Transcribed by Jazmin Lui May 10 2014

ORGAN SYSTEMS – PHYSIOLOGY OF REPRODUCTIVE SYSTEM II – DR. SCHIFF

1. Intro: 3 cycles regulating female reproduction processesOk good morning. Today we’ll be talking about the more interesting half of the population. And certainly from a physiology point of view the more complicated part of the population. After all, basically once you have an adult male all that’s required for him to be fertile, is for someone to say yes (laughter). But in women the reproduction processes are much more complicated. And it’s been likened to a 3 ring circus because there’s 3 things happening and they’re all synchronized. What you’ve got is changes in hormone levels related to changes in the ovaries. You’ve got changes in the ovaries themselves related to ovulation, which Dr. Lopez went through. And there are also changes in the uterus to prepare it for possible implantation of a fertilized egg having become an embryo. And all of these things are going along in synchrony over a periodic cycle that runs about 28 days, more or less. So you have a uterine cycle, you have a hormonal cycle and you have an ovarian cycle. Now I’m not going to spend too much time on the ovarian cycle in terms of maturation of follicles and the like, and eventually ovulation, except to refer you back to what Dr. Lopez said.

2. Hormonal cycleWhat you have in the hormonal cycle, which gets a little complicated compared to that of the males, is basically you have the hypothalamus releasing some gonadotropin releasing hormones, there seems to be an LH releasing hormone and an FSH releasing hormone but these are generally all secreted simultaneous so what you’ve got here is, sort of lumped together as gonadotropin releasing hormone. And they then act on the gonadotropes in the pituitary, some of which produce LH and some of which produce FSH. At this point there is no big difference between male and female, the scheme up to this point is identical. Now what then happens, is you have the follicular, oh I’m skipping here, what you then have is the follicular development which eventually leads to theca cells and granulosa cells, which roughly correspond to the Leydig and Sertoli cells in the male. But, not really, just that there are two different types of cells and the theca cells are generally stimulated by LH and FSH generally stimulates the granulosa cells. And when this develops eventually into a corpus luteum you’ll have theca luteum and granulosa luteum cells. Now in the male, life is simple, the Leydig cells secrete testosterone, period. And that’s where the hormones come from. The corresponding hormones, the estrogens, specifically estradiol, can’t be made by theca cells or granulosa cells. Neither one alone is capable of synthesizing the hormone. What you’ve got is, the theca cells…both are capable of taking the first few steps in

Transcribed by Jazmin Lui May 10 2014

the synthesis. Then, this sort of dead ends here. But since the cells are physically next to each other they can share what they’ve made. And at this particular point – let me save myself some walking and leave the specific notes here – you’ve got pregnenolone which is a dead end in the granulosa cells but can be sent over to the theca cells which are also capable of making pregnenolone. The theca cells can then take the pregnenolone a few more steps to produce androgens, that is DHEA, androstenedione, and that’s a dead end as far as the theca cells are concerned. But the androgens can then shift back, shared again, to the granulosa cells, and the granulosa cells can take these androgens and with and aromatase, and by androgens I mean those same androgens produced in the adrenal cortex, in the zona reticula, but also testosterone. And those androgens including testerone, are subject in the granulosa cells, to an aromatase which produces estrogens, including in the case of testosterone, estradiol. So basically what you’ve got here, in the ovary and eventually in the corpus luteum are 2 different kinds of cells, that between them can make these different kinds of hormones, these estrogens, specifically estradiol. Now, it’s a little more complicated, also, because once you’ve got these estrogens, in particular estradiol, you have a feedback loop because this is the hypothalamic pituitary axis, and there’s a sort of feedback here. But you may notice I didn’t put a minus sign and a circle. Strange things happen in these female people. Most of the time it’s your standard inhibition. But sometimes it switches into a positive feedback. And the mechanism for that switch, which obviously, since estradiol is estradiol, the change somewhere is in the pituitary gonadotropes and somehow they undergo some sort of change, or it’s been suggested that there may be multiple estradiol receptors in these gonadotropes and you know, when I was discussing dopamine and sometimes at low concentrations you get a vasodilation but at higher concentrations you get vasoconstriction? When I was talking about the afferent arteriole in the kidney? See how this whole course comes together? Just like a final exam (nervous laughter). Something changes here and at specific times in the cycle, this is sometimes a plus, a positive feedback. And we’ll go through that in a minute.

Transcribed by Jazmin Lui May 10 2014

3. Hormonal levels over 28 day female cycle

Let’s go to the first diagram that I stuck into the handout. Basically it’s a diagram of an approximately 28 day cycle. And I think just as I did there, you’re going to have, we’re gonna need some colours, I don’t know how you take notes but you’ve got the handout. We’re referring to a 28 day cycle, or 29 or 30, they’re different in different women. It really has no relationship to the moon. Early people considered that –

Transcribed by Jazmin Lui May 10 2014

“hey, this is 28 or 29 days, the phases of the moon, must be a link”. A post hook ergo proctor hook argument, if it follows it must be caused by – which is false. And generally to define this 28 day cycle, day 1 is referred to as the beginning of the menstrual flow. So what you’ve got here is, first of all there’s the sloughing of the uterine lining of the uterus, and you’re assuming there’s no pregnancy here, cause then we’d stop cycling if there is pregnancy. But there’s the sloughing of the uterine flow, but meanwhile the LH and FSH levels are kind of low and are sinking lower, ok? So we’ll say FSH and LH, which are produced in the pituitary and travel through the circulation, they’re kind of low, but FSH and LH stimulate the production of the estrogens including estradiol. So as long as they’re here at all, estradiol levels are slowly rising. And as you go on, up to about day 8, 14, so let’s set up this axis…so let’s say up to about day 10, so up to about here the estradiol is creeping up. And the more estradiol there is, it inhibits, there’s that minus sign, it inhibits the gonadotropes, so the LH and FSH keep going down. OK? Now, something happens around day 10. And this minus changes to a plus. And this is one of the few places in the body, well the first one you ever saw was in sodium channels and excitable tissue, where depolarization increases sodium permeability which further depolarizes the cell. This is positive feedback. There are very few instances of positive feedback in the body because in general homeostasis is maintained by negative feedback. But here’s positive feedback. Now, estradiol, which is high, stimulates FSH and LH secretion. So the FSH heads up, the LH heads up even more so, and because they’re going up the estradiol is going up even more so. So from day 10 up to about, where’s the eraser, I made them a little steeper than they ever would be in real life, let’s just slow this down a little bit, and estradiol is going up up up until about day 13. And about day 13, that plus changes back into a minus. So something happened for about 3 days that led to positive feedback between the estradiol and gonadotropes. Now, the estradiol has gotten even higher because of the high LH and FSH concentrations, so now estradiole is way up there. This now inhibits their production so they head back down after going through a peak at about day 14 they go back down. And when they go down, the estradiole heads back down. But meanwhile, just before day 14 there was this enormous surge of FSH and LH. LH in particular leads to rupture of the Graafian follicle, which is ovulation. So right here on day 14 in this ideal predictable cycle, in which everything happens exactly according to clockwork, which is why they used to call couples you used rhythm method of contraceptive, parents. There’s always a little variation here. So this goes down, you’ve got this peak of LH and FHS, they’re going down. But meanwhile, the LH, luteinizing hormone, it’s called luteinizing hormone because it promotes the formation and maintenance of a corpus luteum. What’s a corpus luteum? Well after the follicle ruptures and

Transcribed by Jazmin Lui May 10 2014

just before ovulation this Graafian follicle has gotten pretty big compared to the size of the ovary. The remaining lining of the Graafian follicle forms what is known as corpus luteum, which is the word for “yellow body”. Corpus is body, luteum refers to yellow. And corpus luteum can cover like, if you look at an ovary, about a 1/3 of it, it’s enormous! And as long as the corpus luteum has formed, it starts producing, of all strange things, estradiol. So the estradiol starts going up again. Now the corpus luteum, unlike the ovary before ovulation, is also capable of producing progesterone. So here’s your estradiol, again, so you keep track of the curves, there’s essentially no progesterone formed along here, but once the corpus luteum forms the progesterone goes up. So you have estradiol up, progesterone up, and what do the estradiol and progesterone do? They A) inhibit the production of LH and FSH. So these fellows keep going down and down. And B) they promote the thickening of the endometrium, the vascularization, and all of the things that Dr. Lopez described in terms of going on in the uterine lining. So you have this thickening and increased vascularization of the uterine lining, so that if the egg that’s been kicked out, happens to be fertilized, it’ll have a nice place to land.

4. Ovulation process (ovary uterus) Now, here’s the egg, shoots out the surface of the ovary, and somehow it’s collected into the oviducts or fallopian tubes. Now how does that happen? Well the fallopian tubes come up to the ovary and partially surround it with finger like projections called fimbriae. And around the time of ovulation these fimbriae grow, and extend to cover more and more of the surface area. They also have cilia on their inner surface, the surface towards the lumen of the fallopian tube, which wave and create a fluid current, from ovary towards down uterus. Because the egg that formed during ovulation, unlike the sperm, don’t have a tail. So they can’t swim. They just passively go with the flow, the current flow of fluid within the fallopian tubes. And the cilia in the fimbriae wave it towards the opening of the fallopian tube, and there are further cilia lining the fallopian tube that create current flow, down towards the uterus and that carries the egg along. So now you’ve got the egg, heading towards the uterus. Now, there are all sorts of things going on, at this particular time interval. It takes 3-4 days for the egg to reach the uterus with this passive flow.