Reduction of vasomotor symptoms and bone mineral density loss with combined norethindrone and long-acting gonadotropin-releasing hormone agonist therapy of symptomatic endometriosis: a prospective randomized trial.

The hypoestrogenic state induced by gonadotropin-releasing hormone agonists (GnRHa) has been shown to suppress symptomatic endometriosis effectively but to elicit vasomotor symptoms and loss of bone mineral density. The role of norethindrone as a supplement to GnRHa in eliminating such side effects was assessed by enrolling 20 patients with symptomatic endometriosis diagnosed laparoscopically in a randomized, prospective, double-blinded trial. All patients received the long-acting GnRHa leuprolide acetate 3.75 mg im every 4 weeks for 24 weeks. Ten patients self-administered norethindrone 5 then 10 mg by mouth daily, whereas the remainder self-administered placebo tablets. Results of this study showed that combination therapy was as effective as GnRHa alone in significantly reducing circulating gonadotropin and estrogen levels (P less than 0.01), extent of visible endometriotic implants (P less than 0.01), and painful symptoms (P less than 0.01). Marked vasomotor and vaginal symptoms experienced by patients given GnRHa alone were minimized in those receiving GnRHa with norethindrone. Lumbar spine bone mineral density loss, measured by dual energy x-ray absorptiometry, was significantly reduced and more completely reversed in patients receiving combination therapy (P less than 0.05). A reversible decrease in high density lipoprotein-cholesterol and increase in low density lipoprotein:high density lipoprotein ratio was noted only in the patients receiving combination therapy, but not in those receiving GnRHa only. The addition of norethindrone to GnRHa is an effective means of treating symptomatic endometriosis while ameliorating side effects induced by GnRHa alone.