Stimulation of Ovarian Steroidogenesis and Ovulation in Mature Female Rats with Type 2 Diabetes Mellitus

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Abstract Type 2 diabetes mellitus (T2DM) negatively impacts the female reproductive system, however, hormonal and functional disturbances in the ovaries and their response to luteinizing hormone receptor (LHR) agonists in T2DM have been poorly studied, and data on allosteric LHR-agonists are lacking. The aim of the study was to evaluate the effect of the allosteric LHR-agonist TP03 and human chorionic gonadotropin (hCG) on ovarian steroidogenesis and ovulation in female rats with diet-induced T2DM. To induce ovulation, rats were administered Follimag (15 IU/rat) and Cetrotide (100 µg/rat, twice) in diestrus and TP03 (25 mg/kg) or hCG (25 IU/rat) 48 h later, analyzing the parameters 8 or 24 h after the injection of LHR-agonists. In T2DM rats, estradiol levels in the blood, the number of preovulatory follicles, and the expression of the ADAMTS-1 metalloproteinase gene, an ovulation marker, were decreased. Treatment with TP03 and hCG increased progesterone levels (after 8 hours) and the expression of the ovarian genes Cyp17a1 (hCG, TP03) and Star (hCG), responsible for ovarian steroidogenesis, as well as the Adamts-1 gene. After 24 hours, corpora lutea were detected in the ovaries of T2DM rats, with hCG and TP03 being comparable in this parameter. Compared to controls, T2DM rats maintained reduced estradiol levels, and the stimulating effect of LHR-agonists on ovarian gene expression was less pronounced. Thus, in T2DM, TP03 is not inferior to hCG in its ability to stimulate ovarian steroidogenesis and ovulation, and this indicates the prospects for its use in assisted reproductive technologies for T2DM.

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