Effects of Different Oral Contraceptives On Ovarian Reserve, Histology, and Micrornas: An Experimental Study
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Abstract
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Abstract
Aim: The aim of the present study was to investigate the effects of different oral contraceptives containing androgenic and antiandrogenic progestins on ovarian follicle reserve, germinal epithelial fibrosis, and microRNA (miRNA) expressions in the ovary.
Materials and Methods: In this prospective study, 35 4-month-old adult female Wistar Albino rats weighing 190–220g and having a regular cycle were randomly divided into five groups during the estrus phase in a single-blind manner. Placebo tablets and oral contraceptives were delivered via gastric lavage for 3 months. Group 1 (control group) received placebo tablets, group 2 received ethinylestradiol (EE) 1.5mcg/day +drospirenone 150mcg/day (Yasmin®), group 3 received EE 1.5mcg/day +cyproterone acetate 100mcg/day (Diane 35®), group 4 received EE 1.5mcg/day +gestodene 3.75mcg/day (Ginera®), and group 5 received EE 1.5mcg/day + levonorgestrel 7.5mcg/day (Microgynon®). Bilateral oophorectomy was performed after 3months. The right ovary was used for the histological examination of the ovarian follicle pool (primordial, primary, secondary, tertiary follicle, fibrosis, corpus luteum [CL], and intra-CL angiogenesis) and surface epithelial change (germinal epithelial degeneration), and the left ovary was used to conduct genetic analysis of miRNAs (mir-21, mir-494, mir-191, and mir 145). Antimullerian hormone (AMH) was measured from intracardiac blood samples. For statistical analysis, the Kruskal–Wallis test was performed, followed by a pairwise comparison with the post-hoc Dunn's test, and p values of less than 0.05 were considered statistically significant.
Results: When compared with Group 1, no significant difference was observed in blood AMH levels in Group 2, but blood AMH levels were found to be significantly decreased in groups 3, 4, and 5. Light microscopy revealed that the number of primordial follicles was similar across the groups, while Group 4 had a significantly lower number of primary, secondary, and tertiary follicles than the control and other experimental groups. Fibrosis and germinal epithelial degeneration were significantly increased in all combined oral contraceptive (COC) groups compared to the control group. mir-21, mir-494, mir-191, and mir-145 expression levels were found to be significantly higher in all COC groups than in the control group.
Conclusion: Different progestin-containing COCs may affect ovarian reserve tests at different levels. Mir-21, mir-494, mir-191, and mir-145 are probably upregulated through the estrogen and progesterone receptor, due to the estrogen and progesterone containing oral contraceptives.
Keywords
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