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

Progestin-only (p-only) contraceptives often cause breakthrough bleeding for unknown reasons. In this study, we aimed to evaluate the long-term effects of p-only contraceptives to gain a better understanding of breakthrough bleeding mechanism. Wistar rats were divided into etonorgesterel implant (Group 1, n = 25), depot medroxyprogesterone acetate injectable (Group 2, n = 25), and control groups (n = 5). Five rats each from groups 1 and 2 were examined every 10 days for up to 50 days after the medication. Uteri and ovaries were removed and prepared for immunohistochemistry and scanning electron microscopy. The tissue nitric oxide (NO) levels were determined by Griess reaction. Dynamic changes of endometrial estrogen and progesterone receptor immunoreactivity were observed in a time-dependent manner in groups 1 and 2. The number of endometrial pinopodes, which are small endometrial protrusions, increased in both groups. There was no difference between groups for the estrogen receptor in the surface epithelium of the ovary. Estrogen-alpha and progesterone receptor in follicular cells decreased in a time-dependent manner. The granulosa cells underwent atrophic and were disorganized. Decreased levels of uterine tissue NO were determined in groups 1 and 2. The effect of some p-only contraceptives make some dynamic changes in the endometrium, ovaries, steroid hormone receptors, cell morphology, and biochemical features of the tissues during their use.