Effect of Different Luteinizing Hormone Receptor Agonists on Ovarian Steroidogenesis in Mature Female Rats

In clinical practice, ovarian steroidogenesis is stimulated and ovulation is induced using such gonadotropin preparations as human chorionic gonadotropin (hCG) and luteinizing hormone (LH) which, however, have a number of side effects, including a reduction in ovarian sensitivity to endogenous LH and ovarian hyperstimulation syndrome. An alternative to hCG and LH could be allosteric LH/hCG receptor agonists, including the thieno-[2,3-d]-pyrimidine derivative TP03 developed in our laboratory. This work was aimed to study the effect of TP03 (40 μg/kg, i.p.) versus hCG (30 IU/rat, s.c.) on ovarian steroidogenesis in mature female rats in the late proestrus phase, including those treated with the gonadotropin releasing hormone (GnRH) antagonist Orgalutran (100 μg/kg, s.c., 3 h before TP03 or hCG administration). Estradiol, progesterone and LH levels were measured in the blood, while expression levels of the steroidogenesis-related genes Star, Cyp11a1, Hsd3b, Cyp17a1, Hsd17b, Cyp19a1 and LH/hCG receptor gene Lhcgr were assessed in the ovaries. Three hours after administration, TP03 and hCG increased blood progesterone levels and stimulated the expression of genes encoding the cholesterol-transporting protein StAR, cytochrome P450c17 and aromatase (cytochrome P450c19), with this effects detected both in control rats with normal LH levels and in Orgalutran-treated rats with reduced LH levels. The effects of TP03 were comparable to those of hCG, but in contrast to hCG, TP03 did not reduce the activity of the hypothalamic–pituitary–gonadal axis, as indicated by the lack of its influence on blood LH levels and ovarian expression of LH/hCG receptors. Our data indicate the ability of TP03 to effectively stimulate ovarian steroidogenesis, as well as good prospects for the development of TP03-based drugs for controlled ovulation induction.