-
17.14 Control of Ovarian Function
- The major factors controlling ovarian function are analogous to the controls described for testicular function.
- They constitute a hormonal system made up of GnRH, the anterior pituitary gland gonadotropins FSH and LH, and gonadal sex hormones—estrogen and progesterone.
- As in the male, the entire sequence of controls depends upon the pulsatile secretion of GnRH from hypothalamic neuroendocrine cells.
- In the female, however, the frequency and amplitude of these pulses change over the course of the menstrual cycle.
- Also, the responsiveness both of the anterior pituitary gland to GnRH and of the ovaries to FSH and LH changes during the cycle.
-
Patterns of hormone concentrations in systemic plasma during a normal menstrual cycle
 - (GnRH is not shown because its concentration in systemic plasma does not reflect GnRH secretion from the hypothalamus into the hypothalamo–hypophyseal portal blood vessels.)
- In Figure 17.22, the lines are plots of average daily concentrations; that is, the increases and decreases during a single day stemming from episodic secretion have been averaged.
-
FSH graph over cycle
-
- FSH increases in the early part of the follicular phase and then steadily decreases throughout the remainder of the cycle except for a small midcycle peak
-
LH graph over cycle
- LH is constant during most of the follicular phase but then shows a very large midcycle increase—the LH surge—peaking approximately 18 h before ovulation. This is followed by a rapid decrease and then a further slow decline during the luteal phase.
-
Estrogen pattern over cycle
-
- After remaining fairly low and stable for the first week, the plasma concentration of estrogen increases rapidly during the second week as the dominant ovarian follicle grows and secretes more estrogen.
- Estrogen then starts decreasing shortly before LH has peaked.
- This is followed by a second increase due to secretion by the corpus luteum and, finally, a rapid decrease during the last days of the cycle.
-
Progesterone pattern over cycle
-
- Very small amounts of progesterone are released by the ovaries during the follicular phase until just before ovulation.
- Very soon after ovulation, the developing corpus luteum begins to release large amounts of progesterone; from this point, the progesterone pattern is similar to that for estrogen.
-
Inhibin pattern over cycle
- Not shown in Figure 17.22 is the plasma concentration of inhibin.
- Its pattern is similar to that of estrogen: It increases during the late follicular phase, remains high during the luteal phase, and then decreases as the corpus luteum degenerates.
-
FSH increase at the end of cycle (16 to 1)
- There are always a number of preantral and early antral follicles in the ovary between puberty and menopause.
- Further development of the follicle beyond these stages requires stimulation by FSH.
- Prior to puberty, the plasma concentration of FSH is too low to induce such development. This changes during puberty, and menstrual cycles commence.
- The increase in FSH secretion that occurs as one cycle ends and the next begins (numbers 16 to 1 in Figure 17.22) provides this stimulation, and a group of preantral and early antral follicles enlarge 2 .
- The increase in FSH at the end of the cycle (16 to 1 ) is due to release from negative feedback inhibition because of decreased progesterone, estrogen, and inhibin from the dying corpus luteum.
-
First week of cycle- FSH and LH
- During the next week or so, there is a division of labor between the actions of FSH and LH on the follicles: FSH acts on the granulosa cells, and LH acts on the theca cells.
- The reasons are that, at this point in the cycle, granulosa cells have FSH receptors but no LH receptors and theca cells have just the reverse.
- FSH stimulates the granulosa cells to multiply and produce estrogen, and it also stimulates enlargement of the antrum.
- Some of the estrogen produced diffuses into the blood and maintains a relatively stable plasma concentration 3 .
- Estrogen also functions as a paracrine or autocrine agent within the follicle, where, along with FSH and growth factors, it stimulates the proliferation of granulosa cells, which further increases estrogen production.
-
Granulosa cells producing estrogen
- The granulosa cells, however, require help to produce estrogen because they are deficient in the enzymes required to produce the androgen precursors of estrogen (see Figure 17.6).
- The granulosa cells are aided by the theca cells.
- As shown in Figure 17.23, LH acts upon the theca cells, stimulating them not only to proliferate but also to synthesize androgens.
- The androgens diffuse into the granulosa cells and are converted to estrogen by aromatase.
- Therefore, the secretion of estrogen by the granulosa cells requires the interplay of both types of follicle cells and both pituitary gland gonadotropins.
-
Cells of ovaries vs cells of testes
- At this point, it is worthwhile to emphasize the similarities that the two types of follicle cells bear to cells of the testes during this period of the cycle.
- The granulosa cell is similar to the Sertoli cell in that it controls the microenvironment in which the germ cell develops and matures, and it is stimulated by both FSH and the major gonadal sex hormone.
- The theca cell is similar to the Leydig cell in that it produces mainly androgens and is stimulated to do so by LH.
- This makes sense when one considers that the testes and ovaries arise from the same embryonic structure (see Figure 17.2).
-
Second week of cycle
- By the beginning of the second week, one follicle has become dominant (number 4 in Figure 17.22) and the other developing follicles degenerate.
- The reason for this is that, as shown in Figure 17.22, the plasma concentration of FSH, a crucial factor necessary for the survival of the follicle cells, begins to decrease and there is no longer enough FSH to prevent atresia.
- We emphasized in the previous section that, during the first week or so of the follicular phase, LH acts only on the theca cells.
- As the dominant follicle matures, this situation changes, and LH receptors, induced by FSH, also begin to appear in large numbers on the granulosa cells. The increase in local estrogen within the follicle results from these factors.
- The dominant follicle now starts to secrete enough estrogen that the plasma concentration of this steroid begins to increase 5 .
- We can now also explain why plasma FSH starts to decrease at this time. Estrogen, at these still relatively low concentrations, is exerting a negative feedback inhibition on the secretion of gonadotropins (Table 17.4 and Figure 17.24).
-
Why a follicle might be dominant
- Although it is not known precisely how a specific follicle is selected to become dominant, there are several reasons why this follicle, having gained a head start, is able to continue maturation.
- 1. First, its granulosa cells have achieved a greater sensitivity to FSH because of increased numbers of FSH receptors.
- 2. Second, its granulosa cells now begin to be stimulated not only by FSH but by LH as well.
-
Estrogen negative feedback effect
- The dominant follicle now starts to secrete enough estrogen that the plasma concentration of this steroid begins to increase 5 .
- We can now also explain why plasma FSH starts to decrease at this time. Estrogen, at these still relatively low concentrations, is exerting a negative feedback inhibition on the secretion of gonadotropins (Table 17.4 and Figure 17.24).
- A major site of estrogen action is the anterior pituitary gland, where it decreases the amount of FSH and LH secreted in response to any given amount of GnRH.
- Estrogen also acts on the hypothalamus to decrease the amplitude of GnRH pulses and, therefore, the total amount of GnRH secreted over any time period.
- As expected from this negative feedback, the plasma concentration of FSH (and LH, to a lesser extent) begins to decrease as a result of the increasing concentration of estrogen as the follicular phase continues ( 6 in Figure 17.22).
- One reason that FSH decreases more than LH is that the granulosa cells also secrete inhibin, which, as in the male, primarily inhibits the secretion of FSH (see Figure 17.24).
-
Effect of oestrogen peak during late follicular stage
- The inhibitory effect of estrogen on gonadotropin secretion occurs when plasma estrogen concentration is relatively low, as during the early and middle follicular phases.
- In contrast, increasing plasma concentrations of estrogen for 1 to 2 days, as occurs during the estrogen peak of the late follicular phase ( 7 in Figure 17.22), acts upon the anterior pituitary gland to enhance the sensitivity of gonadotropin-releasing cells to GnRH (Table 17.4 and Figure 17.25) and also stimulates GnRH release from the hypothalamus.
- The estrogen-induced increase in GnRH release may be mediated by activation of kisspeptin neurons in the hypothalamus described earlier in this chapter.
- The stimulation of gonadotropin release by estrogen is a particularly important example of positive feedback in physiological control systems, and normal menstrual cycles and ovulation would not occur without it.
-
Net result of rapidly increasing oestrogen
- The net result is that rapidly increasing estrogen leads to the LH surge ( 5 8 in Figure 17.22). As shown in Figure 17.22 9 , an increase in FSH and progesterone also occurs at the time of the LH surge.
-
Midcycle surge of LH
- The midcycle surge of LH is the primary event that induces ovulation.
- The high plasma concentration of LH acts upon the granulosa cells to cause the events, presented in Table 17.5, that culminate in ovulation 10 , as indicated by the dashed vertical line in Figure 17.22.
- The function of the granulosa cells in mediating the effects of the LH surge is the last in the series of these cells’ functions described in this chapter. They are all summarized in Table 17.6.
- The LH surge peaks and starts to decline just as ovulation occurs.
- Although the precise signal to terminate the LH surge is not known, it may be due to negative feedback from the small increase in progesterone described earlier (see Figure 17.22) as well as down-regulation of LH receptors in the dominant follicle of the ovary, thereby reducing estrogen-induced positive feedback.
-
LH surge and luteal phase
- The LH surge not only induces ovulation by the mature follicle but also stimulates the reactions that transform the remaining granulosa and theca cells of that follicle into a corpus luteum (11 in Figure 17.22).
- A low but adequate LH concentration maintains the function of the corpus luteum for about 14 days.
-
Corpus luteum and hormones
- During its short life in the nonpregnant woman, the corpus luteum secretes large quantities of progesterone and estrogen 12 ,as well as inhibin.
- In the presence of estrogen, the high plasma concentration of progesterone causes a decrease in the secretion of the gonadotropins by the pituitary gland.
-
Feedback suppression of gonadotropins in the luteal phase
- In the presence of estrogen, the high plasma concentration of progesterone causes a decrease in the secretion of the gonadotropins by the pituitary gland. It probably does this by acting on the hypothalamus to suppress the pulsatile secretion of GnRH.
- Progesterone also prevents any LH surges during the first half of the luteal phase despite the high concentrations of estrogen at this time.
- The increase in plasma inhibin concentration in the luteal phase also contributes to the suppression of FSH secretion.
- Consequently, during the luteal phase of the cycle, plasma concentrations of the gonadotropins are very low 13.
-
Degeneration of corpus luteum
- The corpus luteum has a finite life in the absence of an increase in gonadotropin secretion.
- If pregnancy does not occur, the corpus luteum degrades within 2 weeks 14 . With degeneration of the corpus luteum, plasma progesterone and estrogen concentrations decrease 15.
- The secretion of FSH and LH (and probably GnRH, as well) increases (16 and 1 ) as a result of being freed from the inhibiting effects of high concentrations of ovarian hormones.
- The cycle then begins anew.
-
Control of ovarian function summary
- This completes the description of the control of ovarian function during a typical menstrual cycle.
- It should be emphasized that, although the hypothalamus and anterior pituitary gland are essential components, events within the ovary are the real sources of timing for the cycle.
- When the ovary secretes enough estrogen, the LH surge is induced, which in turn causes ovulation.
- When the corpus luteum degenerates, the decrease in hormone secretion allows the gonadotropin concentrations to increase enough to promote
- the growth of another group of follicles.
- This illustrates that ovarian events, via hormonal feedback, control the hypothalamus and anterior pituitary gland.
-
Function of granulosa cells
- Nourish oocyte
- Secrete chemical messengers that influence the oocyte and the theca cells
- Secrete antral fluid
- The site of action for estrogen and FSH in the control of follicle development during early and middle follicular phases
- Express aromatase, which converts androgen (from theca cells) to estrogen
- Secrete inhibin, which inhibits FSH secretion via an action on the pituitary gland
- The site of action for LH induction of changes in the oocyte and follicle culminating in ovulation and formation of the corpus luteum
-
Sequence of Effects of the LH Surge on Ovarian Function
- 1. The primary oocyte completes its first meiotic division and undergoes cytoplasmic changes that prepare the ovum for implantation should fertilization occur. These LH effects on the oocyte are mediated by messengers released from the granulosa cells in response to LH.
- 2. Antrum size (fluid volume) and blood flow to the follicle increase markedly.
- 3. The granulosa cells begin releasing progesterone and decreasing the release of estrogen, which accounts for the midcycle decrease in plasma estrogen concentration and the small rise in plasma progesterone concentration just before ovulation
- 4. Enzymes and prostaglandins, synthesized by the granulosa cells, break down the follicular–ovarian membranes. These weakened membranes rupture, allowing the oocyte and its surrounding granulosa cells to be carried out onto the surface of the ovary.
- 5. The remaining granulosa cells of the ruptured follicle (along with the theca cells of that follicle) are transformed into the corpus luteum, which begins to release progesterone and estrogen.
|
|
