Endocrinology: Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen--progestin or progestin 'add-back' for 2 years

Treatment of women with leiomyomata with gonadotrophin releasinghormone agonists (GnRHa) for >6 months is not recommendedbecause of concerns regarding adverse sequelae of prolongedhypoestrogenism. It has been postulated that addition of low-dosesex steroids to GnRHa treatment, i.e. ‘add-back’therapy, may avert some of these adverse effects (acceleratedbone resorption, vasomotor flushes) without altering the efficacyof GnRHa therapy. To evaluate the effects of long-term GnRHatherapy on uterine size, bleeding patterns, bone mass and lipids,51 pre-menopausal women with leiomyomata were treated with theGnRHa leuprolide acetate depot, 3.75 mg every 4 weeks for 2years. After 3 months of leuprolide therapy, the women wererandomized to receive either low-dose continuous oestropipate,0.75 mg daily, plus cyclic norethindrone, 0.7 mg on days 1—14each month (the oestrogen–progestin add-back group) orhigher-dose norethindrone, 10 mg daily (the progestin add-backgroup), for the remaining 21 months. Mean uterine volume decreasedby 40% in both treatment groups during the first 3 months onleuprolide treatment. There was no significant change in uterinesize following oestrogen–progestin add-back. However,mean uterine volume in the progestin add-back group increasedto 87% of pre-treatment size by treatment month 12 and 95% ofpre-treatment size by treatment month 24. Mean bone densityof the lumbar spine as measured by dual X-ray absorptiometrydecreased significantly by 2.6% during the first 3 months inall patients, but did not change significantly following steroidadd-back in both treatment groups during the final 21 treatmentmonths. There were parallel and significant increases in meanhaematocrits (Hct) of 4.8% in the oestrogen—progestingroup and 7.8% in the progestin group over the 2-year treatmentperiod. Mean serum high density lipoprotein (HDL) cholesterolconcentration was unchanged in the oestrogen—progestinadd-back group but decreased by 36% in women receiving progestinadd-back. By 6 months after completion of treatment, mean uterinevolume, leiomyoma-related symptoms, Hct and bleeding patternshad returned to pre-treatment values. Thus, the oestrogen—progestinadd-back regimen was superior or equal to the progestin add-backregimen in all safety and efficacy parameters studied; the latterregimen was associated with regrowth of myomatous uterine volumeand with marked depression of cardio-protective HDL cholesterolconcentrations. One 50 year old woman in the oestrogen—progestingroup developed a leiomyosarcoma which was suspected by sonographicchanges in leiomyoma appearance and was thought to be unrelatedto treatment. In conclusion, GnRHa plus oestrogen—progestinadd-back therapy may provide a long-term (i.e.>6 month) medicaltreatment option in women with leiomyomata.