Sex, Hormones and Identity Affect Nociceptive Expression

The Investigators have recently published on differences in pain sensitivity measures between cis and trans individuals in the local area. The investigators observed the anticipated differences in pain sensitivity between CM and CW (CW \> CM), but found that the TW were phenotypically similar to CW in all measures. However, the investigators did not assess hormone level, nor did the investigators recruit TM participants. Here, with the assistance of two local community group stakeholders the investigators will recruit the following groups: CM, CW, TM+T (currently taking exogenous testosterone), TW+E (exogenous estradiol), TM, and TW (n=20/group). The investigators 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. Finally, questionnaires will measure pain state, quality of life (QOL), voice QOL, body image, appearance, self-reported health, masculinity/femininity, community connectedness, gender role, sleep, depression, social support, adverse childhood experiences and stigma.

Aim 1: To determine the impact of gender identity, genetic sex and hormone status on pain sensitivity.

Hypotheses: CM, TM and TM+T will have higher thresholds and lower sensitivity across the majority of pain tests when compared to CW, TW, and TW+E. Gender identity will influence pain sensitivity.

Aim 2: To examine social and psychological factors that contribute to pain sensitivity in our groups.

Hypotheses: Trans individuals will have pain sensitivity scores that align with their identified gender and will not be related to hormone levels or genetic sex. Stress, sleep quality, depression, social support and perceived discrimination will affect pain sensitivity measures.

Aim 3: To quantify differences in immune cell populations and activity between our groups.

Hypotheses: Hormone levels will be directly related to immune cell populations. CM, TW and TM+T will have increased frequencies of NK and CD8+ cells than CW, TM and TW+E. The presence of estradiol will be positively correlated with stimulated cytokine release in T cells.

Inclusion criteria will include:

1) self-identification as one of the above gender identities; 2) age between 18-65; 3) understanding of verbal and written English. There will be considerable heterogeneity within the trans population with respect to gender/sexual expression. Whereas the investigators feel that these factors are important to consider, in order to enhance recruitment and inclusion, the investigators will focus on self-reported gender identity and note other variables of interest. With respect to hormone use, only participants that have been on/off hormone treatment for at least 6 months will be eligible. In both cases, this allow for stabilization of hormone levels and reduced variability. At this time the investigators will restrict our recruitment to self-identified trans and cisgender participants, but recognize that very little research exists on non-binary or genderfluid groups.

Exclusion criteria will be the following:

1) pain in at least 3/7 days/week for the past 3 months; 2) HIV positive diagnosis; 3) cardiovascular or pulmonary disease; 4) regular use of opioid pain medications; 5) uncontrolled hypertension (i.e. SBP/DBP of \> 150/95); 6) current illness accompanied by fever (body temperature \>38 °C); 7) active use of oral contraceptives; 8) prostatectomy, hysterectomy or oophorectomy; 9) hospitalization due to psychiatric illness within the last 6 months. The investigators acknowledge that the rates of HIV are higher in the South and in gender minority populations 46, but our investigation of immune cell reactivity (Aim 3) necessitates this exclusion.

This study will consist of a single visit which will include the following:

Blood Draw: A small amount of blood (2 tsp) will be drawn by a trained and certified nurse. The investigators will be analyzing this blood to determine the participants' levels of oxidative stress. (5 minutes)

Questionnaires: The investigators will be administering a number of questionnaires to assess various aspects related to quality of life, experiences of stigma, depression and social support. These are standard measures for this type of study and will provide necessary information about factors that may influence pain sensitivity. (40 minutes)

Body Measurements: Body weight and height will be measured. The investigators will also be measuring the participants' blood pressure. (5 minutes)

Pain Testing: This will consist of a number of sensitivity tests. (70 minutes)

* Pressure: The investigators will use a handheld probe that has a small rubber tip. This will produce a pressure sensation and the pressure pain threshold will be obtained.
* Heat: Heat pain sensitivity will be tested with a thermal sensory testing machine used widely in clinical settings. This machine has a small square piece that is used to apply heat to the skin. The amount of heat is controlled by a computer. One or more of the following types of heat stimuli will be delivered: 1) a slowly increasing heat stimulus; 2) a series of 5 heat pulses. These heat pulses will be repeated at different temperatures.
* Cold: Cold sensitivity will be assessed with the cold pressor task. The hand is placed into cold water (4-10 C) for up to 60 seconds. With the fingers splayed, the participant is asked for their pain ratings at 30 and 60 seconds.
* Combined pressure and cold: The investigators will use a handheld device with a small rubber tip to apply pressure. As soon as pain is reported, the pressure will be removed. Next, the hand will be immersed into cold water. After 20 seconds, the pressure stimulator will again be applied.

Eligibility Criteria:
Inclusion Criteria:

* self-identification as one of the above gender identities
* understanding of verbal and written English.
* participants that have been on/off hormone treatment for at least 6 months

Exclusion Criteria:

* pain in at least 3/7 days/week for the past 3 months
* HIV positive diagnosis
* cardiovascular or pulmonary disease
* regular use of opioid pain medications
* uncontrolled hypertension (i.e. SBP/DBP of \> 150/95)
* current illness accompanied by fever (body temperature \>38 °C)
* prostatectomy, hysterectomy or oophorectomy
* hospitalization due to psychiatric illness within the last 6 months.