ORG 33628 and ORG 31710 to Control Vaginal Bleeding in Progestin-Only Contraceptive Regimens

ABSTRACT

ORG 31710 and ORG 33628 were used in studies aiming to control vaginal bleeding in combination with progestagen-only contraception in primates. Preclinical evidence in monkeys with ORG 31710 has shown that a monthly supplementary administration to a progestagen-only contraceptive improves cycle control, probably as a result of a local endometrial effect (i.e., blocking of the progesterone receptor). In clinical trials ORG 31710 appeared to be effective for inducing vaginal bleeding after single-dose administration in the luteal phase of a normal cycle and for improving vaginal bleeding patterns of subjects using the 75 μg desogestrel progestagen-only pill (POP). Under POP treatment, ORG 31710 induced monthly bleeding and completely reduced intermittent (or breakthrough) bleedings, albeit for a limited number of days (± 10 days); thereafter, the incidence of spot bleedings returned to average levels with a POP, until the next monthly ORG 31710 administration. The temporary character of the effect was not predicted on the basis of the monkey studies, in which the improved bleeding pattern lasted a full cycle. Similar clinical results have been obtained with ORG 33628 both as administered in the luteal phase of the normal cycle and as given once (and twice) every 28 days in combination with the 75 μg desogestrel POP. Again, the improvement of the (POP-) bleeding pattern was not considered effective enough. In another approach, a continuous combined (daily) treatment of a progestagen (desogestrel) and the compound ORG 33628 was evaluated. It was hypothesized that if properly balanced, the progestagen would provide sustained ovulation inhibition, while the antagonistic activity of ORG 33628 would provide prevention of intermittent vaginal bleedings without antagonizing the inhibition of ovulation. This hypothesis is supported by the observation (from previous studies) that the antagonistic activity is higher at the level of the endometrium than at the level of the hypothalamus/pituitary. The continuous combined concept was studied in a single-center, double-blind, randomized trial of ORG 33628 at three different dosages in combination with the 75 μg desogestrel POP administered to healthy female volunteers. Effects on vaginal bleeding, endometrium, and ovarian function were evaluated. Vaginal bleeding was reduced with increasing doses of ORG 33628, but the inhibition of ovulation appeared to be compromised at the same time. In summary, the available studies suggest that there may be a progestagen/progesterone receptor-antagonist combination that provides the desired cycle control without compromising the inhibition of ovulation, but the ideal regimen or ratio has yet to be found.

Progesterone antagonists (PAs) - selective progesterone receptor modulators (SPRMs) - progestin-only contraception - cycle control - vaginal bleeding - progestagens - ORG 33628 - ORG 31710

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