The inhibins and activins

The inhibins and activins are a family of dimeric growth factors synthesized in the gonads. They exert direct effects both on gonadal and extra-gonadal tissue, and are members of the TGF-P 

Females, too, produce androgens, principally in the follicular theca cells. Androgens are also produced in the adrenals in both male and females. 

The biological activities of androgens (only some of which are specific to males) may be summarized as  

The follicular granulosa cells are the major site of synthesis of female steroid sex hormones the oestrogens. P-Oestradiol represents the principal female follicular oestrogen. Oestriol is produced by the placenta of pregnant females. Oestriol and oestrone are also produced in small quantities as products of P-oestradiol metabolism. 

Testosterone represents the immediate precursor of the oestrogens, the conversion being catalysed by the aromatase complex, i.e. a microsomal enzyme system. The biological actions of oestrogens may be summarized as  

Because of their central role in maintaining reproductive function, the therapeutic potential of gonadotrophins in treating subfertility and some forms of infertility was obvious (Table 8.10). Gonadotrophins are also used to induce a superovulatory response in various animal species, as outlined later. The market for these hormones, while modest by pharmaceutical standards, is. 

Menotrophin Urine of post-menopausal women Contains FSH with some LH activity. Used to induce human follicular growth 

P-FSH Porcine pituitary extract Enriched FSH extract. Contains lower levels of LH and other pituitary proteins. Used to induce superovulatory response in animals 

P-LH Porcine pituitary extract Used to induce ovulation in super-ovulated animals 

PMSG Serum of pregnant mares Exhibits both FSH- and LH-like biological activities — used to superovulate animals 

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P and Pg, exist in foUicular fluid. Control of inhibin secretion involves a feedback relationship in which circulating FSH stimulates inhibin secretion, which in turn reduces the secretion of FSH (8). Both the homo- and the heterodimers of the P-subunits of inhibin promote the secretion of FSH and thus have been termed activins. Activin is secreted by the ovary and the testes into the circulation. In addition, both inhibin and activin have intragonadal autocrine and paracrine effects that influence gonadal steroidogenesis (9). 

Inhibin and Activin. Inhibin, a water-soluble, gonadal factor known for over 50 years to inhibit pituitary function, has been isolated and identified (127—130). Inhibin is a glycoprotein hormone that preferentially inhibits the secretion of FSH. It consists of an a-chain subunit, mol wt 14,000, linked by disulfide bonds to a P-chain subunit, mol wt 18,000. There exist two forms of the P-chain subunit, P-A and P-B. The smaller subunit combines with either the P-A or P-B subunit to form inhibin-A or inhibin-B, respectively. 

Figure 19.1 A diagrammatic representation of the male reproductive tract. Much of the volume of the testes consists of convoluted seminiferous tubules in which the spermatozoa form. In the interstitial tissue that surrounds the seminiferous tubules are the Leydig cells which produce and secrete androgens, oes-tradiol and the peptides inhibin and activin. The epididymis is a single but convoluted tube. Sperm from the epididymis enter the vas deferens and pass through the ejaculatory duct into the urethra, mainly at the time of ejaculation. Just at the transition of the vas deferens to ejaculatory duct, two large glands, the seminal vesicles, drain into the two vasa deferentia. Prior to joining the urethra, the ejaculatory ducts pass through the prostate gland which lies below the bladder and surrounds the upper part of the urethra, into which prostatic fluid is secreted.

Recombinant inhibins and activins have also been produced. This allows detailed study of the role the various members of this family play in the reproductive axis and facilitates assessment of their therapeutic potential. 

The ovary also produces inhibin and activin. These peptides consist of several combinations of and 3 subunits and are described in greater detail later. The oc3 dimer (inhibin) inhibits FSH secretion while the 33 dimer (activin) increases FSH secretion. Studies in primates indicate that inhibin has no direct effect on ovarian steroidogenesis but that activin modulates the response to LH and FSH. For example, simultaneous treatment with activin and human FSH enhances FSH stimulation of progesterone synthesis and aromatase activity in granulosa cells. When combined with LH, activin suppressed the LH-induced progesterone response by 50% but markedly enhanced basal and LH-stimulated aromatase activity. Activin may also act as a growth factor in other tissues. The physiologic roles of these modulators are not fully understood. 

The Sertoli cells in the testis synthesize and secrete a variety of active proteins, including miillerian duct inhibitory factor, inhibin, and activin. As in the ovary, inhibin and activin appear to be the product of three genes that produce a common ot subunit and two subunits, A and B. Activin is composed of the two subunits ( ). There are two inhibins (A and B), which contain the a subunit and one of the subunits. Activin stimulates pituitary FSH release and is structurally similar to transforming growth factor-B, which also increases FSH. The inhibins in conjunction with testosterone and dihydrotestosterone are responsible for the feedback inhibition of pituitary FSH secretion. 

As discussed above, Sertoli cells play a central role in spermatogenesis. These cells also produce the regulatory molecules inhibin and activin, which are members of the TGF superfamily (see review by Vale et al., 1994). In males, activin and inhibin coordinately regulate the level of serum FSH. Inhibin is a peptide hormone produced in response to FSH that exerts negative feedback on the pituitary gland to... 

Vale WW, Bilezikjian LM, Rivier C (1994) Inhibins and activins. In Knobil E Neill JD ed. The physiology of reproduction, 2nd ed. New York, Raven Press, pp 1861-1878. 

The Sertoli cells in the testis synthesize and secrete a variety of active proteins, including mullerian duct inhibitory factor, inhibin, and activin. As in the ovary, inhibin and activin appear to be the product of three genes that produce a common alpha subunit and two beta subunits, A and B. 

During the isolation of inhibin from foUicular fluid, some chromatographic fractions stimulated FSH release from cultured anterior pituitary cells, suggesting the existence of FSH releasing proteins (FRPs). Two FRPs, given the generic term activins, were subsequentiy isolated (131,132). One is composed of two disulfide-finked P-A subunits (activin A) the other consists of similarly finked P-A and P-B subunits (activin AB). 

Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion. Gonadal steroids as well as the peptide hormones activin and inhibin have complex modulatory effects on the gonadotropin response to GnRH. 

Inhibins are members of the transforming growth factor (3 (TGF(3) superfamily of proteins. Inhibin forms include inhibin A and B, and activin A, B, and AB. As described in Chapter 53, inhibin is a negative feedback regulator of FSH secretion in both males and females. The placenta produces large quantities of inliibin A that completely suppress FSH. 

Depaolo, L. 1997. Inhibins, activins and follistatins - the saga continues. Proceedings of the Society for Experimental Biology and Medicine 214(4), 328-339. 

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