Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs

Abstract

Investigations have proved the clinical importance of hypothalmic gonadotropin-releasing hormone (GnRH) and its agonistic and antagonistic analogs. A pulsatile pattern of stimulation of specific receptors in the anterior pituitary gonadotrope has been shown to activate pituitary-gonadal function; continuous administration inhibits it. Clinical research has shown promising results in the induction of ovulation using the pulsatile pattern of GnRH administration in patients with hypogonadotropic amenorrhea. Attempts to use GnRH and its agonists to activate the pituitary-gonadal system in patients with idiopathic delayed puberty has proved logistically impractical because of the duration of treatment required to achieve sexual maturation. Treatment of cryptorchidism by intranasal administration 6 times daily for 4 weeks resulted in complete descent in 38% of the 48 boys and partial descent in 28%. For GnRH nonresponders sequential treatment with human chorionic gonadotropin produced an 86.2% success rate. Because of the ability of GnRH agonists to reversibly suppress the pituitary-gonadal axis without side effects it can be used in diseases mediated by gonadal steroids. Successful halting of precocious puberty through the administration of GnRH to suppress the nocturnal release of gonadotropin has been demonstrated. Unlike treatment with progestational agents no side effects are discerned. Continuous administration of GnRH agonist in patients with endometriosis reduces ovarian estrogens and androgens to castration levels mimicking an ovariectomy. This castration effect highlights the potential use of GnRH agonists in the treatment of metastatic breast cancer. The use of GnRH agonists for the treatment of androgen-dependent prostatic carcinoma has induced clinical improvement with nonmetastatic stage 3 disease and pain relief in metastic stage D disease. In polycystic ovary syndrome administration of GnRH agonist shows promising results. As a potential contraceptive GnRH agonists have not yet demonstrated practical advantages. The actions under study include: ovulation inhibition luteolysis induction induction of luteal phase defect and reduction of testosterone production. Numerous antagonistic analogs of GnRH have been synthesized and have shown some potential contraceptive effects in animal studies.