Study of the pharmacological modification of neuroendocrine mechanisms controlling ovulation in the rat.

Stewart, Ann Wilson

Abstract

The synthetic steroid, RMI 12,936 (17beta-hydroxy-7alpha-methyl-androst-5-en-3-one) inhibits ovulation in the rat. This study investigated the mechanism of action of the drug. The results showed that administration at or before 01:00h on proestrus blocked the preovulatory LH surge, which was restored by LHRH or oestradiol plus progesterone. Administration of oestradiol alone restored ovulation to only 43% of RMI 12,936-treated rats. The negative feedback effect of testosterone on LH release showed similar characteristics. Although RMI 12,936 was shown to be a potent androgen, the peripheral androgenic activity was found not to be correlated with its inhibitory effect on LH release. Instead, it was suggested that RMI 12,936 may act through antioestrogenic and antiprogestational activity. Investigation of the site of action revealed effects: a) at the ovarian level, inhibiting the biosynthesis of oestrogen and progesterone; b) at the adenohypophysial level, preventing full sensitization to LHRH; and c) at the hypothalamic level, inhibiting noradrenergic and tryptaminergic neurotransmission. The first two are not the main sites of antiovulatory activity, since administration of oestradiol plus progesterone - although they restore ovulation - cannot restore full sensitization, and secondly since RMI 12,936 injected into the third cerebral ventricle does not require to be transported to the ovary for effective ovulation blockade. The major site of action was therefore at the hypothalamic level, where RMI 12,936 blocks the neural signal mediated by noradrenaline and triggered by oestrogen. Based on the premise that RMI 12,936 has a similar mechanism of action to that of testosterone, it was proposed that the drug prevents full sensitization of the adenohypophysis by reducing the number of LHRH receptors. During this investigation, adenohypophysial sensitivity to LHRH altered. From observation throughout the year, a pattern emerged indicating the existence of seasonal variation in the mechanisms controlling LH release. This aspect requires further investigation.

Citation

STEWART, A.W. 1982. Study of the pharmacological modification of neuroendocrine mechanisms controlling ovulation in the rat. Robert Gordon's Institute of Technology, PhD thesis. Hosted on OpenAIR [online]. Available from: https://doi.org/10.48526/rgu-wt-1993302

• Thesis Type: Thesis
• Deposit Date: Jun 22, 2023
• Publicly Available Date: Jun 22, 2023
• DOI: https://doi.org/10.48526/rgu-wt-1993302
• Keywords: Ovulation inhibitors; Ovulation; Rats
• Public URL: https://rgu-repository.worktribe.com/output/1993302
• Award Date: Nov 30, 1982