The Neuroregulatory Effects of Gonadal Steroids in Humans

在我们早期使用PET对区域脑血流的研究中，我们首次在人类中报道了诱导性腺功能减退与背外侧前额叶皮层（DLPFC）正常皮层激活模式的消除有关；而雌二醇和黄体酮替代都能恢复工作记忆任务中皮层的正常激活模式。我们正在追求我们最初的发现，卵巢类固醇调节女性前额皮质活动，通过增强旧的金标准成像技术（即O15 PET），其中技术随着时间的推移相对稳定，激活任务范式在这些研究的长期过程中保持相对恒定，使用新的假设驱动，尖端的任务范式和分析方法（即fMRI）。在神经成像过程中，我们采用了几种不同的激活范式以及静息状态测量，这将使我们能够测试与情感障碍现象学相关的神经回路和区域间功能连接（即前额皮质功能，奖励系统）。例如，使用两种功能成像方法（PET与重复扫描和fMRI）的N-back任务，我们正在确定每个女性在每个激素阶段的激活模式，以测试其激活位点的差异。我们在50多名无症状妇女中完成了研究。我们的O15 PET研究的初步结果表明，与性腺功能低下状态相比，雌二醇显著增加了默认网络区域的静息区域脑血流量（rCBF）活动：内侧前额叶皮层（mPFC）和后扣带；而与性腺功能低下状态相比，孕激素显著增加了眶额皮质内侧（mOFC）和壳核的静息rCBF。我们发现雌二醇和黄体酮分别调节mPFC和mOFC的活性，这对于理解雌二醇和黄体酮对情感适应和应激反应的潜在影响具有重要意义。临床前研究已经证明，这些大脑区域是性和性类固醇调节压力对大脑功能和行为的影响的部位。最后，最近的数据证明了基因型对认知表现和情感适应的影响。我们现在首次在人类中发现了性类固醇与卵巢类固醇（即儿茶酚-o-甲基转移酶（COMT）和脑源性神经营养因子（BDNF））调节的特定基因变异之间在任务激活区域脑血流量测量上的显著相互作用。雌二醇减轻了COMT基因型对N-back任务中DLPFC激活的影响，雌二醇与BDNF基因型相互作用调节N-back任务中海马的激活模式。我们之前已经证明，在正常月经周期中，与奖励相关的神经回路发生了变化，在卵泡期，雌二醇水平较高时，对奖励的预期增加了激活。这些数据首次在人类中证明，卵巢类固醇调节奖励系统功能，在奖励预期期间增加眶额皮质和杏仁核的滤泡期激活，在奖励传递期间增加中脑、纹状体和左腹外侧前额叶皮质（VLPFC）的卵泡期激活。在参与GnRH激动剂诱导性腺功能减退研究的女性中，我们采用奖励模式进一步研究了这些发现，在整个月经周期中，我们分别检查了雌二醇和黄体酮与性腺功能减退状态的影响。初步研究结果表明，雌二醇和黄体酮都能调节与奖励相关的神经回路。在预期奖励时，与性腺功能低下的状态相比，雌二醇增加了杏仁核和眶额皮质的活动（与我们之前在整个月经周期的数据一致），与雌二醇和性腺功能低下相比，黄体酮增加了右侧额下回的活动。这些数据表明，性腺类固醇的变化可以调节情感状态，并且与临床前研究一致，这些研究记录了卵巢类固醇对奖励相关行为和大脑区域的调节作用，以及越来越多的文献证明了奖励系统在抑郁症中的重要性。最后，我们在整个月经周期和药理学控制的激素条件下使用结构MRI扫描测量了灰质（GM）体积。与雌二醇和性腺功能减退相比，黄体期和卵泡期海马GM体积增加。

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 (DLPFC); whereas both estradiol and progesterone replacement restored the normal pattern of cortical activation during a working memory task. We are pursuing our original findings that ovarian steroids modulate prefrontal cortical activity in women by augmenting older gold-standard imaging techniques (i.e., O15 PET), in which the technology is relatively stable over time and the activation task paradigms are kept relatively constant over the long-term course of these studies, with newer hypothesis-driven, cutting edge task paradigms and analytic approaches (i.e., fMRI). We employ several different activational paradigms as well as resting state measures during the neuroimaging procedures that will allow us to test neural circuits and interregional functional connectivity relevant to the phenomenology of affective disorders (i.e., prefrontal cortical function, reward system). For example, using the N-back task with two functional imaging methods (PET with repeated scans and fMRI), we are determining the activation pattern for each woman at each hormonal phase to test for variance in their sites of activation. We have completed studies in over 50 asymptomatic women. Preliminary results from our O15 PET studies, demonstrate that estradiol significantly increases resting regional cerebral blood flow (rCBF) activity in regions of the default networks: medial prefrontal cortex (mPFC) and posterior cingulate compared with the hypogonadal state; whereas, progesterone significantly increases resting rCBF in the medial orbital frontal cortex (mOFC) and putamen compared with the hypogonadal state. Our findings that estradiol and progesterone regulate activities within mPFC and mOFC, respectively, have implications for understanding the potential impacts of both estradiol and progesterone on affective-adaptation and stress-responsivity. Preclinical studies have demonstrated that these brain areas are sites at which the effects of sex and sex-steroids modulate the effects of stress on brain function and behavior. Finally, recent data has documented the influence of genotype on cognitive performance and affective-adaptation. We now have identified for the first time in humans significant interactions between sex steroids and variations in specific genes regulated by ovarian steroids (i.e., catechol-o-methyl transferase (COMT) and brain-derived neurotrophic factor (BDNF)) on measures of task-activated regional cerebral blood flow. Estradiol mitigates the effect of COMT genotype on DLPFC activation during the N-back task and estradiol interacts with BDNF genotype to regulate the pattern of activation in the hippocampus during the N-back task. We previously 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. These data demonstrate, for the first time in humans, that ovarian steroids modulate reward system function, with increased follicular phase activation of the orbitofrontal cortex and amygdala during reward anticipation and of the midbrain, striatum, and left ventrolateral prefrontal cortex (VLPFC) during reward delivery. We have further investigated these finding across the menstrual cycle by employing the reward paradigm in women who are participating in the GnRH agonist-induced hypogonadism study in which we examine the effects of estradiol and progesterone separately compared with a hypogonadal state. Preliminary findings demonstrate that both estradiol and progesterone modulate reward-related neurocircuitry. During the anticipation of reward, estradiol increased activity in the amygdala and orbitofrontal cortex compared with the hypogonadal state (consistent with our previous data across the menstrual cycle), and progesterone increased activity within the right inferior frontal gyrus compared with both estradiol and hypogonadism. These data suggest a substrate in which changes in gonadal steroids could modulate affective state, and are consistent with preclinical studies that document the modulatory effects of ovarian steroids on reward-related behaviors and brain regions, as well as a growing literature demonstrating the importance of the reward system in depression. Finally, we have measured grey matter (GM) volume using structural MRI scans across the menstrual cycle and under pharmacologically controlled hormonal conditions. GM volume in the hippocampus increased during the luteal compared with the follicular phase of the menstrual cycle and during progesterone addback compared with both estradiol and hypogonadism. In our previous studies of the effects of gonadal steroids on stress responsivity, we identified that progesterone rather than estradiol has a greater impact on HPA axis activation in humans, unlike in rodents, but the response to progesterone appears to differ in women with PMD and controls. We have conducted dexamethasone-corticotrophin releasing hormone (Dex/CRH) testing in women with PMD and controls in both menstrual cycle and Lupron studies. We have completed a study of 43 women employing Dex/CRH studies. Our data confirm a progesterone-related enhancement of HPA axis function despite dex inhibition, whereas no effects of estradiol on HPA axis function were evident (see Annual Report for project MH002865-06). There has been a widespread presumption in clinical neuroscience that ovarian steroids regulate 5HT transport function leading to sex and sex steroid-related differences in affective adaptation. We employ the 5HT transporter ligand DASB during both naturalistic and experimentally-induced conditions to examine claims that ovarian steroids are important physiological regulators of the 5HT transporter. We have completed a study of 5HT transport function across the menstrual cycle, and are about to complete a similar study in examining 5HT transport function during pharmacologically controlled hormonal conditions. These data will be the first to characterize the effects of sex steroids on5HT transporter function in the human brain, and will either confirm or seriously question the physiologic relevance of the widely embraced assumption that ovarian steroid-related modulations of 5HT function underlie both many of the observed sex-differences in affective disorders and reproductive endocrine-related mood disorders including postpartum and perimenopausal depressions.