I. Introduction The concept that proteins, in addition to steroid hormones, of gonadal origin could play a role in the inhibition of gonadatropin secretion from the anterior lobe of the pituitary was proposed more than 65 yr ago. Only recently, however, has the elucidation of the chemistry and physiology of these proposed gonadal hormones actually been achieved. Mottram and Cramer (1) reported pituitary hypertrophy as determined by the appearance of so-called castration cells in the anterior lobe of pituitary after treatment of the testes with radium. The removal of the testes leads to the development of highly vacuolated, signet-shaped basophil cells in the pituitary (2), termed castration cells, demonstrating a reciprocal relationship between the pituitary and the gonads and suggesting that a secretion of the testes has an inhibitory effect on the pituitary (3). The pituitary hypertrophy after castration or irradiation of the testes was postulated to be due to a lack of some substance from the seminal e...

Inhibins, Activins, and Follistatins: Gonadal Proteins Modulating the Secretion of Follicle-Stimulating Hormone

Serum inhibin concentrations were measured daily by RIA in six normal women throughout one menstrual cycle. The RIA was specific for inhibin, and inhibin subunits and related proteins cross-reacted minimally in it. In the early to midfollicular phase, inhibin levels changed little, while in the late follicular phase, inhibin levels rose, in parallel with estradiol (r = 0.43; P less than 0.05; n = 22), to a peak level of 714 (407-1267) U/L (geometric mean +/- 67% confidence limits) coincident with the midcycle LH and FSH surges. An inverse relationship was found between serum inhibin and FSH during the mid- to late follicular phase (r = 0.42; P less than 0.01; n = 45). Inhibin levels rose further during the luteal phase to a peak level of 1490 (1086-2028) U/L 7-8 days after the LH surge, and they correlated positively with serum progesterone (r = 0.76; P less than 0.001; n = 49) and inversely with serum FSH (r = 0.43; P less than 0.01; n = 49) throughout the luteal phase. We conclude that 1) circulating inhibin is detectable throughout the normal menstrual cycle; 2) in the late follicular phase, inhibin levels rise in parallel with estradiol, consistent with the concept that both are products of the maturing follicle; 3) in the luteal phase, the profile of inhibin suggests that it is a secretory product of the corpus luteum; and 4) the inverse relationship between inhibin and FSH in the follicular phase is consistent with the inhibin hypothesis, while at midcycle there is loss of the inhibitory effect of inhibin on FSH secretion. The inverse relationship between FSH and inhibin during the luteal phase suggests a hitherto unsuspected role for inhibin in the feedback regulation of FSH secretion.

Circulating Immunoreactive Inhibin Levels During the Normal Human Menstrual Cycle

Inhibin, a glycoprotein that preferentially suppresses follicle-stimulating hormone (FSH) secretion, has been isolated from follicular fluid as a heterodimer of two dissimilar subunits linked by disulphide bonds. The larger subunit is termed alpha and the smaller is designated beta. Two forms of inhibin termed A and B have been isolated, the differences being due to variations in the amino acid sequence of the beta-subunit; Inhibin A consists of alpha-beta and Inhibin B of alpha-beta B. Dimers of the beta-subunit, termed activins, have also been found in follicular fluid; these stimulate pituitary FSH secretion. Inhibin is produced in the female by the granulosa cell and corpus luteum under the control of FSH and luteinizing hormone (LH), respectively. The levels in serum rise to peak at mid-cycle and in the mid-luteal phase of the human menstrual cycle, and decline prior to menstruation. In pregnancy, the late-luteal phase decline in inhibin does not occur and the levels increase slowly. Studies suggest that the levels in pregnancy arise from an embryonic source, particularly the placenta. In the male, inhibin is produced by the Sertoli cells under the control of FSH by mechanisms involving cyclic adenosine 3', 5'-monophosphate. Testosterone exerts a minor inhibitory control at supraphysiological levels (10(-5) M), but human chorionic gonadotropin stimulation results paradoxically in a rise in serum inhibin levels. Disruption of spermatogenesis in the rat by cryptorchidism, heat treatment, or efferent duct ligation results in a decline in inhibin levels and a rise in FSH levels, findings consistent with the negative feedback action of inhibin on FSH secretion. As well as their roles in the reproductive system, inhibin and activin have more widespread actions in the haemopoietic, immune and nervous systems as evidenced by the finding of mRNA for its subunits in a range of tissues. Other studies have shown actions on erythroid differentiation and on mitotic activity in thymocytes. These actions suggest that inhibin and activin may function as growth factors as well as regulators of FSH.

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The isolation and physiology of inhibin and related proteins.

Publisher Summary This chapter reviews the primate ovarian cycle and the regulation of its endocrine and gametogenic activities, based on the studies in rhesus and cynomolgus monkeys. Unlike adult male mammals, which continuously produce new sperm, female mammals are born with their lifetime supply of eggs, enclosed in primordial follicles. This pool of primordial follicles serves as a non-replenished, progressively depleted stockpile from which growing follicles and oocytes are continuously withdrawn. Each adult mammalian female ovulates a species-characteristic number of ova each week, month, season, or year—the frequency again being a species characteristic. Thus, litter size and annual fecundity rate of a species are proximately determined by the physiology of the female through the size of the ovulatory quota, frequency of the ovarian cycle, and the duration of pregnancy and lactation. Typically ovulation of a single, fertilizable ovum in each menstrual cycle completes a course of oogenesis that begins during fetal development.

The ovarian triad of the primate menstrual cycle.

Overview MANY excellent reviews have appeared that summarize follicular development from the perspective of gonadotropin-induced follicular differentiation and steroid secretion (1–3). Nevertheless, the process of selection and dominance of an ovulatory follicle during each ovarian cycle remains poorly understood. In this review, we will focus primarily on the role of intragonadal substances in the regulation of follicular maturation. Since previous summaries considered the topic of follicular maturation with respect to prostaglandins (4), insulin, somatomedins (5), relaxin (6, 7), lipoproteins (8), and GnRH (9, 10), further consideration of these topics will not, in general, be repeated here. Rather, we will review the growing body of data emanating from experiments using predominantly follicular tissue and cells from the monotocous primate, cow, mare, and ewe as well as the polytocous sow and rat that address the intraovarian regulation of folliculogenesis.

Intragonadal regulation of follicular maturation.

Publisher Summary This chapter discusses the role of nonsteroidal regulators in control of oocyte and follicular maturation. The ovarian follicle is bathed in a fluid rich in steroid hormones as well as nonsteroidal regulators which interact to serve to control its maturation, responsiveness to gonadotropins, as well as to lead to control of the maturation of its oocyte. The orderly maturation of an ovarian follicle and its oocyte is controlled by pituitary LH and FSH in concert with local intrafollicular regulators. The principal nonsteroidal follicular regulators are an oocyte maturation inhibitor, a luteinization inhibitor, a luteinization stimulator, FSH receptor binding inhibitor, and inhibin-F. OMI is a polypeptide

Kevin G. Osteen

Papers

The role of nonsteroidal regulators in control of oocyte and follicular maturation.