Since the discovery and synthesis of gonadotropin-releasing hormone (GnRH) in 1971, numerous long-acting agonistic and antagonistic analogs have been synthesized. Agonistic analogs were found to desensitize pituitary GnRH receptors with chronic use, resulting in decreased gonadotropin secretion and a hypogonadal state. These analogs are being investigated as potential contraceptives and in the treatment of several conditions in which decreased gonadal steroid production is desired. Substantial progress has been made in these areas. The purpose of this review is to provide the clinician with data regarding the potential clinical utility of this class of peptides.
PIP: This discussion of the therapeutic uses of gonadotropin-releasing hormone analogs begins with a review of development and biochemistry. It reviews the literature, covering true gonadotropin-stimulated precocious puberty, female and male contraception, endometriosis, uterine leiomyomata, hirsutism, premenstrual syndrome and other menstrual cycle related disorders, metastatic prostate cancer, induction of ovulation, and GnRH antagonists. 2 research teams announced the structure and chemical synthesis of gonadotropin-releasing hormone (GnRH) in 1971. Since that time, numerous long-acting agonistic and antagonistic analogics have been synthesized. The majority of analogs in clinical development have resulted from d-amino acid substitutions at position 6. More hydrophobic substitutions generally have led to increased potency. Efforts are in progress to provide the most effective and practical route of administration for GnRH analogs. After initial studies using an intravenous bolus or infusion, most clinical trials have been performed with intermittent subcutaneous injections of the drug. If GnRH is given continuously, it will desensitize pituitary GnRH receptors and inhibit secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Many potent and long-acting agonistic analogs have been synthesized which are capable of inhibiting pituitary gonadotropin secretion. These analogs are being evaluated for conditions in which gonadal suppression is the goal. When used on a continuous basis, several of the agonistic analogs can inhibit ovulation and gonadal steroid production in the female. This means that conditions such as isosexual precocity, endometriosis, uterine leiomyomata, and hirsutism may be treated successfully. The side effects are few, toxicity appears to be low, and menstrual function returns soon after the analog is discontinued. Evidence exists of decrease in bone density after 6 months' use of 1 analog, presumably secondary to decreased serum estrogen concentrations, yet preliminary results suggest that this is reversed within 6 months of stopping treatment. The GnRH analogs have proven successful in the treatment of gonadotropin-dependent precocious puberty and in the medical treatment of metastatic prostatic carcinoma. The GnRH agonists have been less successful as a possible male contraceptive; azoospermia cannot be induced reliably when exogenous testosterone is administered to prevent impotence. GnRH antagonists may find an application for this latter indication. GnRH agonists may be used as adjunctive treatment in ovulation induction. The agonists may be useful in conditions in which it may be desirable to suppress endogenous gonadotropin secretion before administering exogenous gonadotropins.