Applicability of selective progesterone receptor modulators in the treatment of uterine leiomyomata and their future role in the field of gynecology

Abstract

Uterine leiomyomata are benign, monoclonal tumors arising from smooth muscle cells, which belong to one of the most common pathologies of the female genital system. Current pharmacotherapies (oral contraceptives, progestins, GnRH analogs) are ineffective or of limited use for long-term treatment. Although there is still much debate regarding their etiology it is very likely that progesterone and progesterone receptor play a key role in their development. Profound importance of progesterone in the female reproductive system has led to discovery of synthetic progesterone receptor ligands, which can poses the activity ranging from pure agonist activity trough mixed agonist/antagonist activity to pure antagonist activity Development of selective progesterone receptor modulators (SPRM) has created new therapeutic options and has great potential in a number of gynecologic indications. So far, ulipristal acetate has been approved for emergency contraception, mifepristone as a progesterone receptor antagonist because of the unique property of this compound for termination of pregnancy Recently the European Commission has authorized ulipristal acetate for the pre-operative treatment of uterine fibroids. Superior efficacy of ulipristal acetate versus placebo, to reduce excessive uterine bleeding and to reduce total fibroid volume prior to surgery was demonstrated. Moreover non-inferior efficacy of ulipristal acetate versus Gonadotropin Releasing Hormone (GnRH)-agonist to reduce excessive uterine bleeding prior to surgery of uterine fibroids has been documented. Ulipristal acetate is also characterized by a superior side-effect profile in comparison to leuprolide acetate in terms of serum estradiol levels and the proportion of patients with moderate-to-severe hot flashes during treatment. Regarding safety profile, except elevation of liver enzymes after telapristone and onapristone treatment, to date no serious untoward effects of other SPRM have been reported. The issue of endometrial effects of these compounds remains to be resolved, although observation that intrinsic agonist activity of SPRM prevents endometrial proliferation may suggest future use of these agents in prevention of endometrial hyperplasia. Other promising applications, including endometriosis, endometrial cancer Cushing's disease, Alzheimer disease or long-term contraception, are currently in development.