Effects of brain-selective estradiol on gene expression and female sex behavior

描述（由申请人提供）：目前对新的、更安全的雌激素疗法（ET）的需求尚未得到满足，以治疗与雌激素水平低或缺乏相关的症状，包括性动机下降、潮热、睡眠障碍、抑郁/焦虑、脑和脊髓创伤、肌萎缩侧索硬化症和认知功能障碍。目前，只有雌激素单独或与黄体酮或雄激素联合用于治疗这些疾病，包括自然或手术绝经。然而，由于潜在的副作用，许多女性不能或不想服用雌激素，其中最关键的是雌激素对子宫和乳房的影响。然而，雌激素不足会导致绝经后性欲下降，从而导致女性性欲障碍（FSDD）。目前FSDD的激素治疗使用雌激素和睾酮治疗，但其有效性有限。雌二醇本身可以恢复性欲，如果给药的剂量产生卵泡中血清雌二醇水平（100-300pg/ml）。然而，在这样的剂量下，人们担心乳腺癌或子宫癌的风险，因此目前所有的FSDD治疗都使用低雌激素治疗（20pg/ml）与睾酮联合使用，而大剂量的雌二醇可能会增加治疗效果。在这里，我们研究了一种新的和潜在安全的雌激素治疗方法，使用10b，17b-二羟yestra 1,4二烯-3-one （DHED）来恢复大鼠和猴子模型的性接受性和性动机。ded是雌二醇的无活性前体；它不与雌二醇受体结合，因此在其天然形式下不产生雌激素作用。然而，一种酶将ded转化为雌二醇。我们的初步证据表明，这种酶仅在中枢神经系统中表达，因此可能使ded成为17b-雌二醇（E2）的脑选择性前药。ded能穿过血脑屏障，在脑外不起作用，但能将有效量的E2输送到

DESCRIPTION (provided by applicant): There is an unmet need for new and safer estrogen therapies (ET) to treat the symptoms associated with low levels or a lack of estrogens, including decreased sexual motivation, hot flushes, sleep disorders, depression/anxiety, brain and spinal cord trauma, amyotrophic lateral sclerosis, and cognitive dysfunction. Currently only estrogens alone or in combination with progestins or androgens are available to treat these conditions, including natural or surgical menopause. However, many women cannot or do not want to take estrogens because of their potential side effects, the most critical of which are the effects of estrogen on the uterus and the breast. However, estrogen insufficiency contributes to post-menopausal decline in sexual desire that can lead to female sexual desire disorder (FSDD). Current hormonal therapies for FSDD use treatment with an estrogen and testosterone, but their effectiveness is limited. Estradiol by itself can reinstate sexual desire if given at dosages that produce midfollicular serum estradiol levels (100-300pg/ml). However, at such dosages there are concerns about the risk of breast or uterine cancer, thus all current FSDD treatments use hypoestrogenic treatment (20pg/ml) in conjunction with testosterone when larger amounts of estradiol would likely increase treatment effectiveness. Here we investigate a novel and potentially safe estrogen therapy using 10b,17b-dihydroxyestra 1,4 dien-3-one (DHED) to reinstate sexual receptivity and sexual motivation in rat and monkey models. DHED is an inactive precursor of estradiol; it does not bind to estradiol receptors and thus produces no estrogenic effects in its native form. However, an enzyme converts DHED to estradiol. Our preliminary evidence suggests that this enzyme is only expressed in the CNS thus potentially making DHED a brain-selective prodrug for 17b-estradiol (E2). DHED, which crosses the blood brain barrier, would be inactive outside of the brain, but would deliver effective amounts of E2 to the brain. We propose to use sexual behavior as a model estrogen-responsive system with which to test DHED's potential therapeutic effects. Induction of lordosis in ovariectomized females rats using a sequential DHED and progesterone treatment will test the central activity of DHED. We will then use an ovariectomized monkey model of female sexual initiation to test DHED's efficacy in increasing sexual desire. Dr. Prokai will synthesize DHED for this project and undertake in vivo studies on conversion of DHED to E2. Dr. Merchenthaler's lab will investigate estradiol induced gene expression in the brain and periphery after acute or chronic DHED treatment and investigate DHED's capacity to active female rat sexual receptivity. Dr. Wallen's lab will undertake studies of female rhesus monkey sexual initiation during DHED treatment. Preliminary data from rodent models of hypoestrogenic conditions show that DHED is a brain-selective bioprecursor produg for E2, and is likely to be a safe and effective treatment of conditions due to the lack of estrogens (ovariectomy) or low levels of estrogens (menopause). If successful these studies will revolutionize the treatment of clinical problems resulting from hypoestrogenic conditions.