Gonadotropin-releasing hormone agonists bind to pituitary GnRH receptors and stimulate LH and FSH synthesis and release. The agonists have a much longer biologic half-life (3 to 8 hours) than endogenous GnRH (3.5 minutes), resulting in the continuous exposure of GnRH receptors to GnRH-agonist activity. This exposure causes a loss of pituitary receptors and downregulation of GnRH activity, resulting in low FSH and LH levels. Ovarian steroid production is suppressed, providing a medically induced and reversible state of pseudomenopause. A direct effect of GnRH agonists on ectopic endometrium is possible, because expression of the GnRH receptor gene is documented in ectopic endometrium and because direct inhibition of endometriosis cells was shown in vitro (406). In rat models used to study surgical adhesion formation and endometriosis, GnRH-agonist therapy decreased activity of plasminogen activators and matrix MMPs and increased the activity of their inhibitors, suggesting potential GnRH-agonist–regulated mechanisms for reducing adhesion formation (407).
Various GnRH agonists were developed and used in treating endometriosis. These agents include leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, and triptorelin. These drugs are inactive orally and must be administered intramuscularly, subcutaneously, or by intranasal absorption. The best therapeutic effect is often associated with an estradiol dose of 20 to 40 pg/mL (75–150 pmol/L). These so-called depot formulations are attractive because of the reduced frequency of administration and because nasal administration can be complicated by variations in absorption rates and problems with patient compliance (390). The results with GnRH agonists are similar to those with oral contraceptive progestin or gestrinone therapy. Treatment for 3 months with a GnRH agonist is effective in improving pain for 6 months (332).
Although GnRH agonists do not have an adverse effect on serum lipids and lipoproteins levels, their side effects are caused by hypoestrogenism and include hot ﬂashes, vaginal dryness, reduced libido, and osteoporosis (6% to 8% loss in trabecular bone density after 6 months of therapy). Reversibility of bone loss is equivocal and therefore of concern, because treatment periods of longer than 6 months may be required (408,409). The goal is to suppress endometriosis and maintain serum estrogen levels of 30 to 45 pg/mL. More extreme estradiol suppression will induce bone loss (408). The dose of daily GnRH agonist can be regulated by monitoring estradiol levels, by the addition of low-dose progestin or estrogen–progestin in an add-back regimen, or by draw-back therapy.