Vasoactive intestinal peptide modulates steroid hormone secretion via the superior ovarian nerve in a rat model of polycystic ovary syndrome

Ovarian steroidogenesis is an essential process that modulates reproduction. In the cyclic rat, vasoactive intestinal peptide (VIP) stimulates the secretion of steroid hormones, and this is dependent on the superior ovarian nerve (SON). In a rat model of polycystic ovarian syndrome induced by an estradiol valerate injection (PCOS-EV), the increase in SON activity results in elevated levels of norepinephrine (NE) and VIP in the ovary, which in turn leads to a rise in androgen. To analyze whether a greater influx of NE to the ovary, due to the hyperactivity of the SON, modifies the response of the gonad to VIP, PCOS-EV or vehicle-treated rats (Vh) were subjected to: 1) stimulation of the left or right ovary with VIP (L-VIP or R-VIP), or 2) the left or right section of the SON (LSON or RSON) followed by injection of VIP into the denervated ovary. Animals were euthanized 1 h later, and the serum levels of steroid hormones were assessed. In Vh rats treated on estrus, VIP stimulation increased the serum levels of testosterone, irrespective of the ovary injected (Vh L-VIP: 17.3 ± 0.5 or Vh R-VIP: 11.3 ± 1.1 vs. Vh: 6.4 ± 1.3). Section of the SON prior to VIP stimulation did not modify testosterone secretion (Vh LSNO+L-VIP: 15.5 ± 2.7 vs. Vh L-VIP: 17.3 ± 0.5; Vh RSNO+R-VIP: 10.6 ± 0.9 vs. Vh R-VIP: 11.3 ± 1.1). In PCOS-EV rats, VIP stimulation of the left ovary lowered testosterone (EV L-VIP: 11.0 ± 4.0 vs. EV: 24.6 ± 2.5). On the other hand, the effects of VIP injection into the denervated ovary were asymmetric, i.e., treatment in the left ovary not modified testosterone levels (EV LSNO+L-VIP: 6.3 ± 1.3 vs. EV L-VIP: 11.0 ± 4.0), while it decreased testosterone when performed in the right ovary (EV RSNO+R-VIP: 6.9 ± 1.3 vs. EV R-VIP: 29.6 ± 7.6). These results show that, in estrus, VIP has a stimulating effect on testosterone secretion, which is amplified by SON signals. Contrary to this, in the PCOS-EV rat, VIP lowers the elevated levels of androgens that characterize this animal model. Based on present results, we suggest that VIP could be used as a treatment for PCOS.