The backstory of the Unsung Hero of Early Pregnancy: the Corpus Luteum

This week’s episode is the ‘Making Sense of Pregnancy’ version of the broadway play (and now movie) Wicked: it provides the back story of a critical character in pregnancy that you likely didn’t know enough about. 

It also serves as a useful introduction to next week’s show that features the work of a scientist who is trying to untangle one possible path to preeclampsia that seems to arise in women who undergo a certain form of IVF.  

And that story hinges, critically on this temporary organ you are making every month called the corpus luteum. Today I’ll share the current state of research on how the corpus luteum is formed and what it does or, alternatively, all the things I didn’t know about how these temporary organ, critical for the survival of our species, is formed and managed inside a woman’s body.

Transcript

This week’s episode is the ‘making sense of pregnancy’ version of the broadway play (and now movie) wicked: it provides the back story of a critical character in pregnancy that you likely didn’t know enough about. It also serves as a useful introduction to Next week’s show that features the work of a scientist who is trying to untangle one possible path to preeclampsia that seems to arise in women who undergo a certain form of IVF.  And that story hinges, critically on this temporary organ you are making every month called the corpus luteum. Today I’ll share the current state of research on how the corpus luteum is formed and what it does or, alternatively, all the things I didn’t know about how these temporary organ, critical for the survival of our species, is formed and managed inside a woman’s body.

Welcome to making sense of pregnancy.

This show is a new pregnancy reference. I'm finding and talking with experts, doing cutting edge work to better understand what we do and don't know about pregnancy and what you can do to better understand your own experience. Each week, I'll be talking to scientists, doctors, and researchers who are trying to uncover the many mysteries that still exist in reproduction. Giving you the most current evidence-based way to approach this enormous transition in your life.  I hope it  will become your go-to source for how to make your pregnancy better. 

There are many things that line the road to getting  pregnant.

One of the critical first steps is making the eggs, 

Before I jump into this topic, you should know that most of the things I’m going to recount below are insights gained from animal studies…so just keep that in the back of your mind…

When it comes to eggs, the good news is that a lot of the early work has been done for you by your mother; all of the eggs you’ll ever have are made while you are in your mother’s womb. By the fourth month of gestation, you have 6–7 million oocytes in your ovaries and about 1–2 million left at birth. That’s the “easy part”. You haven’t lifted a finger yet and you are kitted out with a pretty sizable pool of eggs or oocytes or more exactly, follicles, which are oocytes wrapped in a layer of granulosa cells, which act like babysitter cells. This whole process, where a follicle forms, proceeds through several growing stages, develops to eventually release the mature oocyte, and turns into a corpus luteum (CL) is known as “folliculogenesis”. We are going to be walking through these steps because they are key to your fertility, your ability to sustain a pregnancy, your long term fertility, your brain health, menopause, and the fate of the free world, 

You might hear about this change in the follicle count, from a cool six million to one million and think, “this sounds like a lot of attrition because it is, and at the same time, more than a million follicles is a big pool from which to select the ones most likely to succeed. The rate of Follicle loss slows after birth, but continues so that when puberty hits, you have about 300,000 to 400,000 follicles. 

Scarcity mindset would be gripping her head in her hands at another big loss here,  and mother nature is looking super wasteful when it comes to follicles; making way more than we’ll ever use.  Why does this happen? Short answer, we don’t know for sure; 

there are theories about why this is happening; one is that the loss in utero is of follicles that have lower developmental potential–something is wrong with them and we are getting rid of them so that you don’t waste precious resources ovulating them; its a selection process…another theory, dealing with the loss after birth is that primordial follicles have different roles. According to this theory, there are two waves of follicle loss and the first wave of follicular degeneration happens, before puberty because these primordial follicles, as they are called, are setting up the ovary to be able to cycle, setting the stage for the endocrine show, (which happens when the ovaries secrete hormones like estrogen and progesterone directly into your bloodstream) while the second wave, the ones that are still around after the onset of puberty are tasked with development with the goal of being used to create babies; it could also be the case that the relatively large pool that exists postpuberty is a hedge against  unpredictable future events like illness, environmental insults, fluctuating fertility—ensuring that you will have the opportunity to have babies for decades? This is a fundamental question because whatever sets the size of the ovarian reserve is also setting the clock for your fertility…it sounds like progress is being made on these questions, but there are  a lot of holes in our understanding of this complicated process.

During the period from puberty to menopause, roughly 37ish years, you’ll lose about 1000 follicles each month until your ovaries decide it’s time to stop preparing eggs and the uterus for pregnancy (ie menopause) when the number of remaining follicles is <1000 (as you can imagine, that in and of itself is a whole process, scientists think that menopause is initiated by changes in the hormonal signaling of this ovarian reserve, and how the ovarian reserve affects the hormone feedback loop in your body between your ovaries and brain will be more obvious when we talk about what’s going on to stimulate follicles to mature)

Let’s imagine we are just beyond the doorstep of puberty, so hormones are up and running; these follicles that have been mostly napping in your ovaries are about to go through alternate periods of  action and inaction, growing and waiting; ultimately, an oocyte does not fully mature until it absolutely has to, which happens when the egg is fertilized with a sperm; 

The birds eye view is that folliculogenesis is going on in the background on a nearly year long cycle and menstruation–which is putting the developed follicle to use (on average a 28 day cycle) is going on more in the foreground, which is to say that you can feel lots of the changes in your hormones that govern the later parts of follicle maturation and prepping the uterus for an embryo; what you may feel is the impact of these hormones on your brain and uterus; hormones are changing your brain every month–recent research shows that your menstrual cycle causes dynamic, reversible changes in brain structure and connectivity, we’re talking about hormone-driven increases and decreases in cortical thickness and gray/white matter volumes in a bunch of brain regions linked to cognition, mood, and sensory processing–likely you are feeling some of that; when the progesterone tap is shut off, in the case where no egg is fertilized, you can often feel your uterus contracting (ie the dreaded cramps–which, I’m going to go out on a limb and say its annoying to have women playing sports on the tampon box, but there is evidence that physical activity can alleviate some of the pain symptoms, bc exercise releases endorphins, which is a natural pain medication, and increasing blood flow to your pelvic area helps to flush out the prostiglandins faster–those inflammatory molecules that are inducing contractions) ;  whether you feel it or not, hormones released by your brain nudge the pituitary to release FSH, follicle stimulating hormone, that wakes up the follicles, but it does this selectively, somehow.  

It starts with the recruitment of a bunch of primordial follicles into the pool of growing follicles 

This year long process can be divided into two phases. The first phase–which takes about 10 months! happens outside the shadow of hormones produced by the brain and pituitary; it is driven by what are called “local factors”, meaning communication between the oocyte, and the cells that surround the oocyte, called granulosa cells and involves  growth and differentiation of the oocyte.  I (and here I’m guessing its me alone) think of the granulosa cells as kind of a grandparent, as the name implies, again, no doubt only to me (etymology is not my strong suit) ; these cells shepard the oocytes through every part of their lives; more on that soon; The second phase, which lasts about two months– is driven by hormones and involves a ballooning of the follicle, both the oocyte and the granulosa cells that surround the oocyte and a third type of cell, the theca cells; This second phase is regulated by FSH and LH as well as by growth factors.

Which follicles are chosen and what does that process look like? This is a question scientists are still working out. As far as I can tell, work on this question has been done on mice or on cells that remain after IVF (which were described in the paper i read about them as “highly drugged” with hormones, so not a base case); this is both frustrating, and makes sense to me; it’s hard to see what’s going on in a human ovary; not only is there chemistry that’s important here, that maybe could be examined in a petri dish, but other things, like how much oxygen is in the environment (low oxygen being preferred by these cells) and the physical pressure on follicles may also play a role in this issue of activation. At present, the consensus, if you can call it that, is that this some element of selection is random, and some is a local issue; it involves signalling between the oocyte and the granulosa cells and signals produced by the ovarian tissue (there’s a paper in the journal Cell from 2021 in which the authors state: recent identification of this specific signaling pathway as the key controller for follicular activation has “made the study of primordial follicle activation a hot research topic in the field of reproduction”–and part of the reason it’s ‘hot’ is that if we knew how to turn follicular development on it might help people with infertility issues by allowing for follicular activation in vitro). This is also important to understand how the ovarian reserve is being protected (or not in conditions where too many follicles are recruited too early and menopause hits in your early forties

Once a bunch of primordial follicles are released from the section of the ovary they were living in (in the cortex maybe?), they are exposed to hormones and they start to grow; and this growth is a competition; in the story of fertilization you always hear sperm cast as these valiant heros, swimming through the reproductive tract, bobbing and weaving to avoid all the obstacles set out before them–obstacles which are weeding out the weaker sperm and trying to screen for the most ‘fit’ sperm; but what you don’t hear about is the competition going on amongst your follicles, which are also in a fight to the death,  competing to see who will be the dominant follicle, the one that will be released into the neighborhood of the fallopian tube; all these follicles are growing in response to FSH. both the oocyte grows and and the granulosa cells surrounding the oocyte grow too; they transform from these flat looking cells into cubes and they multiply and multiply, making more and more layers of cells. 

The follicle that’s most sensitive to FSH, ie has the most FSH receptors and grows the fastest, will win this competition; and it’s a winner take all competition; the dominant follicle gets to go on and maybe become an embryo and all the other follicles die off. 

How does this happen; it looks like as the follicles are stimulated to grow thanks to FSH, the one that grows fastest starts releasing estrogen, more and more estrogen (this is the primary contributor to that estrogen peak–when you feel strong and confident and full of energy, thats a love letter of sorts, sent to you from these granulosa cells; and it’s being sent not to make you feel great, but to switch on a negative feedback loop, telling your pituitary to tamp down on the FSH…so it essentially shuts off the growth supply to the other follicles.

So we have the dominant follicle now; its encased in granulosa cells and these theca cells which will be important to hormone production when the corpus luteum is ultimately formed (and of course, the zona pellucida which is going to try to limit fertilization to one sperm). All along, lutenizing hormone has been produced alongside FSH, but in mid cycle, the LH surges, and that pops the oocyte + zona pellucida jacket + a small gathering of granulosa cells out of the dominant follicle so that it can make its way to the fallopian tube; LH also acts on the fallopian tube. LH tells the fallopian tube that the egg competition is over and there’s a winner. This hormone makes the fingers of the fallopian tube, the fimbrae stiff, and they scrape against the surface of the ovary to create wave action in the surrounding fluid that draws the secondary oocyte to the fallopian tube and then cilia, little hair like projections inside the fallopian tube sweep the oocyte into the ampulla, the cup shaped part of the tube to await the arrival of sperm (or not).

But lutenizing hormone isn’t done. The outside of the dominant follicle, the granulosa cells (among others) that grew and housed the oocyte continues to develop. Blood fills the space that the oocyte used to occupy and the cells in the vicinity take in all kinds of nutrients and it turns yellow (luteal means yellow) and this structure becomes the corpus luteum. Those granulosa cells have launched their babies (the oocyte) and now parent from afar; they develop blood vessels and become this temporary organ; the main switch, again, caused by this LH surge, is that they mostly stop making estrogen and now they focus on churning out lots of progesterone.  it also produces other hormones that stimulate the brain to release factors that support the CL (noones mad at a little self promotion here). It’s also producing a hormone called relaxin, which scientists think helps with the vascular remodeling of the uterus and cervix, prepping the uterus for the placental hook up (or so we think). The other player in this game is the developing embryo, which also secretes hormones that support the corpus luteum.

That’s right; with every period you are creating a temporary organ that secretes hormones to help in the development of your uterine lining which is feeding your developing embryo until the placenta project is completed around 10 weeks into a pregnancy. That progesterone is also keeping your uterus from contracting and shedding the lining that may be home to the embryo. Did you know you were producing a temporary organ each month? That dies off if you don’t get pregnant.

If you don’t get pregnant, the corpus luteum starts to degenerate, which drops the progesterone level, which encourages your uterus to shed the thickened uterine lining, which is your period.

This process is both elegant and extremely complicated; like a ridiculously big symphony played across your body, from brain to ovary to pituitary to granulosa cells, corpus luteum and uterus. 

The corpus luteum is the star of next weeks episode and I wanted to give a bit of back story before you hear about how critical it might be for the development of a healthy pregnancy.

Thanks for listening. If you liked this show, or learned something about your body that you want to share with friends (I didn’t know most of this until the interview I did about two weeks ago), pls pass along this episode.

We’ll be back next week with some very cool research that focuses on the corpus luteum.