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gnrh_agonists

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

indications

endometriosis

  • 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.

IVF

  • 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

metastatic prostate carcinoma

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

contraindications

  • undiagnosed abnormal PV bleeding
  • pregnancy or those who may become pregnant
  • lactation
  • known hypersensitivity to GnRH agonists

specific care in women

patients at high risk of osteoporosis

  • 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

rhinitis

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

interference with lab tests

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

adverse effects in women

initial oestrogenic effects

  • 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

  • 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.

later menopausal symptoms

  • hot flushes
  • change in libido
  • vaginal dryness
  • headaches
  • emotional lability
  • acne
  • myalgia
  • decreased breast size

osteoporosis

  • 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.

rare serious adverse effects

  • hypersensitivity reactions (0.2%)
  • pulmonary fibrosis
  • interstitial pneumonitis
gnrh_agonists.txt · Last modified: 2014/01/29 12:09 (external edit)