Development of Antagonists and Agonists of Follicle Stimulating Hormone

Abstract

The initiation and maintenance of spermatogenesis are under the control of follicle stimulating hormone (FSH) and testosterone. For different mammalian species, it is clear that FSH is an important regulator, in particular during the first wave of spermatogenesis, and that testosterone is the major stimulator of spermatogenesis in adult males. FSH exerts multiple effects on its target cell, the Sertoli cell, and its action is most evident in testis from immature or hypophysectomized animals (Fritz 1978). However, at all stages of development, the actions of FSH and testosterone seem to be highly integrated. Although the importance of FSH in adult males is not clear, in either the human or in animal species, it appears that FSH is necessary for quantitative maintenance and repair of spermatogenesis. It has been shown that the FSH receptor is carefully regulated in adult rats and, presumably, has an important function in spermatogenesis (Heckert and Griswold 1992). A marked quantitative stimulation of spermatogenesis occurs when FSH is administered to intact adult cynomolgous monkeys (Van Alphen et al. 1988). Administration of anti-FSH antibodies to rats leads to a decrease in spermatogonia (Vaishnav and Moudgal 1992). It cannot be excluded that male fertility will be impaired upon inhibition of FSH action. The possibility of inducing male infertility by blocking FSH action is very attractive for two reasons. First, according to current knowledge, testicular Sertoli cells are the exclusive target cells for FSH in the male, which guarantees specificity. Second, lutropin (LH) action and testicular androgen production would not be affected. Different approaches have been considered to interfere with FSH stimulation of the testis, without acting upon LH stimulation of testicular androgen production. In our laboratory, we are trying to develop FSH antagonistic peptides and peptide vaccines directed against FSH. Synthetic peptides and especially synthetic peptide vaccines instead of “native” protein hormone (vaccines) have been predicted to be especially well suited for mass application in developing countries because peptides are relatively cheap, easy to produce, to store, to transport and to modify. However, a major obstacle to the development of anti-FSH vaccines or FSH antagonistic peptides has been the absence of detailed knowledge about the antigenic determinants and receptor sites on the hormone.