Lh

wv pulse ^

generator +

GnRH

anterior pituitary i

Progesterone estradiol inhibin A i '

corpus luteum luteal phase preovulatory follicle midcycle

FIGURE 11 Ovarian-pituitary interactions at different phases of the menstrual cycle. Solid arrows, stimulation; dashed arrows, inhibition. Note that the frequency of the GnRH pulse generator slows in the luteal phase, and that the amplitude may increase at midcycle.

the luteinization process. Conversely, the gradual loss of sensitivity of luteal cells to LH accounts for the decrease in progesterone and estrogen secretion during the latter part of the luteal phase. Thus, one of the unique features of the female reproductive cycle is that changes in steroid hormone production result more from changes in the number or sensitivity of competent target cells than from changes in gonadotropin concentrations (see Chapter 37).

Positive Feedback Aspects

Rising estrogen levels in the late follicular phase trigger the massive burst of LH secretion that just precedes ovulation. This LH surge can be duplicated experimentally in monkeys and women given sufficient estrogen to raise their blood levels above a critical threshold level for 2 to 3 days. This compelling evidence implicates increased estrogen secretion by the ripening follicle as the causal event that triggers the massive release of LH and FSH from the pituitary (Fig. 11, midcycle). It can be considered positive feedback because LH stimulates estrogen secretion, which in turn stimulates more LH secretion in a self-generating explosive pattern.

Progesterone concentrations begin to rise about 6 hours before ovulation. This change is probably a response to the increase in LH rather than its cause. It is significant that large doses of progesterone given experimentally block the estrogen-induced surge of LH in women, which may account for the absence of repeated LH surges during the luteal phase, when the concentrations of estrogen might be high enough to trigger the positive feedback effect (Fig. 11, luteal phase). This action of progesterone, which may contribute to the decline in the LH surge, also contributes to its effectiveness as an oral contraceptive agent. In this regard, progesterone also inhibits follicular growth.

Neural Control of Gonadotropin Secretion

It is clear that secretion of gonadotropins is influenced to a large measure by ovarian steroid hormones. It is equally clear that secretion of these pituitary hormones is controlled by the central nervous system. Gonadotropin secretion ceases after the vascular connection between the anterior pituitary gland and the hypothalamus is interrupted or after the arcuate nuclei of the medial basal hypothalamus are destroyed. Less drastic environmental inputs, including rapid travel across time zones, stress, anxiety, and other emotional changes, can also affect the reproductive function in women, presumably through neural input to the medial basal hypothalamus. As discussed in Chapter 45, secretion of gonadotropins requires the operation of a hypothalamic pulse generator that produces intermittent stimulation of the pituitary gland by GnRH.

Sites of Feedback Control

The ovarian steroids might produce their positive or negative feedback effects by acting at the level of the hypothalamus or the anterior pituitary gland, or both. The GnRH pulse generator in the medial basal hypothalamus drives gonadotropin secretion regardless of whether negative or positive feedback prevails. Gonado-tropin secretion falls to zero after bilateral destruction of the arcuate nuclei in rhesus monkeys and cannot be increased by either ovariectomy or treatment with the same amount of estradiol that evokes a surge of FSH and LH in normal animals. When such animals are fitted with a pump that delivers a constant amount of GnRH in brief pulses every hour, the normal cyclic pattern of gonado-tropin is restored and the animals ovulate each month. Identical results have been obtained in women suffering from Kallman's syndrome, in which there is a developmental deficiency in GnRH production by the hypothalamus (Fig. 12). In both cases, administration of GnRH in pulses of constant amplitude and frequency was sufficient to produce normal ovulatory cycles. Because both positive and negative feedback aspects of gonado-tropin secretion can be produced even when hypothala-mic input is "clamped" at constant frequency and amplitude, these effects of estradiol must be exerted at the level of the pituitary.

Although changes in amplitude and frequency of GnRH pulses are not necessary for the normal pattern of gonadotropin secretion during an experimental or therapeutic regimen, variations in frequency and amplitude nevertheless may occur physiologically in a way that complements and reinforces the intrinsic pattern already described. During the normal reproductive cycle, GnRH pulses are considerably less frequent in the luteal phase than in the follicular phase. Complementing its negative feedback effects, estradiol may decrease the amplitude of GnRH pulses, and progesterone slows their frequency, perhaps by stimulating hypothalamic production of endogenous opioids. It appears that an increase in amplitude of GnRH pulses precedes the LH surge, and there is good evidence that progesterone acts at the level of the hypothalamus to block the estradiol-induced LH surge. Thus, feedback effects of estradiol appear to be exerted primarily, but not exclusively, on the pituitary and those of progesterone primarily, but probably not exclusively, on the hypothalamus.

We do not yet understand the intrapituitary mechanisms responsible for the negative and positive feedback effects of estradiol. As seen with the ovary, changes in hormone secretion may be brought about by changes in

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