Novel treatment avenues for uterine leiomyoma: a new implication for endothelin?

Cysteine-rich angiogenic inducer 61 (CYR61), an angiogenic factor whose expression is decreased in fibroids. The aim of the present study was to determine if CYR61 secretion in smooth muscle cells (SMCs) is regulated by hypoxia and through the endothelin A (ETA) receptor. SMCs from fibroids (fSMC) and the adjacent myometrium smooth muscle cells (mSMCs) were extracted from ten women undergoing hysterectomy for uterine fibroids and cultured with or without 1.0 µM of an ETA receptor antagonist for 24 h under either normal or hypoxic oxygen conditions. Cellular secretion of endothelin-1 (ET-1) and CYR61 were measured via enzyme linked immunosorbent assay in the cell culture media. SMCs were collected to determine cell proliferation and CYR61 protein expression via Western blot. ET-1 secretion was significantly increased in fSMC and was decreased with blockade of the ETA receptor under both normoxia (P=0.0004) and hypoxia (P=0.008). CYR61 expression was decreased in fSMCs and significantly increased with blockade of the ETA receptor under hypoxia (P=0.04). Cell proliferation decreased with ETA blockade under normoxia (P=0.0001) and hypoxia (P=0.001). These results suggest that suppression of CYR61 secretion in fSMC is regulated by the ET-1 and that blockade with ETA could be considered for a future treatment option.

Postpartum preeclampsia management with furosemide: a randomized clinical trial.

OBJECTIVE: This investigation was undertaken to estimate whether a brief postpartum course of furosemide for patients with preeclampsia benefits recovery and shortens hospitalization by enhancing diuresis, lessening severe hypertension, and reducing the need for antihypertensive therapy. METHODS: Two hundred sixty-four patients with preeclampsia were enrolled. After spontaneous onset of postpartum diuresis and discontinuation of intravenous magnesium sulfate, patients were randomly assigned to receive either no therapy or 20 mg oral furosemide daily for 5 days with oral potassium supplementation. Patient outcomes were compared between treatment groups with regard to classification of hypertensive disease. RESULTS: Only postpartum patients with severe preeclampsia (n = 70) who received furosemide compared with controls had significantly lower systolic blood pressure by postpartum day 2 (142 +/- 13 mm Hg compared with 153 +/- 19 mm Hg, P < .004) and required less antihypertensive therapy during hospitalization (14% compared with 26%, P = .371) and at discharge (6% compared with 26%, P = .045). No benefit was shown for patients with mild preeclampsia (n = 169) or superimposed preeclampsia (n = 25). Neither length of hospitalization nor frequency of delayed postpartum complications was positively affected by the intervention. CONCLUSION: Brief postpartum furosemide therapy for patients with severe preeclampsia seems to enhance recovery by normalizing blood pressure more rapidly and reducing the need for antihypertensive therapy. Shortening of hospitalization and reduction of delayed postpartum complications were not benefitted.

Enodthelin 1 is elevated in plasma and explants from patients having uterine leiomyomas.

OBJECTIVE: To determine a role for endothelin (ET) in progression of uterine fibroids. DESIGN: An in vitro model of fibroid and myometrium cultivation. PATIENTS: A total of 32 women undergoing hysterectomies for uterine fibroids and 11 women undergoing hysterectomies for abnormal uterine bleeding (control population). RESULTS: Women with uterine fibroids were hypertensive and displayed significantly greater circulating ET-1 compared to control patients. Secretion of ET-1 was greater from the fibroids compared to myometrium explants. Endothelin 1 secretion was attenuated with blockade of the angiotensin II type 1 or endothelinA receptors. Hypoxia stimulated ET-1 secretion from both myometrium and fibroid explants. Preproendothelin messenger RNA expression increased with hypoxia from fibroid explants compared to normoxic controls. CONCLUSIONS: These data support the hypothesis that uterine fibroids are associated with hypertension and increased ET-1, which is exacerbated with hypoxia. These data suggest a possible link between mechanisms of blood pressure regulation and development of uterine leiomyoma.

Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome.

OBJECTIVE: To compare the effect of clomiphene citrate (CC) and letrozole on endometrial receptivity in women with polycystic ovary syndrome (PCOS). DESIGN: A randomized controlled trial. SETTING: University teaching hospital. PATIENT(S): Ten anovulatory women with PCOS and 5 fertile ovulatory women. INTERVENTION(S): Patients received 2.5 mg of letrozole on cycle days 3-7 (5 patients, 1 cycle) or 50 mg of CC on cycle days 5-9 (5 patients, 1 cycle). MAIN OUTCOME MEASURE(S): Serum estrogen (E) and progesterone (P) endometrial protein and messenger RNA (mRNA) expression of leukemia inhibitory factor (LIF), dickkhopf homolog 1 (DKK-1), fibroblast growth factor 22 (FGF-22), and endometrial mRNA expression of LIF/GP130 receptor (LIFR). RESULT(S): No statistically significant differences were observed between groups compared with fertile ovulatory women when serum E and P were examined, or between body mass index (BMI), and cycle day at time of biopsy. Letrozole increased mRNA expression of LIF, DKK1, LIFR, and FGF-22, whereas CC only increased endometrial mRNA expression of LIF. Letrozole mRNA expression directly translated into increased protein expression of like genes in the endometrium. The CC protein expression of DKK-1 was significantly decreased compared with controls. CONCLUSION(S): Letrozole positively influences a number of markers of endometrial receptivity compared with CC.