Gonadotrophin surge attenuating factor (GnSAF) is a non-steroidal ovarian factor which reduces pituitary responsiveness to GnRH both <I>in vitro</I> and <I>in vivo</I>. GnSAF is present in serum from superovulated women in a 141 kDa molecular weight form. GnSAF bioactivity (suppression of GnRH-induced LH secretion from cultured rat pituitary cells) in serum from superovulated women is not overcome by incubation with an inhibin antibody, demonstrating that it is distinct from inhibin. Under the culture conditions used, the ovarian steroids had no significant suppressive effects on GnRH-induced LH secretion, showing that GnSAF bioactivity is not due oestradiol or progesterone. GnSAF is also present in serum from the follicular phase of spontaneously cycling women with maximal levels being produced during the mid follicular phase. It has been suggested that GnSAF production during the follicular phase suppresses LH release from the pituitary until the levels of oestradiol produced by the developing follicle are high enough to overcome the effects of GnSAF and the LH surge occurs. However, suppression of LH secretion by an enriched GnSAF preparation is potentiated by oestradiol and progesterone, both individually and in combination. This suggests that it is not a rise in steroid positive feedback but a decrease in GnSAF negative feedback which enables the LH surge to occur. Follistatin and GnSAF in combination have additive effects on the suppression of GnRH-induced LH secretion, whereas GnSAF and inhibin in combination cause no greater suppression than they do individually. GnSAF present in inhibin-stripped human follicular fluid is also able to reduce both the GnRH self-priming response, and its augmentation by progesterone, by rat pituitary cells in culture after only 90 minutes exposure. Inhibin and follistatin have no such effects under the same conditions.

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Important physiological changes occur during lactation to allow for nourishment of the offspring. Specific neuronal groups within the arcuate nucleus of the hypothalamus influence prolactin (PRL) secretion, metabolism and fertility during lactation. Our overall goal was to identify gene expression changes in the arcuate nucleus during lactation and examine the roles of PRL and ovarian hormones in regulating expression of select genes. We evaluated transcriptome changes in the arcuate nucleus during lactation using RNA-sequencing. Thirty-seven differentially expressed genes, including neuropeptides, signaling molecules, receptors and enzymes, were identified between suckled and pup-deprived groups. Selected genes were evaluated by qRT-PCR in ovary-intact and ovariectomized lactating models, which included non-lactating, suckled and 24hr pup-deprived lactating groups. The mRNA expression of tyrosine hydroxylase (Th), kisspeptin (Kiss1), and neurokinin B (Tac3) was decreased, whereas mRNA expression of proenkephalin (Penk), parathyroid hormone 2 receptor (Pth2r), insulin-like growth factor binding protein 3 (Igfbp3), membrane progesterone receptor beta (Paqr8), suppressor of cytokine signaling 2 (Socs2) and cytokine-inducible SH2 domain-containing protein (Cish) was increased in suckled lactating rats. In 24hr pup-deprived dams, mRNA expression of Pth2r, Igfbp3, Paqr8, Socs2 and Cish was decreased and Th was increased, as compared to suckled rats. The mRNA expression of Kiss1 and Tac3 was increased and Penk was decreased after 72hr, but not 24hr, pup deprivation suggesting gene expression of these neuropeptides is slow to return to non-lactating levels after removing the suckling stimulus. Tyrosine hydroxylase (TH) protein and enkephalin (ENK) peptide expression was examined by immunohistochemistry. Lactating rats had increased ENK in the median eminence and decreased TH in the median eminence and arcuate nucleus as compared to virgin ovariectomized rats. ENK co-localization with TH in the arcuate nucleus was more predominant in lactating rats. Penk, Igfbp3, Pth2r, Cish, and Socs2 mRNA expression was decreased after 72hr bromocriptine treatment in suckled rats, suggesting that these genes are PRL-regulated. In contrast, gene expression of Th, Tac3 and Kiss1 were increased and Paqr8 was decreased with 72hr pup-deprivation, but expression of these genes, were not altered with bromocriptine treatment, indicating that these genes are regulated by a non-PRL component of the suckling stimulus. The mRNA expression of Kiss1, Socs2 and Igfbp3 was increased and Penk was decreased in ovariectomized as compared to ovary intact lactating rats, suggesting that ovarian hormones influence the expression of these genes during lactation. Our data show gene expression changes in the arcuate nucleus that may contribute to increased PRL secretion (Th, Penk and Pth2r), decreased PRL receptor signaling (Cis and Socs2), reduced fertility (Kiss1 and Tac3), increased metabolism (Igfbp3) and support a role for progesterone membrane actions (Paqr8). The expression of some genes appeared to be selectively regulated by ovarian hormone input and/or PRL feedback.