Intranasal LHRH agonist combined periodically with a progestogen for contraception

Abstract

Mechanism of action and clinical uses of LHRH agonist formulationsIt is now well known that repetitive or continuous exposure of the gonadotroph to pharmacological amounts of natural LHRH or superactive LHRH agonists leads to a down-regulation of LH and FSH secretion and to subsequent inhibition of ovarian function ( Figure 1). The initial effect of an LHRH agonist administration is a maximal and prolonged release of LH and FSH, replacing the usual pulsations by a massive discharge of hormones. Following a single administration of a LHRH agonist, serum gonadotrophin levels remain elevated for several hours and usually return to baseline levels within 24 h. During such a supraphysiological stimulation, the gonadotroph cell becomes refractory to a subsequent dose for several hours after the initial dosing. Repetitive administration produces a progressive inhibition of gonadotrophins and the more frequent the administration, the greater the inhibition of circulating levels of LH and FSH and the decrease in ovarian steroidogenesis.LHRH agonists cannot be administered by the oral route since these small peptides are rapidly destroyed by digestive enzymes before they can be absorbed in the gastrointestinal tract. Besides the administration by s.c. injection, the first alternative mode of administration to be developed was the intranasal spray. Although the absorption through the nasal mucosa is limited, inhibition of ovarian function can be achieved following intranasal insufflation (Figure 2).Several years ago, the first clinical trials using the intranasal LHRH agonist buserelin once daily tested the potential use of this new analog as a new antiovulatory contraceptive approach. Over the subsequent years, multiple intranasal doses and larger s.c. doses of several LHRH agonists have been used, mainly to suppress ovarian steroidogenesis for the treatment of several steroid-dependent gynecological conditions such as endometriosis, leiomyoma uteri and polycystic ovarian disease [1]. In the last few years, slow-release formulations where an LHRH agonist is embedded in biodegradable polylactide-glycolide copolymer, have been developed, such as microcapsules suspension for i.m. injection and a cylindrical implant for s.c. injection. These new formulations can be administered on a monthly basis. Since they produce