The long-term apoptotic effects of progesterone-only contraceptives on endometrium and ovary in rats

Abstract

OBJECTIVE: Apoptosis is necessary for the balance between cell proliferation and cell loss. Various pathologies are related with excessive or deficient apoptosis. We evaluated apoptotic effect of widely used enjectable and implantable progestines on ovarian and uterine tissues via rat study design. DESIGN: Prospective randomise experimental study MATERIALS AND METHODS: Sixtysix Wistar-Albino rats were used. Etonogestrel(IMP) was implanted in 30 rats. Medroksiprogesterone-acetate(MPA) was enjected in another 30 rats. After application of drugs, 6 rats were sacrificed at the each 10th,20th,30th,40th and 50th days. Six rats served as controls. Ovarian and uterine tissues were evaluated for apoptotic index(AI) and caspase-3 immunoreactivity(HSCORE). RESULTS: In both IMP and MPA groups, AI and HScore values in stroma and glandular epithelium of uterus increased with the longer progesterone exposure time. AI and HScore values did not change in endometrium. AI and HScore values also increased with the longer progesterone exposure time in both granulosa and teca-lutein cells of the ovary in IMP and MPA groups. Particularly, increase in AI and HScore values were more prominent after 30 days of progestine exposure for teca-lutein cells of ovary. CONCLUSIONS: Progestine increased apoptosis in ovaries and uterus by the longer exposure time. This effect on uterus is consistent with literature. Apoptotic effect is more prominent by the longer exposure time. Apoptosis increased in ovaries by chronic progesterone exposure which is in contrast with some studies in literature. This effect might be related with chronic supression of gonadotropins and elevation of androgens due to decreased SHBG levels which are indirect effects of progestines. Late reversal of fertility with depot and implant forms of progestines when combined with their apoptotic effects it could be considered that longer duration of progestin usage can cause a shorter period of fertile life.