Female sexuality: modulation by estrogen and androgen

描述（由申请人提供）：研究假设卵巢雌激素的神经活动刺激了女性的性兴趣，雄激素通过与性激素结合球蛋白（SHBG）的相互作用调节这些雌激素的生物利用度。三个项目，利用恒河猴的内分泌功能和行为模型，探讨雌性性起始的激素基础。项目一调查女性在整个月经周期中的性起始，比较在正常周期中使用雄激素受体阻滞剂（氟他胺）或雌激素受体阻滞剂（他莫昔芬）治疗的社会群体背景下女性性起始的发生率。这将阐明是雄激素还是雌激素在神经上调节女性的性动机。项目II验证了SHBG通过这些类固醇对SHBG的不同亲和力调节生物可利用雌激素和雄激素的新假设。本项目采用猴子模型，对切除卵巢后处于生育最佳期的雌性进行激素替代治疗，并验证慢性雌二醇（E2）不再有效刺激雌性性兴趣的假设，因为雌激素被SHBG隔离。它进一步研究了一种雄激素，5 -二氢睾酮（DHT），对SHBG的亲和力明显高于雌二醇，是否可以通过取代SHBG结合的雌二醇来增加游离雌二醇，从而迅速恢复女性的性兴趣。切除卵巢的女性接受慢性雌二醇治疗，模拟卵泡中期雌二醇水平，在单独接受慢性E2治疗期间以及在慢性E2和注射DHT或E2后观察性起始。氟他胺或他莫昔芬与雌激素或二氢睾酮同时服用将区分由神经雄激素或雌激素受体激活引起的行为改变。这些治疗对神经内分泌功能的影响也将被研究。项目III研究慢性雌激素，或慢性雌激素加睾酮，或不同时使用黄体酮的常见人类激素替代疗法，是否能在切除卵巢的雌性猴子中恢复雌性的性兴趣。慢性黄体酮治疗会降低或消除不使用黄体酮恢复女性性兴趣的治疗效果，这一假设将得到验证。我们还将比较这些疗法对神经内分泌功能的影响。这些研究将显著增加我们对卵巢类固醇在调节女性性行为中所起作用的理解。

DESCRIPTION (provided by applicant): The hypothesis is investigated that female sexual interest is stimulated by the neural actions of ovarian estrogens and that androgens regulate the bioavailability of these estrogens through interactions with sex hormone binding globulin (SHBG). Three projects, using a rhesus monkey model of endocrine function and behavior, investigate the hormonal basis of female sexual initiation. Project I investigates sexual initiation in females across the menstrual cycle, comparing the occurrence of female sexual initiation in a social group context during normal cycles treated with an androgen receptor blocker (flutamide) or an estrogen receptor blocker (tamoxifen). This will clarify whether androgens or estrogens act neurally to modulate female sexual motivation. Project II tests the novel hypothesis that SHBG regulates bioavailable estrogens and androgens through these steroids' different affinities for SHBG. This project uses a monkey model of hormonal replacement therapy for reproductively prime females after surgical removal of their ovaries and tests the hypothesis that chronic estradiol (E2) ceases to effectively stimulate female sexual interest as estrogen is sequestered by SHBG. It further investigates whether an androgen, 5a-dihydrotestosterone (DHT), with a markedly higher affinity for SHBG than estradiol can acutely and rapidly reinstate female sexual interest by increasing free estradiol by displacing SHBG-bound estradiol. Ovariectomized females receiving chronic estradiol treatment mimicking mid-follicular estradiol levels will be observed for sexual initiation during chronic E2 treatment alone and following chronic E2 and an injection of DHT or E2. Concurrent administration of flutamide or tamoxifen with the estrogen or DHT will discriminate between behavioral changes resulting from the activation of neural androgen or estrogen receptors. The effects of these treatments on neuroendocrine function will also be investigated. Project III investigates whether common human hormonal replacement therapies of chronic estrogen, or chronic estrogen plus testosterone with or without concurrent progestin, can reinstate female sexual interest in reproductively prime ovariectomized female monkeys. The hypothesis will be tested that chronic progestin therapy reduces or eliminates the effectiveness of therapies that reinstate female sexual interest without progestin. These therapies will also be compared on their effects on neuroendocrine function. These studies will markedly increase our understanding of the role that ovarian steroids play in modulating women's sexuality.