GnRH Agonists, Antagonists, and Assisted Conception
GnRH Agonists, Antagonists, and Assisted Conception
Pituitary stimulation with pulsatile gonadotropin-releasing hormone (GnRH) induces both follicle-stimulating hormone and luteinizing hormone (LH). Blockade of pituitary gonadotropin secretion occurs upon desensitization when a continuous GnRH stimulus is provided by means an agonist or when the pituitary receptors are occupied with a competitive antagonist. The most common indication for blockade of pituitary gonadotropin secretion is with assisted reproduction treatment (ART) where it prevents premature luteinization. Originally by lack of clinically available GnRH antagonist, prolonged daily injection of agonist with its desensitizing effect was introduced for this purpose. Today, single- and multiple-dose injectable antagonists are also available to block the LH surge. This review provides an overview of the use of GnRH agonists and antagonists in assisted reproduction.
A logical consequence of the discovery of the amino acid sequence of gonadotropin-releasing hormone (GnRH) in 1971 was the development of agonistic and antagonistic analogues with many scientific and pharmaceutical perspectives. Agonists would be used as strong sustained stimulators of gonadotropin secretion and the antagonists promised to be a potential tool for chemical hypophysectomy. However, sustained stimulation of the pituitary with GnRH or its agonists caused desensitization, by still far from understood postreceptor mechanisms. This resulted, after a short period of time, in a state of chemical hypophysectomy, the presumed indication for GnRH antagonists. Development of clinically safe agonists was relatively simple by just changing one or two amino acids. It required almost 30 years of trial and error with replacement of three or more amino acids to obtain an antagonist with an acceptable pharmacokinetic, safety, and commercial profile. The most promising indication for GnRH analogues was the use in controlled ovarian hyperstimulation (COH) protocols for the prevention of a premature luteinizing hormone (LH) surge. In vitro fertilization (IVF) in the natural or stimulated cycle was hampered by the occurrence of premature luteinization and ovulation. Placebo-controlled studies of GnRH agonists revealed that, without an agonist, in about 20% of women there was a premature LH increase that lead to the cancellation of the IVF cycle. Preventing this untimely physiological change is clearly beneficial. Moreover, the oocyte yield is higher with more embryos, allowing better selection and leading to an increase in pregnancy rate. Since the introduction of GnRH agonists in IVF, many treatment regimens have been developed. In most centers the long agonist protocol has become the standard procedure. The immediate and dose-dependent suppressive action of antagonist, by competing with GnRH for pituitary binding sides, provides a convenient alternative for agonists. Despite the long period of research, GnRH antagonists are in an advanced stage of clinical development. This review will focus on the use of GnRH analogues in the most used assisted reproductive techniques (ART).
Abstract and Introduction
Abstract
Pituitary stimulation with pulsatile gonadotropin-releasing hormone (GnRH) induces both follicle-stimulating hormone and luteinizing hormone (LH). Blockade of pituitary gonadotropin secretion occurs upon desensitization when a continuous GnRH stimulus is provided by means an agonist or when the pituitary receptors are occupied with a competitive antagonist. The most common indication for blockade of pituitary gonadotropin secretion is with assisted reproduction treatment (ART) where it prevents premature luteinization. Originally by lack of clinically available GnRH antagonist, prolonged daily injection of agonist with its desensitizing effect was introduced for this purpose. Today, single- and multiple-dose injectable antagonists are also available to block the LH surge. This review provides an overview of the use of GnRH agonists and antagonists in assisted reproduction.
Introduction
A logical consequence of the discovery of the amino acid sequence of gonadotropin-releasing hormone (GnRH) in 1971 was the development of agonistic and antagonistic analogues with many scientific and pharmaceutical perspectives. Agonists would be used as strong sustained stimulators of gonadotropin secretion and the antagonists promised to be a potential tool for chemical hypophysectomy. However, sustained stimulation of the pituitary with GnRH or its agonists caused desensitization, by still far from understood postreceptor mechanisms. This resulted, after a short period of time, in a state of chemical hypophysectomy, the presumed indication for GnRH antagonists. Development of clinically safe agonists was relatively simple by just changing one or two amino acids. It required almost 30 years of trial and error with replacement of three or more amino acids to obtain an antagonist with an acceptable pharmacokinetic, safety, and commercial profile. The most promising indication for GnRH analogues was the use in controlled ovarian hyperstimulation (COH) protocols for the prevention of a premature luteinizing hormone (LH) surge. In vitro fertilization (IVF) in the natural or stimulated cycle was hampered by the occurrence of premature luteinization and ovulation. Placebo-controlled studies of GnRH agonists revealed that, without an agonist, in about 20% of women there was a premature LH increase that lead to the cancellation of the IVF cycle. Preventing this untimely physiological change is clearly beneficial. Moreover, the oocyte yield is higher with more embryos, allowing better selection and leading to an increase in pregnancy rate. Since the introduction of GnRH agonists in IVF, many treatment regimens have been developed. In most centers the long agonist protocol has become the standard procedure. The immediate and dose-dependent suppressive action of antagonist, by competing with GnRH for pituitary binding sides, provides a convenient alternative for agonists. Despite the long period of research, GnRH antagonists are in an advanced stage of clinical development. This review will focus on the use of GnRH analogues in the most used assisted reproductive techniques (ART).
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