Division of Reproductive Endocrinology and Infertility, Yale University, 333 Cedar Street, New Haven, Connecticut 06510, USA.
Endocrinology. 2011 Aug;152(8):3226-32. doi: 10.1210/en.2010-1010. Epub 2011 May 17.
Endometriosis is a common estrogen-dependent disorder. Medical treatments currently consist of progestins or GnRH agonists; however, neither is fully effective and both entail significant side effects. Selective estrogen receptor (ER) modulators (SERM) have tissue-selective actions, acting as an ER agonist in some tissues and ER antagonist in others. The SERM bazedoxifene (BZA) effectively antagonizes estrogen-induced uterine endometrial stimulation without countering estrogenic effects in bone or central nervous system. These properties make it an attractive candidate for use in the treatment of endometriosis. Experimental endometriosis was created in reproductive-age CD-1 mice. After 8 wk, 10 animals received i.p. injections of BZA (3 mg/kg·d) for 8 wk, whereas 10 received vehicle control. Mice were killed, and implant size was assessed. The mean size of the implants after treatment was 60 mm(2) in the control group and 21 mm(2) in the BZA treatment group (P = 0.03). Quantitative PCR and immunohistochemical analysis were used to determine the effect on endometrial gene expression. PCNA, ERα, and LIF mRNA and protein expression were significantly decreased in endometrium of the treated group. Caspase 3 mRNA expression was increased. Expression of PR and Hoxa10 were not significantly altered by treatment. There was no evidence of ovarian enlargement or cyst formation. Decreased PCNA and ER expression demonstrated that the regression of endometriosis likely involved decreased estrogen-mediated cell proliferation. BZA may be an effective novel agent for the treatment of endometriosis due to greater endometrial-specific estrogen antagonism compared with other SERM.
子宫内膜异位症是一种常见的雌激素依赖性疾病。目前的医学治疗方法包括孕激素或 GnRH 激动剂；然而，这两种方法都不是完全有效的，并且都伴随着显著的副作用。选择性雌激素受体（ER）调节剂（SERM）具有组织选择性作用，在某些组织中作为 ER 激动剂，而在其他组织中作为 ER 拮抗剂。SERM 巴多昔芬（BZA）有效地拮抗雌激素诱导的子宫子宫内膜刺激，而不会抵消雌激素对骨骼或中枢神经系统的作用。这些特性使其成为治疗子宫内膜异位症的有吸引力的候选药物。在生殖年龄的 CD-1 小鼠中创建了实验性子宫内膜异位症。8 周后，10 只动物接受了腹腔注射 BZA（3mg/kg·d）8 周，而 10 只接受了载体对照。杀死小鼠，并评估植入物的大小。对照组植入物的平均大小为 60mm(2)，BZA 治疗组为 21mm(2)(P=0.03)。使用定量 PCR 和免疫组织化学分析来确定对子宫内膜基因表达的影响。PCNA、ERα 和 LIF mRNA 和蛋白表达在治疗组的子宫内膜中显著降低。Caspase 3 mRNA 表达增加。PR 和 Hoxa10 的表达不受治疗的显著影响。没有卵巢增大或囊肿形成的证据。PCNA 和 ER 表达的降低表明，子宫内膜异位症的消退可能涉及到雌激素介导的细胞增殖减少。与其他 SERM 相比，BZA 可能是一种有效的新型治疗子宫内膜异位症的药物，因为它对子宫内膜的雌激素拮抗作用更强。
