TRANSPIRE is an observational study of ~200 individuals who (1) will be initiating gender-affirming hormone therapy (GHT) or (2) are gender minority individuals who do not use GHT. The primary outcome will be to identify how the presence of chronic pain changes overtime with GHT through the use of surveys, quantitative sensory testing (QST), brain MRIs, and qualitative interviews.

Following recruitment and consent, participants will complete baseline survey measures and will repeat those measures at 1 months, 3 month, 6 months, and 12 months. QST measures, brain MRIs, and Qualitative Interviews will be offered to participants in cohort (1) and will be completed at baseline and 12 months.

In most chronic pain syndromes there is a 1.5-2 times higher incidence in females compared to males after puberty, which may in part be due to differences in sex hormone levels and receptors and/or other unknown mechanisms related to sex and/or gender. Gender-affirming hormone therapy (GHT) is routinely used in gender minority (GM) persons' gender-affirming medical care. Masculinizing GHT includes the use of testosterone, whereas feminizing GHT includes estrogen and progesterone, often in conjunction with an anti- androgen. In 2011, The Institute of Medicine identified GM adults as an understudied population in critical need of more health-related research. The GM community includes those who identify as transgender men (TGM), transgender women (TGW), and as non-binary (persons whose gender is not binary). There are only a few studies on how GHT is related to the presence and severity of pain in GM persons. Previous research has shown that GM persons have been reported to have an overall greater prevalence of multiple chronic pain syndromes compared to cisgender persons (persons whose gender corresponds to their sex assigned at birth). Retrospective and cross-sectional studies have identified that GHT may affect the presence and severity of chronic pain in the GM population, with masculinizing GHT being potentially associated with improvements in chronic pain and feminizing GHT with estrogen/progesterone and anti-androgens potentially worsening chronic pain. Investigators hypothesize that the presence of androgenic hormonal influences is protective against the development of a specific chronic pain mechanism, nociplastic pain - pain that appears to be driven by the central nervous system (CNS). The mechanisms that underlie nociplastic pain are not entirely understood, but it is thought that amplified and/or dysregulated pain and sensory signaling within the CNS plays a substantial role. Numerous chronic pain syndromes have been identified as primarily nociplastic and include fibromyalgia, tension headache, and chronic low back pain. These and other pain syndromes often co-occur and are recognized by the NIH as Chronic Overlapping Pain Conditions (COPCs). A large knowledge gap exists and thus presents a unique opportunity to study how GHT may influence the presence and severity of pain in GM persons using a rigorous longitudinal design.

Aim 1: To characterize the trajectory of pain and pain-related symptoms in GM adults taking GHT.

Aim 2: To perform quantitative sensory testing (QST) and functional brain neuroimaging of GM adults undergoing GHT to examine the mechanism(s) that underlie changes in pain and sensory sensitivity associated with GHT.

Aim 3: To perform qualitative studies of how GHT affects gender affirmation, psychological wellbeing, and the experience of pain. Investigators will perform and communicate results of these studies using a community-engaged approach.

Data from our work will better enable clinicians to inform GM patients about potential pain-related changes that may occur with GHT and support future studies on mechanisms-based interventions to treat and mitigate chronic pain during gender-affirming care.

Inclusion Criteria:

• Informed consent provided by the participant
• Ages 18-50 years
• English speaking
• GM persons who have been deemed to be an appropriate medical candidate to take gender-affirming hormone therapy for gender incongruence -OR- GM persons who are not taking gender-affirming hormone therapy

Aim 2 (QST and MRI) Additional Inclusion Criteria:

• GM persons who have been deemed to be an appropriate medical candidate to take gender- affirming hormone therapy for gender incongruence
• Stable doses of analgesic medications for at least 30 days prior to screening
• Right handed
• Normal visual acuity or correctable to at least 20/40 for reading instructions in the MRI
• Willingness to refrain from pain medications such as NSAIDs, acetaminophen, and opioid medications for 12 hours prior to neuroimaging and QST
• Willingness to refrain from alcohol and nicotine on day of QST and neuroimaging
• Willingness to refrain from physical activity or exercise that would cause muscle and/or joint soreness for 48 hours prior to testing (routine exercise or activity that does not lead to soreness is acceptable)
• Investigators will attempt to recruit individuals with no chronic daily use of adjunctive pain medications, including tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids as these drugs can influence neuroimaging and QST findings, or have individuals be weaned off of these meds at least two weeks prior to being studied. In previous smaller imaging studies investigators could accomplish this, but this may not be possible in this large of a study. If the study team does need to allow individuals into these cohorts while on such medications because of pragmatic issues, this information will be recorded and patients will be asked to remain on a stable dose for at least two weeks prior to MRI and QST assessments.
• Able to lie still on their back for 1.5 hours for MRI scans

Exclusion Criteria:

• Inability to provide informed consent
• Age less than 18 years or greater than 50 years
• Severe physical impairment (e.g., blindness, deafness, paraplegia)
• Co-morbid medical conditions that may significantly impair physical functional status (e.g., history of non-skin malignancy, or autoimmune disorder)
• Pregnant or nursing
• Liver failure
• Self-reported liver cirrhosis
• Self-reported hepatitis
• Severe Cardiovascular disease (examples: history of myocardial infarction, unstable angina, severe coronary artery disease, congestive heart failure, or severe valvular abnormalities) that are self-reported by patient or by medical record
• Prisoner
• Current litigation for chronic pain
• Current disability proceedings
• Active psychotic or suicidal symptoms
• Current drug or alcohol use disorder
• History of gonadectomy surgery

Aim 2 (QST and MRI) Additional Inclusion Criteria:

• Contraindications to MRI (e.g., metal implants, pacemaker, etc.)
• Severe claustrophobia precluding MRI and evoked pain testing during scanning
• BMI > 40 or unable to lie comfortably in MRI
• Current, recent (within the last 6 months), or habitual use of artificial nails or nail enhancements. (Artificial nails can influence pressure pain sensitivity at the thumbnail)
• Peripheral neuropathy
• Diagnosed epilepsy or seizure history

All gender minority persons

Gender minority individuals from within the greater Kansas City area