Disturbances of hormonal status and ovulation process in infantile female rats with polycystic ovary syndrome induced by dehydroepiandrosterone

BACKGROUND: Rodent models of polycystic ovary syndrome (PCOS), including those induced by dehydroepiandosterone (DHEA), are used to study the pathogenesis of polycystic ovary syndrome (PCOS). However, ovarian steroidogenesis and ovulation markers in this model remain poorly understood. There are no data on the ability of luteinizing hormone (LH) receptor agonists to stimulate ovulation in rats with this PCOS model, which is important for assisted reproductive technologies. AIM: To study ovarian steroidogenesis, ovulation markers, and ovarian morphology in infantile female rats with DHEA-induced PCOS and to evaluate the effect of the TP03 allosteric agonist, 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]-pyrimidine-6-carboxamide, on these parameters. METHODS: Female Wistar rats, starting at 23–26 days of age, were treated with DHEA (6 mg/100 g/day, subcutaneously) for 6 weeks. Body and ovarian weights, blood testosterone, progesterone, and estradiol levels (ELISA), ovarian gene expression (RT-PCR), and ovarian morphology (number of tertiary and preovulatory follicles, corpora lutea, and follicular cysts) were assessed microscopically. To stimulate ovulation, PCOS rats were treated with Follimag (15 IU/rat) and after 48 hours with TP03 (25 mg/kg), after 16 hours the studied parameters were assessed. RESULTS: In DHEA-treated rats, ovarian weight, the number of tertiary follicles and corpora lutea from previous cycles, progesterone levels, and the expression of genes responsible for steroidogenesis (Star, Cyp11a1, Cyp17a1) and ovulation (Adamts-1, Vegf-a) decreased. Testosterone levels increased, and follicular cysts were detected, consistent with the pathogenesis of PCOS. Treatment with Follimag and TP03 increased ovarian weight, progesterone levels, and cytochrome CYP17A1 gene expression, and stimulated ovulation by inducing the formation of corpora lutea. Additionally, luteinized unruptured follicles were detected in the ovaries, which was associated with decreased expression of the metalloproteinase ADAMTS-1 and VEGF-A genes, which are involved in follicular rupture. CONCLUSION: Treatment of infantile rats with DHEA-induced PCOS with TP03 induces ovulation and, in addition to normal corpora lutea, luteinized unruptured follicles are formed as a result of decreased expression of genes involved in follicle rupture.