Figure 1A depicts the major features of the regulation of the hypothalamic-pituitary-ovarian axis. The pulsatile secretion of GnRH from the median eminence is under the control of several inputs from various areas of the brain. These neurotransmitters may include dopamine, norepinephrine, and opioids. Circadian rhythms, which do influence GnRH and gonadotrophin secretion in other mammalian species, do not have a strong influence in humans, but sleep itself appears to have direct effects on the nature of LH secretion, which vary with the reproductive status of the individual. As discussed in Chapter 12, it is now believed that by far the most crucial input to GnRH neurons is the peptide kisspeptin-1 (Kiss-1) from the arcuate nucleus; in the female, there are also kisspeptide neurons in the anteroventral periventricular nucleus. Stimulation of GnRH secretion is manifested in both the amplitude and especially the frequency of its pulses.
Fig1. The Hypothalamic-Pituitary-Ovarian Axis. A. Under the influence of Kiss1 peptide from the arcuate nucleus (ARC) or the anteroventral periventricular nucleus (AVPV), hypothalamic neurons in the median eminence release GnRH in a pulsatile fashion. GnRH stimulates pituitary gonadotrophs to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Prior to ovulation, the target cells for LH are the thecal cells of the follicle and those of FSH are the granulosa cells. As described in Figure 2, these two components of the follicle collaborate to synthesize estrogen. After ovulation (the luteal phase of the cycle) LH stimulates the production of progesterone and estrogen by the corpus luteum. These steroids exert negative feedback inhibition on LH and FSH release at the level of the pituitary and on GnRH secretion, primarily at the arcuate nucleus by inhibiting Kiss-1 secretion. Just prior to ovulation, estrogen has a positive (green dashed line) feedback effect on GnRH secretion, through Kiss-1 secretion by the AVPV and at the pituitary. Inhibin B, secreted by the follicle and inhibin A, secreted by the corpus luteum, exert negative feedback on FSH secretion by the pituitary. B. FSH secretion is under local control by activin which stimulates its secretion and follistatin which binds to and blocks the effect of activin. As shown in part A, ovarian inhibins inhibit FSH secretion by blocking activin binding to its receptor.
Fig2. Estrogen synthesis in the ovary. The two-cell model for estrogen synthesis in the pre-ovulatory follicle is depicted. Under the stimulation of LH (luteinizing hormone), mediated by adenyl cyclase (AC) activation leading to increased StAR (steroid acute regulatory protein), cholesterol (Chol.) is converted by Cyp 11A1 (cholesterol side chain cleavage; also known as P450scc) to pregeneolone (Preg.) in the mitochondria of the thecal cell. Pregnenolone is converted to androstenedione (A-dione) which crosses the basement membrane surrounding the follicle and enters the granulosa cells. Cyp 19A1 (aromatase), elevated by FSH stimulation of the granulosa cells, converts A-dione to estrone. Finally, estrone is converted to estradiol by 17β-hydroxysteroid dehydrogenase (HSD17B1).
GnRH is transported to the gonadotrophs in the anterior pituitary where the secretion of FSH and LH is increased. However, the responses of FSH and LH secretion to GnRH are quantitatively and qualitatively different. For example, blocking the GnRH receptor inhibits LH secretion almost completely but reduces FSH secretion by only 50%. In another example of differential control of the gonadotrophins, increased GnRH pulse frequency favors LH secretion and decreased pulse frequency leads to increased FSH and decreased LH secretion.
During the majority of the follicular phase (first half) of the cycle the target cells of LH are the thecal cells and those of FSH are the granulosa cells. This responsiveness is determined by the type of receptor each cell expresses. Both gonadotrophins play a role in stimulating steroidogenesis by the ovarian follicle, as detailed in Figure2. FSH is necessary for the continued growth and maturation of the follicle until ovulation. During the last stages of follicle development, the granulosa cells also express the LH receptor in preparation for the direct participation of the midcycle surge of this gonadotrophin in ovulation. During the last stages of follicle development, the granulosa cells also express the LH receptor in preparation for ovulation in which the midcycle surge of the gonadotrophin participates directly.
Following ovulation, when thecal and granulosa cells of the follicle have differentiated into the corpus luteum, LH from the pituitary is required for the pro duction of progesterone, which is necessary for the growth of the uterine endometrium.
