Inhibition of Steroid Sulfatase Decreases Endometriosis in an In Vivo Murine Model

Endometriosis is an estrogen-dependent disorder. Treatment with hormonal therapy suppresses estrogen and leads to regression of lesions. However, hormonal therapy is associated with significant morbidity, adverse effects, and recurrence of lesions, and therefore other treatment approaches are needed. Steroid sulfatase (STS) has a pivotal role in the formation of biologically active estrogens from inactive steroid sulfate in endometrium of patients with and without the disease. The enzyme catalyzes the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate (DHEAS) to their unconjugated forms, estrone and DHEA, respectively. In one study, expression of STS was 5-fold higher in ovarian endometriosis compared with normal endometrium. However, a more recent study found no difference in STS activity for endometrial lesions with high-STS activity. STS inhibitors are a class of agents potentially useful for therapy in patients with endometriosis. Estradiol-3-O-sulfamate (E2MATE) is a potent, long-acting, and orally active STS inhibitor. This study tested the therapeutic potential of E2MATE for endometriosis by determining its effect on STS activity in endometrial fragments in vitro and also by assessing its impact of STS in vivo on endometriosis-like lesion formation and proliferation using a mouse model of endometriosis. STS activity was measured in vitro in human endometrial explants cultured for 24 hours in the presence or absence of E2MATE. STS activity in vivo was assessed in endometrial lesions, which had been induced in mice by injection of disease-free human endometrial tissue. Mice with induced lesions received daily oral doses of E2MATE or a vehicle alone for 21 days. Plasma estradiol levels and STS activity were measured in the induced lesions and in normal mouse uterus, liver, and leukocytes. The presence of endometriosis-like lesions (glands and stroma) was quantified histologically by measurement of lesion number, weight, and size. Expression of lesion STS and the progesterone receptor (another marker of estrogenic action), proliferation, and apoptosis rates were determined with immunohistochemistry. Addition of E2MATE to the culture medium inhibited STS activity significantly in endometrial explants after 24 hours of culture (P < 0.001). There was no difference between plasma estradiol levels in mice treated with E2MATE (1.0 and 0.5 mg/kg) and untreated controls, whereas treatment inhibited STS activity significantly in murine liver (P < 0.001), leukocytes (P < 0.001), and uterus (P < 0.05), and also induced endometriotic lesions (P < 0.05). Treatment with E2MATE reduced the weight (P < 0.01) and size (P < 0.05) of lesions, but did not affect the proliferation and apoptosis rates or STS expression. Mouse uteri showed less stromal edema after E2MATE treatment. In contrast, no edema was observed in the stroma of induced lesions. Progesterone receptor expression action was increased in the lesions after treatment (P < 0.001). These findings show that E2MATE can inhibit STS activity in endometrial tissue in vitro. In vivo treatment can suppress endometriosis development without affecting circulating estradiol levels, suggesting a possible therapeutic role for this compound in endometriosis.