The Neuroregulatory Effects of Gonadal Steroids in Humans

在我们对GnRH激动剂诱导的性腺功能减退和激素替代的情绪和行为影响的研究中，我们观察到，在健康的年轻男性和女性中，分别只有不到10%和30%的人出现了临床上有意义的情绪症状和性兴趣丧失(尽管90%到100%的参与者经历了潮热)。在GnRH激动剂诱导的性腺功能低下期间，男性和女性的性功能下降幅度更大的预测与基线的性功能有关，但与激素水平无关。具体地说，性欲水平最高的男性和女性在性腺功能减退和激素治疗的最大益处期间面临着最大的性功能丧失的风险。此外，我们观察到男性脑脊液中睾酮的神经类固醇代谢物安多酮(但不是睾酮)水平的变化与性腺功能低下和睾酮替代期间的性功能有关。我们试图研究GnRH激动剂单独诱导的性腺功能减退和激素替代可能导致的认知功能变化，但我们的努力一直是否定的，我们一直无法证实早期的研究表明，性类固醇的短期变化对认知测试成绩有显著影响。具体地说，我们没有观察到情节记忆、空间记忆(通过虚拟的Morris水迷宫测量)或工作记忆功能的差异。这些神经心理测试数据与最近关于自然更年期的研究是一致的，然而，它们与基础神经科学中的几项研究的结果以及通过手术诱导更年期的较小临床样本的结果形成了对比。我们的研究检测了性激素变化对应激反应和HPA轴功能的影响，先前已经证明，孕酮，而不是雌激素，诱导了应激激素反应的增加，这可能与严重的PMD和PPD女性有关。此外，我们发现在应激反应上的性别差异，男性比女性有更大的HPA轴反应，在缺乏性类固醇的情况下保持不变，因此反映了应激轴的组织变化，而不是性腺类固醇的存在或不存在的急性激活效应。 在我们早期使用正电子发射计算机断层扫描(PET)对局部脑血流的研究中，我们首次在人类中报道，在工作记忆任务中，诱发性腺功能低下与前额叶背外侧皮质以及后下颞叶和顶下小叶皮质激活的正常模式的消除有关；而雌二醇和孕激素的替代都恢复了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，我们展示了正常月经周期中与奖赏相关的神经回路的变化，在卵泡期的奖赏预期期间，当雌二醇水平较高时，活动增加。我们用GnRH激动剂诱导的性腺功能减退和卵巢类固醇替代范式来探索这些发现，并发现：1)在性腺功能减退期间，左侧眶前叶皮质、左侧背内侧前额叶皮质、左侧后海马的静息局部脑血流量(RCBF)增加；2)与性腺功能减退和孕酮替代相比，在心理旋转期间，右侧的认知激活的局部脑血流量增加；3)与孕酮替代相比，雌激素替代时参与期待回报的几个脑区(例如，眶前叶皮质和海马回)的激活增加；4)与黄体酮相比，雌二醇替代时腹侧纹状体和嘴前扣带回皮质的激活程度更高。事实上，在孕激素替代条件下，并没有发现奖赏相关区域有更大的激活。 总之，我们对实验诱导的男性和女性性腺功能低下症的研究揭示了与情绪和行为调节相关的几个生理系统的变化(例如，局部脑血流，HPA轴)，并为我们对生殖内分泌相关情绪障碍(即，PMD、PPD和更年期过渡期间的抑郁)的研究提供了信息。此外，这些研究还允许在人类身上检查(在某些情况下是第一次)个别性腺类固醇的影响。此外，我们对没有经历生殖衰老潜在中枢神经系统影响的年轻女性和男性的性腺功能低下症的影响进行了检查，这使我们能够做出推断，以便在未来关于年龄和性腺类固醇对大脑功能的交互影响的研究中进行测试。尽管如此，在生殖功能的其他极端操作中，无症状志愿者的情绪或行为(性功能除外)没有统一或明显的变化，这强调了性腺类固醇的变化本身不能解释在激素转换期间经历抑郁的一些男性或女性的情绪和行为的观察到的变化。最后，我们小组正在进行的研究正在使用这些相同的范例来探索基因组变异在性腺类固醇的行为和生理反应中的作用。

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.