Sex, Hormones and Identity affect Nociceptive Expression (SHINE)Project Summary It is often reported that females demonstrate lower pain thresholds and higher sensitivity than males in experimental pain tests. However, “sex” and “gender” are often used interchangeably to describe these differences, but genetic sex and gender identity are not always congruent. As a result, human subjects may be categorized as male or female based upon genetic sex even if they do not identify as a man or woman, respectively. Transgender (trans) men and women (TM and TW) are a minority group whose gender identity is different than their genetic sex (as opposed to cisgender men and women; CM and CW). As a result, TM and TW may experience stigma, prejudice and depression, putting them at greater risk for negative health outcomes and impacted quality of life. Thus, this understudied community provides a unique opportunity to investigate the role of gender identity (trans vs. cis), sex assigned at birth (male vs. female) and hormonal status (elevated testosterone vs. elevated estrogen) on pain and well-being, while providing a better understanding of the needs of the community. Specific aims of this study include: 1. To determine the impact of gender identity, sex assigned at birth and hormone status on pain sensitivity. 2. To examine social and psychological factors to contribute to pain sensitivity in our groups. 3.To quantify differences in immune cell populations and activity between our groups. With the assistance of local community stakeholders we will recruit the following groups: CM, CW, TM+T (currently taking exogenous testosterone), TW+E (exogenous estradiol), TM, and TW (n=20/group). We will use quantitative sensory testing to assess sensitivity to cold, pressure, and heat via standardized protocols. Blood samples will be taken for assessment of stress and reproductive hormone levels, immune cell populations and stimulated cytokine release, as well as salivary samples to measure stress reactivity. Finally, questionnaires will measure pain state, quality of life, voice quality of life, body image, appearance, self-reported health, masculinity/femininity, community connectedness, gender role, sleep, depression, social support, adverse childhood experiences and stigma. Together, this will be the first exploration of the impact of gender identity, sex assigned at birth and hormonal status on quality of life, pain sensitivity and immune cell activity in trans individuals. This investigation will also provide critical information with respect to the needs of this underserved and critically understudied population.