The hypothalamopituitaryovarian axis

The hypothalamo—pituitary—ovarian axis is a classical example of a closed loop endocrine negative feedback system. Pulsatile secretion of gonadotropin-releasing hormone (GnRH), from hypothalamic peptidergic neurons drives the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. Whilst LH secretion depends on GnRH input, there is a GnRH-independent component of FSH secretion, probably driven by intrapituitary secretion of activin (Corrigan et al 1991), and illustrated by the ability of dispersed pituitary cell cultures to continue to secrete FSH, but to cease secreting LH (Farnworth et al 1988). The gonadotropins in turn drive ovarian production of steroid and peptide hormones. Oestradiol is the major steroid secretory product of the granulosa cell, where it is formed as a result of the action of aromatase on testosterone derived from the surrounding theca under LH control. Progesterone is the product of granulosa—lutein cell secretion following formation of the corpus luteum. The inhibins are gonadal glycoprotein hormones, again predominantly the product ofthe ovarian granulosa cell, though there is also evidence of thecal inhibin secretion. Two major types of inhibin have been isolated, inhibin A and inhibin B. Evidence from the localization of inhibin subunits within the ovary (Roberts et al 1993) and from studies of circulating inhibin levels (Groome et al 1996), indicates that inhibin A is a product primarily of the dominant follicle. Inhibin B on the other hand is the product of the cohort of growing follicles from which the dominant follicle is selected. The secretory patterns of the two inhibins differ. Inhibin A levels are quantitatively low throughout much of the follicular phase of the cycle and show a late follicular phase rise in parallel with the preovulatory rise in serum oestradiol. Inhibin A levels peak at mid cycle, fall briefly and then rise to reach their highest levels during the luteal phase, when inhibin A is a product of the corpus luteum, its secretion being parallel to that of progesterone. In the late luteal phase, circulating concentrations of oestradiol, progesterone and inhibin fall. Inhibin B, on the other hand, shows an early follicular phase rise and fall, parallel to the rise and fall in circulating FSH. A mid cycle peak occurs in parallel with that of inhibin A, but following this peak, inhibin B falls to low concentrations and remains low throughout the luteal phase until the initiation of the luteal—follicular transition, when its levels rise, closely associated with the intercycle rise in FSH. The inhibins specifically inhibit the synthesis and secretion of pituitary FSH by mechanisms that have not yet been clarified. Recently, two types of molecules have been recognized which may function as components of an inhibin receptor system, betaglycan

(Lewis et al 2000) and p120 (Chong et al 2000). The precise signalling mechanisms are still being elucidated. Oestradiol also exerts negative feedback effects on pituitary FSH and LH secretion, and acts predominantly at the hypothalamic level. Under certain circumstances, oestradiol exerts a paradoxical positive feedback effect involved in the generation of the mid-cycle LH surge. When operating as a negative feedback system, the pituitary—gonadal axis can be conceptualized as a system in which FSH and LH drive the ovarian production of oestradiol and the inhibins, which in turn feed back to negatively regulate gonadotropin secretion. In this model, a primary defect in ovarian inhibin secretion, for example, would be expected to lead to a monotropic increase in circulating FSH levels.

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