The reproductive hormone cascade is driven by the brain decapeptide, gonadotropin-releasing-hormone (GnRH), which in turn stimulates pituitary gonadotropins which regulate ovarian and testicular sex hormones and gamete production. Total ablation of GnRH actions through desensitization with GnRH agonists or inhibition with GnRH antagonists reduce sex steroids to castration levels. Substitution of glycine in position six with a D-amino acid enhances a beta II turn which increases binding affinity, reduces degradation and metabolic clearance.
These analogues are extensively used to treat prostatic cancer and other hormone-dependent diseases.
However, reduction of sex steroids to castration levels results in unwanted side effects such as bone loss and flushing. To ameliorate this bifunctional GnRH-steroid molecules have been developed as well as orally-active GnRH analogues which can be dose adjusted to partially inhibit sex steroids.
Recently, novel neuropeptides, kisspeptin Kp) and neurokinin B (NKB) were discovered as regulators of GnRH secretion. Their cognate receptors have therefore become a target for the partial inhibition of GnRH and ensuing sex steroids. Kp antagonists inhibit GnRH neurone firing, GnRH secretion, gonadotropin secretion and sex steroids. They delay progress through puberty and prevent the ovulatory surge of LH gonadotropin but do not lower basal LH and steroids. Hence they have promise as novel female contraceptives and the treatment of a number of hormone-dependent diseases, such as endometriosis, uterine fibroids, polycystic ovarian disease and benign prostatic hyperplasia, without causing bone loss and flushing.