so that we can make the hormones we need to make. But no, I wouldn't say so. I think obviously the lifestyle factors that can stop you from ovulating will stop you from making progesterine because progesterone is a hormone made after ovulation happens. So if you're an intensive exerciser or you're super skinny and you don't release an egg every month, your progesterone levels will be low. The other thing to say about progesterone, and sometimes people get really upset about progesterone because they've gone and done a blood test on a particular day and they've had a level that they've looked at and they've interpreted. We know that if we measure progesterone multiple times on the same day, we're going to get different levels because it's a pulsatile hormone, So it releases in pulses. And we also know that different stages of the menstrual cycle, we expect progesterone to be at a different level. So for example, a low progesterine at the beginning of a menstrual cycle is normal. And a high progesterone after you've ovulated and you're near your peak is normal. And a low progesterone towards the end of your cycle is normal. And if a pregnancy has not occurred or if a pregnancy has occurred but the body senses that that pregnancy is abnormal, dropping your progesterone is the correct thing for the body to do in response to that. Because we want to, if you're not pregnant, bring on another cycle. And we want to be an effective bouncer to select a healthy baby. So if there's a baby with a chromosome problem that's serious and that embryo due to that fact is not making HCG in a normal pattern. We hope that the body will recognize that and, you know, reject that pregnancy and drop the hormones to let go of that pregnancy. And when the body does that, it's fully appropriate and the body is doing the right thing. So there are sometimes people who worry that their progesterons dropping inappropriately that there might be a good embryo and the body despite that good embryo and that good HCG signal is not making enough progesterone and that's what we call a luteal phase deficiency and while that is possible it's also not a common thing i think there's a lot more people who read about the idea of a lutele phase deficiency and worry about it than actually have that problem one thing that we know is a nice sign that can tell you that you definitely don't have a luteal phase deficiency is if you have a regular menstrual cycle of a normal length. So if you have a 28 day cycle, I can tell you you do not have a luteal face deficiency. If you have a 24 day cycle, it's possible you may, depending on when you ovulate in that month. So that's one of the things that we ask you when we see you in fertility practice, how long is your menstrual cycle? And we talk about menstrual cycle from day one to day one. So we don't count or minus the bleeding days. We include them. So it's from the day of your first period to the day of your second period that the day that the bleeding starts that defines the menstrual cycle.
Jordi Morrison: You've mentioned that progesterone is a pulse, what did you say?
Dr. Raelia Lew: Pulsatile hormone.
Jordi Morrison: Pulsatile hormone and that it's hard to measure because it changes throughout the day and it changes throughout the cycle. You've described what would be happening if the progesterone was doing the right thing and your levels are right. But how do you assess that your patients have a healthy hormonal balance? Not just progesterone, but I suppose all hormones.
Dr. Raelia Lew: So progesterone, it's because the length of their cycle. That's the key indicator. And it's also the pattern. So there's a normal pattern of a menstrual cycle. And so we can judge hormonal levels to know where you're at in your cycle and to know if that cycle is functional and regular. But medical history gives you a lot of information. So you don't have to measure hormones to know that a menstrual cycle is functional. If someone has a regular cycle, you can infer that.
Jordi Morrison: And is there a point where a woman who's trying to get pregnant where she should be concerned about having a hormonal imbalance?
Dr. Raelia Lew: Definitely one of the things we measure and look into in women who are having difficulty getting pregnant is their hormones. But we look into that in the context of casting a wide net and looking at lots of things and also asking lots of questions. and we get just as much information from asking questions as we do from measuring blood hormones in terms of inferring whether someone has a regular or functional ovulation and we can also do things like have a look at anatomy, look at the ovulation signs and symptoms to know if someone's releasing an egg. It's a very straightforward thing if the problem that someone has is they're not ovulating and it's a very the most common problem that causes that's polycystic ovarian syndrome if that's the only thing that's stopping someone from getting pregnant then correcting that and helping them to ovulate is often the first step to try to help them in IVF it's a little bit different So there's different types of IVF stimulations. There's different hormones involved and different people's bodies respond differently to what's going on. And so we'll often measure hormones in IVF to make sure that we're putting an embryo back at the appropriate moment and to make sure that the body is providing the right hormonal environment. And we do always in a stimulated IVF cycle top up progesterone in the luteal phase because we know that in that context and it's completely doctor caused medication caused progesterine is insufficient after the egg retrieval and it's to do with the dynamic of follicles not in the natural body but just how they respond to drugs so we know that And that's quite often why if we have a good prognosis patients, and this is the case in my practice and my patients will be familiar with is, a freezing first approach and then making your embryos and putting them back into a more natural cycle does achieve higher pregnancy rates predictably for a large proportion of our patients, not everybody. We know that in a poor responder population or low responder where, and this can be because patients are older, it can be because embryos are fragile, that is a situation where they might do better with a fresh transfer. So it does come down to the individual, and we manage the hormone levels specifically to that person, so we will be checking them often.
Jordi Morrison: And are there any other than cycle length, are there any common signs of low that can affect for conception?
Dr. Raelia Lew: There's not really signs, except for getting your period really early, which I guess is the same thing as short cycle length.
Jordi Morrison: Yeah.
Dr. Raelia Lew: So it's really that. That's the main issue. There's not really other symptoms or signs that you would pick up that would point to a luteal phase concern. It's the dropping of the progester and the getting of the period before we hope or expect expected to come. That's the main sign and symptom.
Jordi Morrison: Do you just, if you got the questions up, okay, I'll just read them out to you and you just let me know if I should ask them, because we've covered quite a bit. So I've got, what are some of the most common signs of low progesterone that can affect conception? How does the, how does inadequate progesterone impact implantation or early pregnancy? What are some ways to test for just, progesterone deficient? I think the problem's looking me hold on one second. Do you want to tell us, yeah, the questions here we have kind of covered, do you want to ask me that the different types of progesterone that we can use as medicine?
Dr. Raelia Lew: Yeah, sure.
Jordi Morrison: So you've mentioned supplementing progesterone throughout fertility care. What are the types of progesterone that you can use to do this?
Dr. Raelia Lew: We use micronized progesterone. So we use the progesterone hormone itself as opposed to progestergens. When we use things like HRT, we can often use different types of activators of the progesterone receptor, but we don't really like to do that in IVF or fertility medicine because we want to give the natural style of progesterone. We know that that doesn't cause any potential harm or when it's given as an exposure to a baby because it's the same hormone that people make in pregnancy themselves so we give natural micronized progesterone we can give it in many ways so one way is oral but that's not used very often and the reason is that when progesterine is given orally because of the way we metabolize it you have to give really high doses for it not to be first broken down and that means that you have very high levels of side effects with oral progesterone. And the kinds of side effects you get from progesterone can be things like breast tenderness, feeling really drowsy and sleepy, feeling really bloated and yucky, having the bowel be a bit sluggish, having ligaments being a bit stretchy and potentially sore. So we tend not to give oral as the main way of giving progesterone. So ways that we can avoid the oral and first past metabolism are by giving it vaginally. Now, a lot of people don't like vaginal progesterone because it can build up. It can have residue. It can cause sometimes irritation. But it is quite well absorbed that way and it will be given that way often in IVF. You can give it rectally as well. well. And again, that's culturally not common in Australia, but it is a way that you can give it. You can give it as a subcuticular injection. So you can give it as an injection that you self -administer daily. And there's also progesterone in oil, which can be given as an intramuscular injection, very effective but very sore. So we try not to use that if we don't have to. It is used more commonly in other countries. So people will see that if they go online and read sources from places like America. We don't use it as often in Australia. I do use it sometimes. It is a very effective method of getting progesterine levels nice and high. So those are the main ways. And then within those ways, there are different brands. I won't mention brand names on the podcast, but suffice it to say, particularly with the vaginal progesterine, there are different different creams, gels, tablets, you know, dissolving peceries, compounded peceries. There's different ways of giving vaginal progesterone.
Jordi Morrison: Yeah. We've really talked about progesterone in the context of fertility and IVF. But what if someone's conceived naturally? Do they sometimes need progesterone supplementation? and how would we know this?
Dr. Raelia Lew: Sometimes progesterone will be given for the prevention of miscarriage or the prevention of preterm birth in certain patient populations, particularly if they have demonstrated a risk previously or had an adverse pregnancy event previously, like having a shortened cervix or having a baby very early. So sometimes we'll do that. Sometimes if we have a patient who has what we call a threatened miscarriage, which means they've bled in early pregnancy, but the pregnancy is ongoing, we might give some progesterine therapeutically because it's a very calming hormone that assists in placental formation and we want to do everything we can to settle down their bleed and help them move forward with their pregnancy. So there are circumstances where a doctor will prescribe progesterone in the first trimester. It can do no harm. It may potentially mask an inevitable loss. So sometimes when we support a pregnancy that wasn't quite right and the bleeding might have been because the body was trying to resolve the pregnancy, we might prolong the inevitable because giving progesterone won't make a pregnancy that's wrong, turn right. But it can sometimes be useful to help in a situation where there's early pregnancy bleeding. Also another important time that we must give progesterone for longer is an artificial cycle where we've put an embryo back. So that's when we've completely replaced the hormones of early pregnancy with medication. It's a less commonly used technique, but it might be used, say, for women who it's really hard to get them to ovulate, or it might be used for someone who's menopausal and is trying to get pregnant after her menopause and so we're fully replacing everything. Quite often it's used in donor egg cycles to synchronise the donor and the recipient's cycle. There's different reasons that we would use an artificial cycle sometimes. And with an artificial cycle, progesterone is not being made by a corpus luteum in the body and it has to be replaced up and to the point where the placenta is the main progesterone making factory. And so that usually would continue to somewhere between 10 and 12 weeks gestation.
Jordi Morrison: And finish off, Raelia, are there any common misconceptions about progesterone and fertility?
Dr. Raelia Lew: There are. So one common problem, and this is a reason why women should not self -prescribe or self -source progesterone, is that if you introduce it at the wrong time of your cycle, it's contraceptive. That's how the morning after pill works. How that works is that you have an oops moment and you think, oh, you know, I might get pregnant, I don't want to be pregnant. So what you do is you take very high -dose progesterone to prematurely close the receptivity of the uterus. So you will get the same effect if you yourself introduced progesterone too early. So definitely it should not be used throughout the cycle. It would be contraceptive if you did that. And definitely it should not be introduced before ovulation is 110 percent confirmed because then again it could be contraceptive and have the opposite effect to the desired effect. So I would say don't self -prescribe progesterone. Don't self -diagnose progesterone deficiency. If you need help, see a doctor.
Jordi Morrison: Great news. Great advice as always. Thank you, Raelia.
Dr. Raelia Lew: Thanks, Jordi.
Hosted by Dr Raelia Lew and Jordi Morrison
Dr Raelia Lew is a RANZCOG Board Certified CREI Fertility specialist, Gynaecologist and the Director of Women’s Health Melbourne.
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