gonadotrophin releasing hormone agonists (GnRH agonists)

pharmacology

GnRH agonists stimulate release of pituitary gonadotrophins LH and FSH, with consequent initial increase of ovarian and testicular steroidogenesis.
continuous dosing rather than physiologic pulsatile dosing gradually abolishes the stimulatory effect on the pituitary gland.
Within three to four weeks, daily administration leads to decreased pituitary gonadotrophin secretion and/or the secretion of gonadotrophins with lowered biological activity with consequent suppression of gonadal steroidogenesis and inhibition of functions and tissues that depend on gonadal steroids for their maintenance.
ongoing Rx results in a menopause-like state in women and androgen deficiency states in males
use in males:
- often used for Rx of metastatic prostate Ca

the main indication is laparoscopically proven endometriosis in patients with ongoing symptoms and who do not wish to get pregnant.
- usual dose: 6 month course of nafarelin 400micrograms inhaled daily induced amenorrhoea in approximately 65%, 80% and 90% of patients after 60, 90 and 120 days, respectively.

controlled down regulation of ovaries prior to in-vitro fertilisation (IVF)
The purpose of down regulation is to provide a more controlled stimulation for subsequent stimulation and thereby minimise the occurrence of spontaneous ovulation and premature luteinisation.
75% of women on nafarelin 400microgram inhaled bd achieve down regulation by 38 days of Rx

examples of GnRH agonists used:
- goserelin depo injection every 3 months
- nafarelin
- buserelin
- leuprolide acetate 1mg s/c daily

These include women with chronic anovulation/ menstrual disturbances due to weight loss, athletic or other forms of hypothalamic amenorrhoea, immobilisation, glucocorticoid usage or a strong family history of osteoporosis.
prior Rx with GnRH
these patients should have bone mineral density testing prior to Rx

patients with rhinitis may need to use a nasal vasoconstrictor 30min prior to dosing to ensure absorption.

Diagnostic tests of pituitary-gonadal function conducted during the treatment and 4 to 8 weeks after discontinuation of nafarelin therapy may therefore be misleading.

potential for clinical flare-up of endometriotic symptoms and lesions within the first few weeks of treatment due to the transient rise in oestradiol secretion.
Transient cyst formation that may accompany GnRH agonist use is more common when GnRH agonists are commenced in the follicular phase of the cycle (flare effect).
oestrogen-sensitive migraine, epilepsy.
ovarian hyperstimulation but not usually true ovarian hyperstimulation syndrome:
- exaggerated follicular response to gonadotrophin stimulation and is triggered by the luteinising agent (ie. hCG administration or a spontaneous LH surge)
- this causes hypovolaemia, oliguria, ascites, pleural effusions, haemoconcentration, electrolytic disturbances and hepatic dysfunction.

Functional ovarian cysts have been reported to occur in the first two months of therapy.
Many, but not all, of these events occurred in patients with polycystic ovarian disease.
These cystic enlargements may resolve spontaneously, generally within four to six weeks of therapy, but in some cases discontinuation of drug and/ or surgical intervention may be required.

after 6 months Rx with nafarelin:
- vertebral trabecular bone density and total vertebral bone mass, measured by quantitative computed tomography (QCT), decreased by an average of 8.7% and 4.3%, respectively, compared to pretreatment levels.
- There was partial recovery of bone density in the post-treatment period; the average trabecular bone density and total bone mass were 4.9% and 3.3% less than the pretreatment levels, respectively.