The goal of add-back therapy is to treat endometriosis and endometriosis-associated pain effectively while preventing vasomotor symptoms and bone loss related to the hypoestrogenic state induced by GnRH analogues. Add-back therapy can be achieved by administering progestins only, including norethisterone, 1.2 mg, and norethindrone acetate, 5 mg, but bone loss is not prevented by medrogestone, 10 mg per day (409–411). Add-back therapy can be achieved by tibolone, 2.5 mg per day, or by an estrogen–progestin combination (i.e., conjugated estrogens, 0.625 mg, combined with medroxyprogesterone acetate, 2.5 mg, or with norethindrone acetate, 5 mg; estradiol, 2 mg, combined with norethisterone acetate, 1 mg) (405,408,410–414). Treatment for up to 2 years with combined estrogen and progestagen add-back appears to be effective and safe in terms of pain relief and bone density protection; progestagen only add-back is not protective (415).
GnRH agonists should not be prescribed to girls who have not yet attained their maximal bone density, as some concern remains about the long-term effects of GnRH analogues on bone loss. In one report, bone mineral density reduction occurred during long-term GnRHagonist use and was not fully recovered up to 6 years after treatment (416). Use of add-back therapy (2 mg estradiol and1mg norethisterone acetate) did not affect this process (416). Drawback therapy was suggested as an alternative in a study showing that 6 months of intake of 400 μg per day of nafarelin was as effective as a draw-back regimen consisting of 1 month of intake of 400 μg per day of nafarelin followed by 5 months of 200 μg per day of nafarelin, with similar estradiol levels (30 pg/mL) but less loss of bone mineral density (417).
Treatment of rats with induced endometriosis using the nonsteroidal aromatase inhibitor fadrozole hydrochloride or YM511 resulted in a dose-dependent volume reduction of endometriosis transplants (418,419). In one case report, treatment of severe postmenopausal endometriosis with an aromatase inhibitor, anastrozole, 1 mg per day, and elemental calcium, 1.5 g per day for 9 months resulted in hypoestrogenism, pain relief after 2 months, and after 9 months a 10-fold reduction in the 30-mm diameter size of red, polypoid vaginal lesions, along with remodeling to gray tissue (420).