General

Hypothalamic gonadotropin-releasing hormone (GnRH), also named luteinizing-hormone-releasing hormone (LHRH), was first isolated from porcine hypothalami in 1971 [17]. GnRH is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly.NH₂) that plays an important role in the control of gonadal function and normal ovarian cyclicity. It is now called GnRH-I, as in man a second (GnRH-II) and third form (GnRH-III) of GnRH were later identified [24-25]. GnRH-II differs from GnRH-I by three amino acid residues (His⁵Trp⁷Tyr⁸GnRH-I) and is expressed at higher levels outside of the brain [20]. Like GnRH-I, it plays a role in a variety of reproductive and non-reproductive functions [1]. GnRH-III differs from GnRH-I by four amino acids (His⁵Asp⁶Trp⁷Lys⁸GnRH-I) and its distribution of expression in the brain indicates that it functions as a neurohormone at the hypothalamic-pituitary axis, next to other functions [25]. Moreover, it has been shown to have an antiproliferative effect on cancer cells [12] and it is not able to induce LH and FSH release in mammels [11].

The regulation of the ovarian cycle is dependent on a continuous interaction between the hypothalamus, the pituitary gland and the ovaries. GnRH is secreted by the hypothalamus in a pulsatile fashion [21]. Subsequently, GnRH is transported to the anterior pituitary, where it binds to specific receptors on the gonadotrope cells. This results in the biosynthesis and secretion of FSH and LH from the pituitary gonadotrope cells.

Receptor Structure

The cDNA sequence of the GnRH receptor was first elucidated in the early 1990's [2,9]. This receptor is a member of the rhodopsin-like (class A) G protein-coupled receptor (GPCR) superfamily. The receptor consists of seven α-helical transmembrane domains with typical sequence signatures of class A-like GPCRs and an extracellular amino terminal domain. A unique feature is the absence of an intracellular carboxy terminal domain [14]. A full length GnRH-II receptor transcript has not been identified in humans thus far, although it is present in other mammals. Thus in man there is one functional receptor with three endogenous ligands that all have a high affinity for the receptor [6,13,18].

The GnRH type I receptor is predominantly coupled to the G_q-protein, through which it regulates the biosynthesis and secretion of the gonadotropins, FSH and LH. However, signal transduction can also occur via other G-proteins or even in a G protein-independent manner [14].

Ligands

Over the past decades several peptide agonists and antagonists for GnRH receptors have been developed [3-4,8]. In addition, quite a few non-peptide antagonists from various chemical classes have been reported, of which some were shown to be active in vivo after oral adminstration [16,22]. Combined site-directed mutagenesis and homology-based receptor modelling pointed to amino acids in the third and seventh transmembrane domains as being critically important for peptide and non-peptide ligand binding. The binding site of non-peptide GnRH antagonists is currently thought to partially overlap with the binding site of the endogenous ligand GnRH and may also use some of the residues that are crucial for peptide binding [7].

Recently, the first evidence arose that besides the traditional agonist recognition site there is an allosteric site that modulates orthosteric ligand binding and subsequent biological effects [19].

GnRH receptor agonists and antagonists have been shown to be beneficial in IVF procedures. It should be noted that (peptide) agonists are used to desensitize the receptor, which in turn also results in a decreased gonadotrope function [15]. In addition, GnRH receptor ligands may also be applied in a number of sex hormone-dependent conditions [10,23]. Notably, various peptide GnRH receptor agonists and antagonists are marketed for the treatment of prostate, breast, uterine and ovarian cancer, leiomyomas, infertility, benign prostatic hyperplasia (BPH), IVF, premenstrual syndrome and endometriosis [5].

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