Date of Award


Degree Type


Degree Name

Doctor of Philosophy


The effect of the gonadal steroid, 3{dollar}\alpha{dollar}-hydroxy-4-pregnen-20-one (3HP), is intact and castrate rats and in primary cultures of rat anterior pituitary cells and the possible interaction of 3HP with the signal transduction pathways of luteinizing hormone-releasing hormone (LHRH) was examined.;Intact or gonadectomized, male or female, prepubertal or adult rats treated with 3HP (0-200 {dollar}\mu{dollar}g/100 g BW; 1-4 days) showed a selective reduction in serum FSH levels (25%-60%) without any apparent effect on serum LH levels. The FSH-suppressing effect of 3HP was found to be dose-related, suggesting that 3HP action may be physiological. 3HP was effective in young male rats (10 d) and gonadectomized adult male rats, where 3HP showed its greatest suppression of serum FSH. Comparison of the effect of 3HP with that of some of its metabolites or other gonadal steroids showed that only 3HP had a selective FSH-suppressing effect.;In vitro, 3HP selectively inhibited the basal and LHRH-induced secretion of FSH, with no effect on LH secretion, in cells from both male and female rats. Inhibition of FSH secretion by 3HP was dose-dependent with the doses as low as 10{dollar}\sp{lcub}-16{rcub}{dollar} to 10{dollar}\sp{lcub}-14{rcub}{dollar}M exhibiting significant FSH-suppressing activity (by 35%). The cell content of FSH was unaffected by 3HP suggesting that synthesis, as well as release, of FSH is depressed by 3HP. As in the in vivo studies, none of the 18 other steroids tested, nor inhibin, had a similar selective FSH-suppressing action. It was concluded that FSH suppression by 3HP is specific to the structure of this molecule and that even minor alterations in the structure result in a loss of activity.;The effect of 3HP on the calcium signal and protein kinase C (PKC) activation produced by LHRH was examined in vitro. In experiments employing the calcium ionophore, A23187, FSH secretion, but not LH secretion, was stimulated beyond the level produced by LHRH alone. Furthermore, although stimulated by calcium, it appears that FSH, but not LH, secretion is relatively calcium-independent and will occur in the absence of elevated calcium as revealed by treatment with the calcium channel antagonists, verapamil and nifedipine. The evidence suggests that 3HP acts to modify the FSH response to the calcium signalling pathway and that 3HP action of LHRH-induced FSH secretion might occur via an increase in the requirement of FSH secretion for calcium. Inhibition of PKC activity does not mimic the effect of 3HP. However, the inhibition of FSH release brought about the 3HP can be lessened by the activation of PKC. The activity of 3HP may also be due in part of down-regulation of the FSH gene. These studies have provided insight into the mechanism of 3HP action and further studies may help to completely elucidate this mechanism.



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