Characterizing the influence of endogenous and exogenous sex steroid hormones in the stress response

性激素，如雌激素、黄体酮和睾酮对认知、情感状态和应激反应有广泛的影响。事实上，性激素在月经周期中的波动与大脑活动和连接的改变、应激激素（如皮质醇）和促炎细胞因子（即免疫细胞释放的信号分子）的改变相对应。尽管在过去的10年里，生物学研究中出现了将女性纳入研究范围的转变，但性别通常不是研究的重点。因此，对于性激素的变化，例如通过月经周期或使用激素避孕药，如何影响女性的生物应激反应，我们的理解仍然存在重大差距。全世界有超过1亿妇女使用激素避孕药，迫切需要系统地检查性激素的改变如何影响女性生物学，因为这些可能对认知、行为和健康产生重大影响。因此，这个研究项目的首要目标是研究性激素在对压力源的生物反应中的作用，以及通过激素避孕药破坏性激素的长期影响。首先，我们将在实验室中研究性激素是否解释了男性和女性在对急性社会压力源的反应中所看到的性别差异。我们将进一步评估生理反应（如皮质醇和细胞因子水平）如何根据月经周期阶段和激素避孕药的使用而有所不同。我们也将通过一种叫做表观遗传学的过程，探索性激素和激素避孕药是如何映射到基因表达的。此外，一项为期2年的前瞻性研究将使我们能够评估性激素、激素避孕药和表观遗传模式与后期皮质醇和炎症特征的长期关系。目前的研究项目将有助于揭示性激素对年轻女性的短期和长期生物学影响。此外，本研究将通过确定自然循环女性和使用激素避孕药的女性中表观遗传变化的顶级位点，为性激素的靶点提供新的见解。重要的是，这项研究将区分雌激素和黄体酮激素避孕药的生物学后果。这些发现可能会为有关特定激素避孕药建议的政策提供信息，这可能会直接影响行为，使女性能够根据证据做出决定，确定哪种类型的激素避孕药最适合她们。

Sex hormones, such as estrogen, progesterone and testosterone have widespread influences on cognition, affective states, and stress reactivity. Indeed, fluctuations of sex hormones across the menstrual cycle correspond to altered brain activity and connectivity, alterations in stress hormones, such as cortisol, and pro-inflammatory cytokines (i.e., signaling molecules released by immune cells). Although there has been a shift in the past 10 years to include females in biological research, sex is most often not the focus of the investigation. As a result, significant gaps remain in our understanding as to how alterations in sex hormones, for example through the menstrual cycle or use of hormonal contraceptives, affects biological stress responses in females. With over 100 million women worldwide using hormone contraceptives there is a pressing need for the systematic examination of the how alterations of sex hormones impact female biology, as these may have significant consequences on cognition, behaviour and well-being. Therefore, the overarching objective of this program of research is to examine the role of sex hormones in biological responses to stressors and the long-term implications of disrupting sex hormones, through hormonal contraceptives. First, we will examine whether sex hormones account for sex differences seen between males and females in response to an acute social stressor in the laboratory. We will further assess how biological responses (e.g., cortisol and cytokine levels), to this laboratory stressor will differ according to menstrual cycle phase, and hormonal contraceptive use. We will similarly explore how sex hormones and hormonal contraceptives map onto gene expression, through a process called epigenetics. Moreover, a 2-year prospective study will allow us to assess the long-term associations of sex hormones, hormonal contraceptives and epigenetic patterns with later cortisol and inflammatory profiles. The current program of research will help reveal the short- and long-term biological implications of sex hormones among young females. Moreover, this research will provide novel insights into the targets of sex hormones by identifying top sites marked by epigenetic changes among naturally cycling females and those using hormonal contraceptives. Importantly, this research will tease-apart the biological consequences of estrogens versus progestin-only hormonal contraceptives. These findings could potentially inform policies regarding recommendations for specific hormonal contraceptives, which could directly impact behaviours, allowing females to make evidence-based decisions as to if, and what type of hormonal contraceptive is best for them.