Background: Telapristone (CDB-4124 or Proellex®) is a PRM (progesterone antagonist) under development for treatment of uterine fibroids and endometriosis in women. Enclomiphene citrate (Androxal®, EnCyzix®) is a SERM (estrogen antagonist) under development for testosterone restoration in men with secondary hypogonadism. Telapristone exhibits potent antiproliferative effects on the endometrium. In human studies longer than four months a dose-dependent suppression of endometrial thickening was observed by ultrasound and confirmed by tissue biopsy. As the dose of the drug was increased there was an increase of anti-proliferative and pro-apoptotic events. Enclomiphene citrate has been administered to rodents, dogs, baboons and humans and elevates total serum testosterone levels in male baboons and humans. In a study evaluating the effects of clomiphene and its isomers, enclomiphene (trans-Clomiphene citrate) and zuclomiphene (cis-Clomiphene citrate), in nine male baboons, Enclomiphene citrate was safely administered with maximal effects on serum testosterone at an oral dose of 1.5 mg/kg of body weight for 12 days. We have shown that the effects are driven by its central anti-estrogenic action. Administration to men has demonstrated no decreases in bone mineral density measured by DEXA, a consideration for any SERM. This study investigated combinations of anti-hormones for the treatment of cancers of the female reproductive system, (i.e., breast, uterine, and ovarian) and was driven by ProellexâÂÂÃ?â??Ã?â?¬ÂÂÃ?â??Ã?â?¢s anti-proliferative effects. Dual administration with Androxal has the potential of preserving bone parameters while providing an estrogen antagonist. Methods: Baboons were used to approximate findings in human subjects due to the relatedness of the reproductive system and cycle. Three cycling females per group were treated for six months with appropriate doses of Proellex, Androxal or a combination of the two. Cycling, physical signs, hormones, uterine ultrasounds, DEXA analysis and clinical chemistry were assessed. Results: Proellex did not disrupt the tumescence index, an estrogen dependent index of female baboons. Enclomiphene completely stopped the index. Both Proellex and Androxal, alone and in combination, stopped vaginal bleeding, an indication of cycle disruption, perhaps centrally. One unusual finding was that Enclomiphene induced development of a distinct color of the baboon sex skin. This color is indicative of pregnancy, but chorionic gonadotropins were negative. Blood chemistries, compared to controls, were unchanged in all groups. DEXA analysis demonstrated no changes in body composition. No changes in uterine and ovarian pathology were seen compared to controls. Conclusion: Administration of Proellex and Androxal were shown to have disruptive effects on baboon reproductive cycling while producing few other non-hormonal detrimental effects.
