LONG-TERM MEDICAL THERAPY FOR LEIOMYOMATA UTERI - A PROSPECTIVE, RANDOMIZED STUDY OF LEUPROLIDE ACETATE DEPOT PLUS EITHER ESTROGEN-PROGESTIN OR PROGESTIN ADD-BACK FOR 2 YEARS

Treatment of women with leiomyomata with gonadotrophin-releasing hormo ne agonists (GnRHa) for > 6 months is not recommended because of conce rns regarding adverse sequelae of prolonged hypoestrogenism. It has be en postulated that addition of low-dose sex steroids to GnRHa treatmen t, i.e. 'add-back' therapy, may avert some of these adverse effects (a ccelerated bone resorption, vasomotor flushes) without altering the ef ficacy of GnRHa therapy. To evaluate the effects of long-term GnRHa th erapy on uterine size, bleeding patterns, bone mass and lipids, 51 pre -menopausal women with leiomyomata were treated with the GnRHa leuprol ide acetate depot, 3.75 mg every 4 weeks for 2 years. After 3 months o f leuprolide therapy, the women were randomized to receive either low- dose continuous oestropipate, 0.75 mg daily, plus cyclic norethindrone , 0.7 mg on days 1-14 each month (the oestrogen-progestin add-back gro up) or higher-dose norethindrone, 10 mg daily (the progestin add-back group), for the remaining 21 months. Mean uterine volume decreased by 40% in both treatment groups during the first 3 months on leuprolide t reatment. There was no significant change in uterine size following oe strogen-progestin add-back. However, mean uterine volume in the proges tin add-back group increased to 87% of pre-treatment size by treatment month 12 and 95% of pre-treatment size by treatment month 24. Mean bo ne density of the lumbar spine as measured by dual X-ray absorptiometr y decreased significantly by 2.6% during the first 3 months in all pat ients, but did not change significantly following steroid add-back in both treatment groups during the final 21 treatment months. There were parallel and significant increases in mean haematocrits (Hct) of 4.8% in the oestrogen - progestin group and 7.8% in the progestin group ov er the 2-year treatment period. Mean serum high-density lipoprotein (H DL) cholesterol concentration was unchanged in the oestrogen progestin add-back group but decreased by 36% in women receiving progestin add- back. By 6 months after completion of treatment, mean uterine volume, leiomyoma-related symptoms, Hct and bleeding patterns had returned to pre-treatment values. Thus, the oestrogen-progestin add-back regimen w as superior or equal to the progestin add-back regimen in all safety a nd efficacy parameters studied; the latter regimen was associated with regrowth of myomatous uterine volume and with marked depression of ca rdioprotective HDL cholesterol concentrations. One 50 year old woman i n the oestrogen-progestin group developed a leiomyosarcoma which was s uspected by sonographic changes in leiomyoma appearance and was though t to be unrelated to treatment. In conclusion, GnRHa plus oestrogen-pr ogestin add-back therapy may provide a long-term (i.e. > 6 month) medi cal treatment option in women with leiomyomata.