Female sexuality: modulation by estrogen and androgen

描述（由申请人提供）：研究了以下假设：女性性欲是由卵巢雌激素的神经作用刺激的，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，使用恒河猴模型的内分泌功能和行为，调查女性性启动的激素基础。项目I调查了女性在整个月经周期中的性启动，比较了在接受雄激素受体阻滞剂（氟他胺）或雌激素受体阻滞剂（他莫昔芬）治疗的正常周期期间，在社会群体背景下女性性启动的发生率。这将澄清是否雄激素或雌激素的神经行为，以调节女性的性动机。项目II测试了SHBG通过这些类固醇对SHBG的不同亲和力调节生物可利用的雌激素和雄激素的新假设。该项目使用激素替代治疗的猴子模型，用于手术切除卵巢后的生殖初期女性，并测试慢性雌二醇（E2）不再有效刺激女性性兴趣的假设，因为雌激素被SHBG隔离。它进一步研究了雄激素，5 α-双氢睾酮（DHT），与SHBG的亲和力明显高于雌二醇，是否可以通过取代SHBG结合的雌二醇增加游离雌二醇，急性和快速恢复女性的性兴趣。接受模拟卵泡中期雌二醇水平的长期雌二醇治疗的卵巢切除雌性动物，将在单独长期E2治疗期间和长期E2和注射DHT或E2后观察性启动。氟替卡松或他莫昔芬与雌激素或双氢睾酮同时给药可区分由神经雄激素或雌激素受体激活引起的行为变化。还将研究这些治疗对神经内分泌功能的影响。项目III研究了慢性雌激素或慢性雌激素加睾酮（伴或不伴雌激素）的常见人类激素替代疗法是否可以恢复生育初期卵巢切除雌性猴的雌性性兴趣。该假设将被检验，即慢性孕酮治疗降低或消除了在没有孕酮的情况下恢复女性性兴趣的治疗的有效性。还将比较这些疗法对神经内分泌功能的影响。这些研究将显着增加我们对卵巢类固醇在调节女性性行为方面所发挥作用的了解。

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.