ABSTRACT
Gonadotropin releasing hormone (GnRH) is the primary hypothalamic regulator of reproductive function. With the help of a very small amount (250ug) of GnRH derived from 160000 porcine hypothalami, a group of scientists at Andrew Schally’s peptide laboratory in New Orleans was able to unravel the chemical structure of this compound in 1971.1,2 Roger Guillemin was able to characterize and also synthesize independently this neuroendocrine hormone. They both received the Nobel prize for their achievement. GnRH is a decapeptide which, like several other brain peptides, is synthesized as a part of a much larger precursor peptide, the GnRH associated peptide (GAP). This peptide is made up of a sequence of 56 amino acids. The availability of the synthetic hormone for dynamic endocrine testing and receptor studies created new insights into the physiological role of GnRH in the hypothalamic pituitary gonadal axis.3 GnRH is produced and released from a group of loosely connected neurons located in the medial basal hypothalamus, primarily within the arcuate nucleus, and in the preoptic area of the ventral hypothalamus. It is synthesized in the cell body, transported along the axons to the synaps and released in a pulsatile fashion into the complex capillary net of the portal system of the pituitary gland.4 The synthesis and release of the pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), was shown to be dependent on this pulsatile GnRH pattern.5-7 In the human, the critical range of pulsatile release frequencies ranges from the shortest interpulse frequency of about 71 minutes in the late follicular phase to an interval of 216 minutes in the late luteal phase.810 High frequent (>3pulses/hour) and continuous exposure of the pituitary to GnRH failed to produce normal LH and FSH release patterns while its sensitivity appeared to be greatly dependent on gonadal steroids and proteins.11-13
After the discovery of the chemical structure of native GnRH, many analogs were synthetically produced. Most analogs were able to elicit a huge FSH and LH release from the pituitary and were therefore called GnRH agonists. However, under continuous administration of a GnRH agonist the normal synthesis and subsequent release of LH, and to a lesser extent FSH, became blocked (Fig 39.1). Other analogs caused an instant
fall in gonadotropin secretion from the pituitary by competitive receptor binding, and were designated as GnRH antagonists. Nowadays GnRH agonists have gained a wide field of clinical applications.14 Suppression of the pituitary ovarian (or testicular) axis for a limited or even extended period of time is the main goal to be achieved in these treatments. The introduction of the GnRH antagonists into clinical practice has been hampered for a long time by problems concerning solubility, direct allergy like side effects owing to histamine release and cost factors.15,16
GnRH ANALOGS NOWADAYS ON THE MARKET
The elucidation of the structure, function and metabolic pathways of native GnRH has prompted an intensive effort by research laboratories and the pharmaceutical industry to synthesize potent and longer-acting agonists and antagonists.17 Over the past three decades, thousands of analogs of GnRH have been synthesized. Only seven of the agonistic analogs of GnRH have become approved and clinically used drugs. The first major step in increasing the potency of GnRH was made with substitutions of glycine number 10 at the C terminus.
