Hypothalamicpituitarygonadal Axis

The secretion of the principal gonadal steroids, estrogen and progesterone, is governed by cyclic changes in ovarian follicular and corpus luteum development over the course of the menstrual cycle. Critical to the proper functioning and timing of the monthly hormonal cycle is the pulsatile secretion of gonadotropin-releasing hormone (GnRH). GnRH secretion from the hypothalamus drives the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotropes (Midgley and Jaffe 1971). During the early follicular phase, FSH plays the major role in maturing the follicle (diZerega and Hodgen 1981), and the developing follicle secretes increasing amounts of estradiol as it matures. Maturation-induced increases in estradiol exert a negative feedback on FSH secretion and both negative and delayed positive feedback effects on LH secretion (Karsch et al. 1983). The change in estradiol feedback from negative to positive late in the follicular phase is complemented by rising progesterone and results in the midcycle surge in LH necessary for ovulation. Following ovulation, progesterone levels continue to rise as a result of active secretion from the corpus luteum. LH secretion is necessary for the maintenance of the corpus luteum and subsequent estrogen and progesterone secretion and also facilitates estradiol production by the follicle and controls the secretion of hormones by the corpus luteum but is inhibited by progesterone (Chabbert et al. 1998). In the absence of fertilization, regression of the corpus luteum occurs, with the subsequent fall in estrogen and progesterone leading to the onset of menses.

The pulsatile secretion of GnRH is driven by a pulse generator in the arcuate nucleus of the hypothalamus (Knobil 1990). This pulsatile pattern of GnRH secretion is critical for the control of serum LH, FSH, and ovulation. Indeed, continuous administration of the GnRH agonist leuprolide in a nonpulsatile pattern suppresses ovulation as effectively as does inadequate secretion of GnRH. Studies in primates with arcuate lesions have demonstrated that administration of GnRH pulses in frequencies that are too fast or too slow results in low serum concentrations of LH (Belchetz et al. 1978).

LH secretory pulses in the peripheral circulation are used as the marker of GnRH secretory pulses. In humans, the follicular phase of the menstrual cycle is characterized by reasonably constant amplitude LH pulses every 1-2 hours (Reame et al. 1984). During the luteal phase, pulse amplitude becomes much more variable and pulse frequency decreases. The slowing of the LH pulses during the luteal phase is due to the actions of progesterone on the GnRH pulse generator (Goodman and Karsch 1980;

Soules et al. 1984; Steele and Judd 1986). Gonadal steroids exert negative feedback effects on the amplitude and frequency of GnRH pulses and through this mechanism (in addition to direct actions on the pituitary) inhibit the secretion of LH and FSH. Likewise, central opioids, particularly (^-endorphin, exert a tonic inhibition on GnRH secretion (Ferin and Vande 1984). Circadian changes in LH secretion are not as prominent as those of the HPA axis (Jaffe et al. 1990). During puberty and following recovery from anorexia- or exercise-induced amenorrhea, nighttime secretion of LH becomes particularly prominent. Furthermore, nighttime slowing of LH pulses during the early follicular phase also occurs in normal women (Soules et al. 1985).

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