BISC 307L 2nd Edition Lecture 22 Current LectureEndocrine Events of Ovarian & Menstrual CyclesThe first and third row showchanges in importanthormones over the course ofthe ovarian cycle. The averageduration of the cycle is 28days. The 2nd row shows whatthe follicle looks like, and thebottom is what theendometrium or innermostlayer of the uterus, looks like. The 28-day cycle can bedivided into two halves – afollicular phase and a lutealphase. The follicular phase isthe first 14 days, dominatedby the events going on in thefollicle in the ovary. The lutealphase is dominated by the corpus luteum, the remnants of the follicle after ovulation has occurred. Day 1 is the onset of menstruation, which is the first appearance of blood out of the vagina. In the first few days of the cycle, levels of estrogen are falling. This estrogen has been coming fromthe corpus luteum, and it is degenerating so estrogen levels are falling. But then estrogen stops falling, and begins to increase because the follicle is growing (the theca cells are secreting testosterone, which the granulosa cells convert to estradiol, and that accounts for the rising levels). There is also a positive feedback cycle involved, because the estrogen itself stimulates the granulosa cells, which are estrogen dependent, greatly increasing the levels of estrogen. As the follicle grows and secretes more estrogen, estradiol rises.In particular, there are 6-10 follicles that move on to the second phase. Through mechanisms that are not understood, one follicle begins to grow more than the others. It grows faster and faster, and the others stop growing and regress. In rare cases, two of them will ovulate simultaneously, and if they both get fertilized you get fraternal twins. So the follicle increases its output of estrogen, but ovulation occurs which injures the follicle, so estradiol levels dip. But that’s just a temporary reduction because the remnant of the follicle that stays behind in the ovary will differentiate into the corpus luteum, which pumps out estrogen and progesterone in increasingly higher levels. So the estrogen levels (purple trace in the 3rd row) increase as the corpus luteum develops. Progesterone is seen to be low in the first half because it is only secreted by the corpus luteum, which develops in the second half of the cycle. So in the third week we have high levels of progesterone and moderately high levels of estradiol. But the corpus luteum has a fixed lifespan– it will last only 10 days or so, and then degenerate unless it gets continued gonadotropin support (FSH and LH). The levels of FSH and LH are pretty low, however, except for the spike in the very middle. They reach their lowest levels in the second half of the cycle, which is due to the high output of progesterone and estrogen in the second half that feeds back and inhibits theGnRH and therefore FSH and LH secretion. These low levels of gonadotropins doom the corpus luteum to regression in 10 days. However, if fertilization occurs one of the extra embryonic membranes of the fetus called the chorion will secrete a chorionic gonadotropin that will support the corpus luteum and its estrogen and progesterone secretion throughout pregnancy. The early appearance of chorionic gonadotropin is the basis for pregnancy tests, and the most reliable early sign of pregnancy. Inhibin levels are also shown on the third row - inhibin is secreted by granulosa cells, so its profile of secretion is about the same as that of estrogen. This all began at menarche, the beginning of reproductive cycling in girls, and continues for 30-40 years, before becoming irregular and ceasing at menopause. The traditional explanation of menopause is that the original supply of follicles at birth become depleted because no new ones are produced. After menopause, the levels of gonadosteroids are low because the follicles that secrete estrogen or progesterone are no longer available. And because of the lack of negative feedback suppression, levels of gonadotropins are high. Because estrogen supports secondary sex characteristics in women (like deposition of fat, vaginal secretion during intercourse, libido, bone and muscle strength), those things tend to wane in women during menopause. Small dosages of estrogen given as hormone replacement therapy can reverse many of these changes and have been used extensively recently to fix these side effects. However, it was found that it raised chances of getting cancer, so the number of women in developed countries who chose this route declined rapidly.Pictured in the fourth row of the diagram is the endometrium of the uterus. This tissue is sensitive to estrogen and progesterone, and it will grow and differentiate in response to those hormones. At the beginning, levels of estrogen and progesterone are falling, but they’ve been high for a while (at the end of the previous cycle) so the endometrium has grown thick. Within a short period of time, the endometrium begins degenerating through necrosis (they are murdered), not apoptosis. As the tissue expanded, it became vascularized, so these spirally blood vessels (called spiral arteries) grew with the wall, and supplied blood to the thickened endometrium. From the beginning of week 2 to the end of the cycle, estrogen and progesterone are high, preventing the synthesis of prostaglandins from the endometrium. These prostaglandins, if theywere present, would cause vasoconstriction. In their absence, blood flow is fine. But when the levels of estrogen and progesterone fall at the end of the cycle due to the regression of the corpus luteum, prostaglandin secretion is no longer suppressed. The smooth muscle of the spiral arteries strongly constricts in response to these prostaglandins, and the tissue dies a necrotic death because its blood supply is cut off. These tissues become ischemic (loss of blood supply) and die. After several days of this, the tissue is pretty degenerated and no longer able togenerate prostaglandins, so prostaglandin levels go down as the tissue dies and vasoconstrictionis relieved, which results in more and more bleeding, or menstruation. So menstruation (external bleeding) is due to tissue being unable to produce any more prostaglandins. And the point of this bleeding is to lift this degenerated tissue and flush it out of the uterine cavity. Prostaglandins also activate contraction of the myometrium in different women, so prostaglandin synthesis can cause painful