The Neuroregulatory Effects of Gonadal Steroids in Humans

性腺类固醇对人类的神经调节作用

• 批准号: 7735199
• 负责人: Peter Schmidt
• 金额: $ 75.7万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7735199
• 关键词: Acute; Adrenal Glands; Affective; Age; Aging; Agonist; Amygdaloid structure; Androgens; Anterior; Behavior; Behavioral; Binding; Brain; Brain region; Cerebrospinal Fluid; Cerebrovascular Circulation; Characteristics; Clinic; Cognition; Cognitive; Collaborations; Condition; Corticotropin-Releasing Hormone; Data; Development; Dexamethasone; Endocrine; Episodic memory; Estradiol; Estrogens; Expectancy; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genetic; Genomics; Goals; Gonadal Steroid Hormones; Hippocampus (Brain); Hormonal; Hormones; Hot flushes; Human; Hypogonadism; Individual; Inferior; Investigation; Lateral; Left; Libido; Lobule; Magnetic Resonance Imaging; Measures; Memory; Menopause; Menstrual cycle; Mental Depression; Methodology; Mood Disorders; Moods; Neuropsychological Tests; Neurosciences; Organizational Change; Ovarian; Parahippocampal Gyrus; Parietal; Participant; Pattern; Physiological; Positioning Attribute; Positron-Emission Tomography; Postpartum Depression; Predisposition; Prefrontal Cortex; Prevalence; Process; Progesterone; Psyche structure; Reporting; Research Personnel; Rest; Rewards; Risk; Role; Rotation; Sampling; Sex Characteristics; Sex Functioning; Short-Term Memory; Steroids; Stress; Symptoms; System; Temporal Lobe; Testing; Testosterone; Time; Variant; Ventral Striatum; Woman; age effect; base; biological adaptation to stress; cingulate cortex; clinically significant; cognitive function; dysphoria; experience; hormone therapy; human WNT2 protein; hypothalamic-pituitary-adrenal axis; interest; male; men; mood regulation; morris water maze; neuroimaging; performance tests; proliferative phase Menstrual cycle; reproductive; reproductive function; reproductive hormone; response; virtual; volunteer

In our studies of the mood and behavioral effects of GnRH agonist-induced hypogonadism and hormone replacement, we have observed the development of clinically significant mood symptoms and loss of sexual interest in less than 10% and 30%, respectively, of healthy, young men and women in whom hypogonadism was induced by GnRH agonist (despite the presence of hot flushes experienced by 90 to 100% of these participants). The prediction of greater declines in sexual functioning during GnRH agonist-induced hypogonadism in both men and women was associated with baseline sexual functioning but not hormone levels. Specifically, those men and women with the highest levels of libido were at risk for experiencing the greatest loss of sexual functioning during hypogonadism and the greatest benefits of hormone therapy. Additionally, we observed that in men changes in cerebrospinal fluid levels of the neurosteroid metabolite of testosterone, andosterone, (but not testosterone), correlated with sexual functioning during both the hypogonadal state and testosterone replacement. Our efforts to examine possible changes in cognitive function associated with GnRH agonist-induced hypogonadism alone and hormone replacement have been negative, and we have been unable to confirm earlier studies that short-term changes in sex steroids significantly impact on cognitive test performance. Specifically, we have observed no differences in episodic memory, spatial memory (as measured by the virtual Morris Water Maze), or working memory functions. These neuropsychological test data are consistent with recent studies across the natural menopause, however, they are in contrast to the results of several studies in basic neuroscience, and those of smaller clinic-based samples of women in whom menopause was induced surgically. Our studies examining the effects of changes in sex steroids on the stress response and HPA axis function have previously demonstrated that progesterone, but not estrogen, induces an increased stress hormone response that may be relevant in both women with severe PMD and PPD. Additionally, we identified that the sex differences in stress responsivity, with males having a greater HPA axis response than females, is maintained in the absence of sex steroids and, therefore, reflects organizational changes in the stress axis rather than acute activational effects of the presence or absence of gonadal steroids. In our earlier studies of regional cerebral blood flow using PET, we reported for the first time in humans that induced hypogonadism was associated with the elimination of the normal pattern of cortical activation in the dorsolateral prefrontal cortex as well as the posterior inferior temporal cortices and the inferior parietal lobule; whereas both estradiol and progesterone replacement restored the normal pattern of cortical activation during a working memory task. Additionally, in a related project, we demonstrated changes in reward-related neurocircuitry across the normal menstrual cycle with increased activations during the expectancy of the reward during the follicular phase, when estradiol levels are high. We have pursued these findings with the GnRH agonist-induced hypogonadism and ovarian steroid replacement paradigm and have identified the following: 1) Increased resting regional cerebral blood flow (rCBF), in the left lateral orbitofrontal cortex, left dorsomedial prefrontal cortex, left posterior hippocampus, during hypogonadism; 2) Increased cognition-activated regional cerebral blood flow in the right precuneous during mental rotation after estradiol replacement compared with both hypogonadism and progesterone replacement; 3) Increased activation of several brain regions involved in the anticipation of rewards (e.g., orbitofrontal cortex and hippocampal gyrus)during estradiol replacement compared with progesterone replacement; 4) Increased activation of the ventral striatum and rostral anterior cingulate cortex during estradiol replacement compared with progesterone at the time of reward delivery. Indeed, no reward-related region was found to have greater activation during progesterone replacement conditions. In summary, our studies of experimentally-induced hypogonadism in men and women have revealed changes in several physiologic systems relevant to the regulation of mood and behavior (e.g., regional cerebral blood flow, HPA axis) and inform our investigations of reproductive endocrine-related mood disorders (i.e., PMD, PPD, and depression during the menopause transition). Additionally, these studies have allowed examinations in humans (in some cases for the first time) of the effects of individual gonadal steroids. Additionally, our examination of the effects of hypogonadism in younger women and men, who were not experiencing the potential CNS effects of reproductive aging, have allowed us to make inferences to be tested in future studies about the interactive effects of age and gonadal steroids on brain function. Nonetheless, the absence of uniform or pronounced alterations in mood or behavior (except sexual function) in asymptomatic volunteers during otherwise extreme manipulations of reproductive function emphasizes that alterations in gonadal steroids alone cannot explain the observed changes in mood and behavior in some men or women who experience depression during hormone transitions. Finally, ongoing studies within our group are now exploring the role of genomic variation in both the behavioral and physiologic responses to gonadal steroids using these same paradigms.

在我们研究GnRH激动剂引起的性腺功能障碍和激素替代品的情绪和行为影响时，我们观察到了临床上重要的情绪症状的发展以及在不到10％和30％的性兴趣中，健康的年轻男性和女性在不到10％和30％的情况下，尽管他们在gnrh agonist的情况下促成了他们的降压症，但在他们的情况下，他们的参与者（尽管有90％的经验丰富的经验）。 在GNRH激动剂诱导的男性和女性中，性功能下降的预测较大，男性和女性都与基线性功能相关，而与激素水平无关。 具体来说，那些性欲最高的男人和女性面临着在性能期间最大的性功能丧失和激素治疗的最大好处的风险。 此外，我们观察到，在男性中，睾丸激素的神经类固醇代谢产物的脑脊液水平变化，雄激素（但与睾丸激素无关），与性功能相关，与性功能相关。 我们为检查与GNRH激动剂引起的性腺功能不全和替代激素相关的认知功能可能变化的努力是阴性的，我们无法确认性类固醇短期变化对认知测试性能的短期变化显着影响。 具体而言，我们已经观察到情节记忆，空间记忆（通过虚拟莫里斯水迷宫衡量）或工作记忆功能没有差异。 这些神经心理学测试数据与自然更年期的最新研究一致，但是它们与基本神经科学的几项研究的结果以及较小的基于诊所的妇女样本的结果形成鲜明对比，这些妇女的更年期是通过手术诱导的。 我们的研究研究了性类固醇对应激反应和HPA轴功能的影响的影响，以前证明，孕酮但没有雌激素会诱导重量激素反应增加，这可能与患有严重PMD和PPD的女性有关。 此外，我们确定在不存在性类固醇的情况下，维持压力反应性的性别差异，男性具有比女性更大的HPA轴反应，因此可以反映应力轴的组织变化，而不是性腺类固醇存在或不存在性腺类固醇的急性激活作用。 在我们先前对使用PET的区域脑血流的研究中，我们首次在人类中报道了诱导性性腺功能减退与消除背侧前额叶皮层中皮质激活的正常模式以及下颞下皮层和下侧侧叶;而雌二醇和孕酮的替代均恢复了在工作记忆任务中皮质激活的正常模式。 此外，在一个相关的项目中，我们证明了整个正常月经周期中与奖励相关的神经记录的变化，当雌二醇水平较高时，在卵泡期期望奖励期间的激活增加。 我们已经通过GNRH激动剂引起的性腺原发性和卵巢类固醇替代范例来追求这些发现，并确定了以下几点：1）在左侧甲状腺左侧皮质中增加静止静止的脑血流（RCBF），左侧甲状腺皮质，左侧偏侧额叶前颈前病和左侧posteref posteref posteref posterers hypoccons hypoccons himpoccons himpocames himpocames himpocames himpocAmpOccAuspAuspAuspAuspUSAD，; 2）与性交和孕酮替代相比，雌二醇替代后心理旋转期间右前旋转期间的认知激活区域脑血流增加； 3）与孕酮替代相比，雌二醇替代过程中涉及奖励期望的几个大脑区域的激活增加（例如，甲状腺皮质和海马回）的激活增加； 4）与奖励交付时孕酮相比，雌二醇替代过程中腹侧纹状体和to骨前扣带回皮层的激活增加。 实际上，在孕激素替代条件下，没有发现与奖励相关的区域具有更大的激活。 总而言之，我们对男性和女性实验诱导的性腺功能不全的研究揭示了与情绪和行为调节有关的几种生理系统的变化（例如，区域大脑血流，HPA轴），并为我们对生殖性内分泌相关情绪障碍的生殖研究调查（即PPD，PPD，ppd，transition the Menopease the Menopive）。 此外，这些研究还允许在人类类固醇的影响的人类（在某些情况下）进行检查。 此外，我们对不产生衰老的潜在中枢神经系统作用的年轻女性和男性对年轻男性和男性的影响的检查使我们能够在未来的研究中对年龄和性腺类固醇对脑功能的互动效应进行测试。 尽管如此，在非症状的志愿者中，情绪或行为（除性功能除外）的缺乏均匀或明显的改变，否则在极端对生殖功能的极端操纵过程中，仅性腺类固醇的改变就无法解释某些男性或女性在激素过渡期间经历抑郁症的男性或女性的情绪和行为的变化。 最后，我们小组中正在进行的研究正在探索使用这些相同范式对性腺类固醇的行为和生理反应中基因组变异的作用。