Hypothalamic hormone: gonadorelin
Sexual hormones are secreted by the gonades, testes and ovaries. They are steroids. Their secretion is controlled by the hypothalamic-pituitary complex which releases stimulins which are polypeptides.
The hypothalamus releases several hormones, one of which is gonadorelin or GnRH (gonadotropin releasing hormone), also called LHRH (luteinizing hormone releasing hormone).
GnRH is a decapeptide which controls pituitary secretion of LH (luteinizing hormone) and FSH (follicle-stimulating hormone). It i s secreted physiologically in a pulsatile way by intermittent discharges, at the frequency of approximately 0.5 to 1 discharge per hour. These discharges are elicited by a structure sometimes called the pulsatile hypothalamic generator.
This secretion is modulated by transmitters, and is decreased by gonadal hormones testosterone in men, estradiol and progesterone in women. However, in women, in the middle of the menstrual cycle, it is the rise in the concentration of estradiol which elicits the release of GnRH and ovulation.
GnRH released by the hypothalamus directly reaches the pituitary gland by the venous portal system.
Effects
GnRH activates the GnRH receptor, a member of the G protein-coupled receptors and elicits pituitary secretion of FSH and LH
The effects of GnRH are different according to its mode of administration:
- In pulsatile administration, i.e. discontinuous, approaching physiological secretion, it increases the release of FSH and LH. It stimulates the transcription of the genes which code for the alpha and beta protein subunits of gonadotropins.
- In continuous administration, the maintenance of a constantly high concentration of GnRH induces, after a transitory stimulation, a discontinuation of FSH and LH secretions by desensitization of its receptors.
In absence of FSH and LH, there is fall in the secretion of estrogens or androgens, leading to a true chemical castration. The effect of continuous administration of GnRH is generally reversible in approximately two months after the discontinuation of its administration.
The administration of antagonists of GnRH leads to the same consequences as continuous administration of GnRH.
Use
GnRH or gonadorelin and its analogues, triptoreline, leuproreline, busereline, gosereline and nafarelin, are marketed in different forms:
- Preparations for pulsatile administration by intravenous route, a pulse every 90 minutes, during several days. This administration is done using a special perfusion pump. Gonadorelin is used to induce ovulation for the treatment of female infertility.
• Preparations for continuous and long duration of action are intended for the treatment of prostate cancer, the most frequent therapeutic use, and the treatment of precocious puberty and endometriosis (endometriosis is defined by the presence of an ectopic endometrial tissue, either genital level, or extra-genital). At the onset of continuous administration, in the treatment of prostate cancer for example, there is a stimulation of testosterone release and an aggravation of the symptoms.
- The same gonadorelin analogue, according to the preparations, can be used either as a stimulant, or as an inhibitor of the secretion of gonadotrophins.
Antagonists of gonadorelin
Analogues of GnRH which inhibit the pituitary receptors of GnRH and inhibit its effects are available. The best known analogues are cetrorelix (Cetrotide*), a synthetic decapeptide, and ganirelix (Orgalutran*). Their administration immediately inhibits, without an initial stimulation, the secretion of FSH and of LH and they are used in endocrinology and cancerology. One of their therapeutic uses is, for in vitro fertilization,: to inhibit the premature LH surges and ovulation in women undergoing controlled ovarian stimulation to induce ovocyte maturation.
Abarelix (Plenaxis*), which is also a peptide analogue of gonadorelin, is a more recent antagonist of gonadorelin.
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