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GnRH激动剂诱导的性腺功能减退的健康年轻男性和女性中，分别有不到10%和30%的人出现了临床显着的情绪症状和性兴趣丧失（尽管90%到100%的参与者都出现了潮热）。在GnRH激动剂诱导的性腺功能减退期间，对男性和女性性功能更大下降的预测与基线性功能有关，但与激素水平无关。具体来说，那些性欲最高的男性和女性在性腺功能减退期间性功能丧失的风险最大，激素治疗的好处也最大。此外，我们观察到，男性脑脊液中睾酮、安固酮（但不是睾酮）的神经类固醇代谢物水平的变化与性腺功能低下和睾酮替代期间的性功能相关。我们对GnRH激动剂诱导的性腺功能减退和激素替代相关的认知功能可能变化的研究结果是阴性的，我们也无法证实早期的研究表明，性类固醇的短期变化会显著影响认知测试的表现。具体来说，我们没有观察到情景记忆、空间记忆（通过虚拟莫里斯水迷宫测量）或工作记忆功能的差异。这些神经心理学测试数据与最近关于自然绝经的研究一致，然而，它们与基础神经科学的几项研究的结果，以及那些通过手术诱导绝经的妇女的小规模临床样本的结果相反。我们的研究检查了性类固醇变化对应激反应和下丘脑轴功能的影响，之前的研究表明，黄体酮（而不是雌激素）诱导应激激素反应的增加，这可能与严重PMD和PPD的女性有关。此外，我们发现应激反应的性别差异，男性比女性有更大的HPA轴反应，在没有性激素的情况下保持不变，因此，反映了应激轴的组织变化，而不是性激素存在或不存在的急性激活效应。

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.