Changes in temperature perception in transgender persons undergoing gender-affirming hormone therapy

Changes in temperature perception in transgender persons undergoing gender-affirming hormone therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Changes in temperature perception in transgender persons undergoing gender-affirming hormone therapy Haiko Schlögl, Pauline Zimmermann, Martin Kaar, Theresa Bokeloh, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5967812/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Feb, 2026 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract Temperature perception differs between the two biological sexes male and female with lower thermal detection thresholds found in women compared to men. However, underlying mechanisms of these differences and the influences of sex hormones are not yet sufficiently understood. To assess the effects of sex hormones on temperature perception, we measured temperature detection and pain thresholds with quantitative sensory testing and subjective temperature sensation in transgender patients undergoing gender-affirming hormone therapy (GAHT). We included 12 trans women (male-to-female transgender) and 17 trans men (female-to-male transgender) before and 3 and 6 months after start of GAHT. As a control group, we also measured 13 cis women and 10 cis men without hormone treatment at the same timepoints. Temperature detection thresholds in persons assigned female at birth at baseline were lower than in persons assigned male at birth. Accordingly, in trans women, temperature detection thresholds improved with feminizing GAHT. Pain detection thresholds did not differ between assigned sexes at birth and did not change with time. In a group of trans women undergoing GAHT with estrogen and cyproteroneacetate, for the first time we could show that the ability to detect changes in temperature detection improved, which is in congruence with a higher temperature sensitivity of women compared to men. Future studies need to assess at which neurobiological processing stages the relevant changes occur and what molecular mechanisms play a role. Health sciences/Endocrinology/Endocrine system and metabolic diseases Health sciences/Neurology/Neurological disorders Biological sciences/Physiology Transgender gender-affirming hormone therapy (GAHT) sex differences temperature perception temperature sensation quantitative sensory testing (QST) Figures Figure 1 Figure 2 Highlights - We found an improvement in temperature detection ability during gender-affirming hormone therapy (GAHT) over 6 months in trans women (male-to-female transgender) - In persons assigned female at birth in the absence of hormone treatment, temperature detection thresholds were lower than in persons assigned male at birth - We neither found differences in cold and heat pain thresholds between sexes nor significant changes during GAHT in trans women or trans men - We neither found differences in subjective temperature sensation between sexes nor significant changes during GAHT in trans women or trans men - Sex hormones testosterone and estradiol might be relevant factors for sex differences in temperature perception and sensation. Further studies in larger cohorts are necessary. Introduction Temperature perception is an important part of body homeostasis. Correct temperature sensing is needed to keep body temperature, a co-regulator of all physiological processes, in the optimal range 1 . Furthermore, thermal stimuli to the skin play an important role in thermal comfort 2 . Women have lower thermal detection thresholds than men and are therefore more sensitive in thermal detection 3 – 8 . Also, women show higher cold-wetness perception at the skin, which is associated with thermal discomfort 9 , 10 , and have higher unpleasantness and pain intensity ratings for extreme temperatures 3 , 11 . The reasons for sex differences in temperature and pain sensation, perception and thermoregulatory responses are still unknown and it is unclear, which roles the sex hormones testosterone and estrogen play 1 . Multiple levels of temperature signaling may be involved. Free nerve endings of C-fibers and Aδ-fibers with temperature sensitive channels/receptors (such as TRPV1, TRPM2 and TRPM8) transmit temperature signals to the dorsal horn of the spinal cord, from where spinothalamic and spinoparabrachial projections ultimately relay signals to subcortical targets in thalamus and hypothalamus. The latter sends efferent signals to effector organs to keep temperature homeostasis, e.g., via shivering, sweating or behavioral changes 1 , 12 – 15 . Study results on the effects of sex hormones on these pathways are contradictory. Animal data suggest that the activity of cold receptor TRPM8 is directly modulated by testosterone 16 , and castration of male mice increased sensitivity to mild cold 17 . While the effects of testosterone have been investigated more in depth, animal data on the molecular mechanisms mediating the action of estradiol on TRPM8 is scarce and it is not yet clear if estradiol affects receptor function 18 . Few studies investigated the influence of sex hormones on TRPM2 receptors, which are involved in warm perception, in elaborated animal and in vitro models 19 , 20 , but which have limited significance for physiology in healthy humans. To our knowledge, no human study so far investigated direct effects of sex hormones on thermosensation 1 . One reason of this unsatisfactory state of knowledge is that performing prospective interventional studies with sex hormones in healthy persons is not possible. Using a cohort undergoing gender-affirming hormone therapy (GAHT) offers the unique opportunity to prospectively assess direct effects of testosterone and estrogen during therapy intraindividually when being applied to the respective other assigned sex at birth (i.e., biological sex). During GAHT, the sex hormone concentrations of the assigned sex at birth are changed to match the perceived gender. This approach helps not only to disentangle the role of sex hormones in temperature perception and sensation in human physiology, but also to gain a better understanding of the effect of GAHT, which is highly relevant for the increasing number of trans persons seeking hormonal treatment 21 , 22 . We hypothesized that with quantitative sensory testing and a temperature sensation questionnaire we could detect changes in temperature perception and sensation in transgender persons undergoing GAHT in the magnitude of known differences between men and women 3 . We show for the first time that during GAHT in trans women temperature perception improved and suggest that sex hormone concentrations influence thermosensation. Methods Study cohort: Transgender persons and control group Patients with gender incongruence (diagnosis number after the international statistical classification of diseases and related health problems [ICD]-10 F64.0, ICD-11 HA60) were recruited at the endocrinological outpatient clinic of the University Hospital Leipzig. Measurements were performed between 01/2021 and 10/2023, as a part of a larger trial monitoring various effects of GAHT (clinicaltrials.gov registration number NCT04838249). Twelve trans women (male-to-female transgender) and 17 trans men (female-to-male transgender) participated in the study. The study is observational, the decision for GAHT was solely based on patient’s demand and clinical need, and independent from the study. The control group of persons without gender incongruence were recruited through both analog and online advertisements and were measured between 01/2021 and 10/2023, comprising 13 cis women and ten cis men. Baseline characteristics of the four groups are summarized in Table 1 . Inclusion criteria for patients and control persons were age ≥ 18 years and for patients a signed informed consent about the GAHT. Exclusion criteria for both groups included serious medical conditions (e.g., uncontrolled high blood pressure, heart insufficiency, history of stroke, malignant diseases, or chronic infections), uncontrolled endocrine diseases (e.g., hypercortisolism, pituitary disease, hypo- or hyperthyroidism) and previous GAHT. All study participants consented to participating in the study. Table 1 Baseline characteristics and laboratory data of the study population Assigned male at birth Assigned female at birth Characteristics Trans women (n = 12) Cis men (n = 10) p Trans men (n = 17) Cis women (n = 13) p Age (years) 25.2 (6.1) 24.8 (3.9) 0.54 22.6 (4.7) 24.8 (4.1) 0.05 Weight (kg) 74.4 (16.5) 76.9 (10.4) 0.63 71.5 (20.7) 65.7 (16.4) 0.12 Body Mass Index (kg/m²) 23.5 (6.1) 23.7 (4.0) 0.92 25.9 (7.0) 23.0 (2.9) 0.17 Body surface (m²) 1.92 (0.21) 1.98 (0.19) 0.38 1.83 (0.23) 1.76 (0.29) 0.16 Body fat mass (kg) 16.1 (14.1) 14.7 (4.4) 0.97 25.5 (13.3) 17.4 (7.0) 0.04 Body fat free mass (kg) 59.1 (4.3) 62.75 (8.7) 0.35 47.7 (7.3) 47.8 (9.1) 0.64 Testosterone concentration (nmol/l) 15.40 (5.82) 18.47 (8.0) 0.20 1.06 (0.5) 0.98 (0.7) 0.36 Estradiol concentration (pmol/l) 90.3 (36.2) 105.5 (75.9) 0.34 222.0 (234.0) § 3 87.0 (269.5) 0.18 Median (interquartile range) and Mann-Whitney-U test for not-normally distributed data. § n = 9: 4 cis women, who took hormonal contraceptive with ethinylestradiol were excluded for this specific calculation; † missing data of one participant. Gender-affirming hormone therapy Treatment was performed following international guidelines 23 , 24 , with trans women receiving estradiol and cyproteroneacetate and trans men receiving testosterone. Medication was controlled and adjusted following regular checks of blood concentrations of testosterone and estradiol. The employed preparations and concentrations are listed in Table 2 . Table 2 Preparations and concentrations used in the study for gender-affirming hormone therapy 3 Months 6 Months Trans women n = 12 n = 11 Estradiol Estradiol gel 0,6 mg/g, 1.25–5 g/d 9 8 Estramon patch 75 µg/24 h 3 3 Cyproteroneacetate 10 mg − 12.5 mg/d 12 11 Trans men n = 17 n = 13 Testosterone Testosterone undecanoate injection 1000 mg, approx. every 3 months 7 5 Testosterone gel 16.2 mg/g, 1.25–2.5 g/d 10 8 Hormone therapy was performed following international guidelines 23 , 24 . In trans women, estradiol was given transdermally via gel or patch, in trans men testosterone was applied transdermally via gel or intramuscularly via injection following patient’s preferences. Cyproteroneacetate was given as tablet. Experimental design Baseline measurements in patients were obtained immediately before the start and after 3 and 6 months of ongoing GAHT. In the control group, measurements were conducted at the same time intervals and study protocol was identical for both patients and controls: In the morning anthropometric data was assessed and a fasting blood draw was performed. Body surface was calculated by Mosteller formula 25 . Body composition (body fat mass, body fat free mass) was determined using body impedance analysis 26 . At approximately 11 am, participants had lunch and at approximately 12:30 pm quantitative sensory testing was performed in the outpatient clinic of the Clinic for Neurology at the University Hospital Leipzig. Room and skin temperature at the hand were measured after entering the room. If the skin temperature was below 28°C, participants were instructed to hold their hands under warm water for 20 seconds, after which the temperature was measured again. After that, participants had to complete a questionnaire addressing temperature sensation ( see Temperature sensation questionnaire). Then, quantitative sensory testing was started, performed as described below, and skin temperature of the hand was measured again after removing the thermode. Quantitative sensory testing Quantitative sensory testing was performed using the Main Station Neurosensory Analyzer Model TSA-II (2001), Medoc, Ramat Yishay, Israel with its standard 30 x 30 mm thermode (Peltier-element) with temperature sensors and an accuracy of 0.3°C 27 . The thermode was placed at the palm as suggested by previous literature 28 – 31 of the non-dominant hand and fixed with velcro tape. Participants were instructed to press a button with their dominant hand, as soon as they detected a change in temperature at the site of thermal stimulation. In the first set of measurements, the thermode’s temperature decreased according to the method of limits with a rate of 0.3°C/sec from its baseline temperature set at 32°C until the participant pressed the button. In the second set of measurements, the thermode’s temperature increased accordingly. Four measurements for cold perception and four for warm perception were conducted and the respective means were calculated and used for further analyses. Before the next sets of measurements, participants were instructed to press the button as soon as they felt a heat or cold induced pain. Again, starting from the skin indifference temperature of 32°C, the thermode’s temperature decreased/increased at a rate of 1.5°C/sec until the button was pressed or the lowest possible temperature of 0°C/highest possible temperature of 50°C was reached 27 . Temperature sensation questionnaire Participants answered an 18 question long questionnaire based on “The experienced temperature sensitivity and regulation survey” 32 . Statements regarding temperature sensation were rated by participants on a numeric rating scale ranging from zero to ten. The questions were designed to assess temperature sensations in everyday situations and to quantify the experience of hot and cold flushes. All questions and possible answers, as well as how questions were grouped for calculation of the two summary scores are listed in the Supplemental material. Statistical analysis Four cis women, who were treated with hormonal contraceptives with ethinylestradiol during the measurements were excluded for the analysis of estradiol concentrations, as ethinylestradiol suppresses endogen estradiol secretion and is not detected by our used estradiol laboratory assay (leaving nine participants in this subgroup). Due to small group sizes (< 20 persons) we used non-parametric tests throughout the measurements (Mann-Whitney-U test, mixed model analyses with GraphPad Prism 10.0.2, Durbin-Skillings-Mack 33 test and Conover pairwise rank comparison 34 with XLSTAT, version 2023.3.1–1416). In comparison to these tests, we performed Friedman’s and Dunn’s test under exclusion of participants with missing data and results are reported in the supplement. Correlation analyses between temperature detection thresholds and age, body mass index (BMI), fat mass, fat free mass, room temperature and average monthly temperature were performed with GraphPad Prism 10.0.2 using Spearman correlation including all baseline measurements. Correlation analyses of fat mass and fat free mass were separately calculated for assigned female and male sex at birth due to sex differences in body composition. Results Anthropometric and laboratory parameters Baseline characteristics are summarized in Table 1 . As expected, testosterone serum concentrations decreased in trans women during 6 months of GAHT (p ≤ 0.0001) (Conover’s procedure: 0 vs. 3 months p ≤ 0.05, 0 vs. 6 months p ≤ 0.05, 3 vs. 6 months p ≥ 0.05) and estradiol concentrations increased (p = 0.001) (Conover’s procedure: 0 vs. 3 months p ≤ 0.05, 0 vs. 6 months p ≤ 0.05, 3 vs. 6 months p ≥ 0.05). In trans men, testosterone concentrations increased (p ≤ 0.0001) (Conover’s procedure: 0 vs. 3 months p ≤ 0.05, 0 vs. 6 months p ≤ 0.05, 3 vs. 6 months p ≥ 0.05), while serum estradiol concentrations did not change (p = 0.602). Neither testosterone concentrations in cis men and cis women (p = 0.471 and p = 0.743), nor estradiol concentrations (p = 0.762 and p = 0.725) changed. In the interaction analysis between trans women and cis men there were differences in testosterone (p ≤ 0.0001) and estradiol (p = 0.03) concentration-changes over the study period, between trans men and cis women there were differences in testosterone concentration-changes (p ≤ 0.0001), but not in estradiol concentrations (p = 0.58, Fig. 1 ). Quantitative sensory testing for temperature perception Correlation analyses including all baseline measurements showed no significant correlations between “cold” and “warm” detection thresholds and age, BMI, fat mass, fat free mass and the average monthly temperatures at the time of the measurements (all p > 0.05). Room temperature correlated with “warm” detection thresholds (r=-0.32, p = 0.028) (Suppl. Fig. S1 ), but not with “cold” detection thresholds (r = 0.17, p = 0.26). In quantitative sensory testing, median (interquartile range) threshold values for discriminating “cold” and “warm” at baseline measurement were in persons assigned female at birth lower (-1.04 [0.73] and 1.31 [0.74] °C) than in persons assigned male at birth (-1.50 [1.34] and 1.83 [0.81] °C) (p = 0.006 and p = 0.01; Cohen’s d 0.73 and 0.74) (Fig. 2 a). In trans women, over the period of 6 months of GAHT, the thresholds for both “cold” (p = 0.004) and “warm” (p = 0.045) detection decreased (both p > 0.05 in post-hoc tests). There were no changes in temperature detection thresholds in trans men (p = 0.75 and p = 0.82), cis women (p = 0.95 and p = 0.19), and cis men (p = 0.10 and p = 0.29) (Fig. 2 b). In the interaction analysis, neither between trans women and cis men there were significant differences in “cold” and “warm” threshold-changes (p = 0.89 and p = 0.98), nor between trans men and cis women (p = 0.54 and p = 0.58). Mann-Whitney-U and Wilcoxon test, respectively, did not show statistically significant differences in room temperature at measurements between assigned sexes at birth at baseline and in trans women over the three measurements in 6 months (data not shown). Temperature threshold for pain sensation (i.e. “cold pain” or “heat pain”) did not differ between the assigned sexes at birth, nor were there changes in this measure in any of the four study groups over the study period (data not shown). Temperature sensation questionnaire Correlation analyses showed no correlations between “summary score cold” and age, BMI, fat mass, fat free mass, current room temperature and the average monthly temperatures at the time of the measurements (all p > 0.05). “Summary score warm” showed no correlation with age, fat mass, fat free mass, current room temperature and the average monthly temperatures at the time of the measurement (all p > 0.05), but a positive correlation with BMI (r = 0.32, p = 0.022) (Suppl. Fig. S1 ). We did not find differences in summary scores for cold and warm feelings in daily situations at baseline between persons assigned female and male at birth, and no changes during the period of 6 months of GAHT in neither group (data not shown). We did not find differences in the occurrence of cold and hot flushes as reported by questionnaires at baseline between persons assigned female and male at birth (p = 0.95 and p = 0.06). Trans men reported over the period of 6 months of GAHT an increase in sudden feelings of coldness (p = 0.034, post-hoc: non-significant in Conover’s procedure), but no changes in hot flushes (p = 0.56). No changes in sudden feelings of coldness and heat were detected in trans women (p = 0.77 and p = 0.56), cis men (p = 0.24 and p = 0.32) and cis women (p = 0.94 and p = 0.55) (data not shown). Results of the evaluation of the room temperature and all statistical analyses calculated with Friedman- and Dunn’s Test under exclusion of participants with missing data are presented in the Supplemental material. These control analyses qualitatively supported the results from the main analyses. Discussion When measuring temperature detection thresholds using quantitative sensory testing, we saw 1) lower warm and cold detection thresholds in persons assigned female at birth compared to male at birth, which is in accordance with previous literature 3 – 8 and 2) a threshold reduction over the observation period of six months in persons assigned male at birth treated with estrogen and testosterone blockers. A possible mechanism leading to the observed effects is that testosterone interacts with the androgen receptor and TRPM8 and reduces the channel activity of the cold receptor TRPM8. This is supported by a study in mice where hypogonadism was induced in male animals through castration and they became more sensitive to mild cold 17 . However, data on the effects of testosterone on TRPM8 is inconclusive; e.g., in a cell culture study, testosterone activated the cold receptor TRPM8 and opened it completely in lipid layers 16 . Also, estrogen may influence receptor signaling 35 . E.g., in the luteal phase of the female menstrual cycle when progesterone and estrogen concentrations are higher than in the follicular phase, the threshold for cold perception is lower 36 . However, data on the effects of estradiol on temperature receptors are scarce and it is not yet clear if the molecule affects receptor function 18 . Another mechanism that could contribute to the improvement of temperature detection thresholds in trans women undergoing GAHT may be the skin softening effect of therapy. In cis persons, skin thickness is different in men vs. women 37 . After start of GAHT, softening of skin is observable already after three to six months of GAHT 23 , 38 . In a study using a thermal model describing the temperature evolution in skin, thicker skin seemed to decrease thermal perception 39 . However, another study investigating only male participants did not find associations between skin thickness at the fingertip and thermotactile perception 40 , 41 . Having investigated the first 6 months of GAHT, we cannot say whether the changes in temperature perception in trans women will persist during lifelong treatment, increase, or vanish after adaption to the new hormonal situation. Bodily changes in trans women under GAHT, e.g., breast growth, redistribution of body fat or decrease of the growth rate of body hair have a visible onset after three to six months after the start of GAHT and reach their maximum after two to five years of GAHT 23 , 38 . In trans men who were treated with testosterone, we did not see significant changes in temperature perception. In this group, testosterone serum concentrations increased from the female reference range to within the male reference range through therapy. However, usually during the first 6 months of treatment with testosterone, the hypothalamic-pituitary-gonadal axis is not yet suppressed and still gonadotropin releasing hormone, luteinizing/follicle stimulating hormone and consequently estradiol are secreted. The process of hypothalamic-pituitary-gonadal axis suppression though testosterone therapy with inhibition of ovulation and menstrual bleeding, and accompanying decease of ovarian estrogen secretion in many patients takes longer 23 . Also in the sample of trans men studied here, median estrogen concentrations after 6 months of treatment were not yet reduced compared to baseline measurements. Limitations to our study include that, first, our group sizes are relatively small for conducting a clinical study. However, the median temperature detection thresholds in our group were 0.3°C lower in persons assigned female at birth than in persons assigned male at birth, which was in the range of 0.2–0.4°C described before in the cohort of 1252 participants 3 . Second, as our results did not withstand the interaction analysis we cannot be sure that GAHT was causal for observed effects, but measurements in trans persons may have changed over the study period for different reasons (e.g., habituation to the study procedures). Nevertheless, this study tried to minimize this limitation as control groups underwent the same measurements in the same time intervals. Our findings are especially of importance, since there is an increase in the prescription of GAHT 21 , 22 in transgender persons and our study helps to gain further knowledge of changes in body physiology in persons undergoing GAHT. Considering that thermosensation also influences body temperature regulation 1 , a better understanding of how sex hormones influence temperature sensation is also important for persons exposed to more extreme temperatures due to climate change. To investigate underlying mechanisms which are causal for the observed changes in temperature perception, subsequent studies are necessary. Conclusions Taken together, in our study we show for the first time, that temperature perception thresholds decreased in persons with male testosterone serum concentrations during treatment with estrogen and testosterone blockers, and thus transitioned to a female hormonal situation. With our study setup and methods, in trans women under GAHT we found changes over time in temperature perception that were comparable to the differences between assigned sexes at birth. Future studies are needed to assess the mechanisms behind these changes to gain a better physiological understanding of how sex hormones affect temperature perception. Declarations Disclosure statements: Haiko Schlögl received financial support for this study from Besins Healthcare. Matthias Blüher received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors have no conflicts of interest. Grants or fellowships supporting the writing of the paper: Pauline Zimmermann and Franziska Labinski received a 6 months scholarship from the German Diabetes Society ( Deutsche Diabetes Gesellschaft e.V .) during their medical studies. Trial registration: NCT04838249. Ethics approval and consent to participate The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). The Ethics Committee of the University of Leipzig approved this research project (approval no. 023/20-ek), according to the national research ethics regulations. All participants gave their written consent for all study procedures. Consent for publication Not applicable. Availability of data and material The datasets generated and/or analysed during the current study are not publicly available due patient confidentiality. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided. Competing interests Haiko Schlögl received financial support for this study from Besins Healthcare. Matthias Blüher received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors have no conflicts of interest. Funding Pauline Zimmermann and Franziska Labinski received a 6 months scholarship from the German Diabetes Society ( Deutsche Diabetes Gesellschaft e.V .) during their medical studies. Authors’ contributions PZ: data analysis, conduction of the study, writing, reviewing and editing of the manuscript; MK: conduction of the study, reviewing and editing of the manuscript; TB: conduction of the study, reviewing and editing of the manuscript; LM: conduction of the study, reviewing and editing of the manuscript; FL: conduction of the study, reviewing and editing of the manuscript; FE: reviewing and editing of the manuscript; MB: funding acquisition, resources, reviewing and editing of the manuscript; MS: funding acquisition, resources, reviewing and editing of the manuscript; SH: conceptualization, conduction of the study, reviewing and editing of the manuscript; HS: conceptualization, funding acquisition, data analysis, conduction of the study, project administration, writing, reviewing and editing of the manuscript. All authors read and approved the final manuscript. Acknowledgements We thank all participants for their partaking in the study. 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Biol. 100, 103029 (2021). Kenshalo, D. R. Changes in the cool threshold associated with phases of the menstrual cycle. https://journals.physiology.org/doi/epdf/ 10.1152/jappl.1966.21.3.1031 (1966) doi:10.1152/jappl.1966.21.3.1031. Van Mulder, T. J. S. et al. High frequency ultrasound to assess skin thickness in healthy adults. Vaccine 35, 1810–1815 (2017). Hembree, W. C. et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 102, 3869–3903 (2017). Chen, C. & Ding, S. How the Skin Thickness and Thermal Contact Resistance Influence Thermal Tactile Perception. Micromachines 10, 87 (2019). Lundström, R., Dahlqvist, H., Hagberg, M. & Nilsson, T. Vibrotactile and thermal perception and its relation to finger skin thickness. Clin. Neurophysiol. Pract. 3, 33–39 (2018). Park, S., Roh, S.-H. & Lee, J.-Y. Body regional heat pain thresholds using the method of limit and level: a comparative study. Eur. J. Appl. Physiol. 119, 771–780 (2019). Additional Declarations Yes there is potential Competing Interest. Haiko Schlögl received third party funding for this study from Besins Healthcare. Matthias Blüher received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors have no conflicts of interest. Supplementary Files Supplement.docx Supplemental Material Cite Share Download PDF Status: Published Journal Publication published 07 Feb, 2026 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5967812","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":419167001,"identity":"b5ddb853-5b46-4014-b23b-544d52c0af69","order_by":0,"name":"Haiko Schlögl","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-3967-5318","institution":"University of Leipzig","correspondingAuthor":true,"prefix":"","firstName":"Haiko","middleName":"","lastName":"Schlögl","suffix":""},{"id":419167002,"identity":"a45c5898-4785-4573-82c2-023f81d211eb","order_by":1,"name":"Pauline Zimmermann","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Pauline","middleName":"","lastName":"Zimmermann","suffix":""},{"id":419167003,"identity":"4347722c-d677-404b-999e-bf8c98d8ddfa","order_by":2,"name":"Martin Kaar","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Kaar","suffix":""},{"id":419167004,"identity":"5124e751-c48e-404b-aa01-ff8390dae43f","order_by":3,"name":"Theresa Bokeloh","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Theresa","middleName":"","lastName":"Bokeloh","suffix":""},{"id":419167005,"identity":"aadf56c6-41cf-4166-b0fb-ec1ced0cb334","order_by":4,"name":"Lotta Moll","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lotta","middleName":"","lastName":"Moll","suffix":""},{"id":419167006,"identity":"b5beed23-94de-4033-a59f-d86083a59a80","order_by":5,"name":"Franziska Labinski","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Franziska","middleName":"","lastName":"Labinski","suffix":""},{"id":419167007,"identity":"fc8771eb-d9c9-4d3b-82e6-cdcb9ee01508","order_by":6,"name":"Falk Eippert","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Falk","middleName":"","lastName":"Eippert","suffix":""},{"id":419167008,"identity":"276a5257-e9fa-4675-8b4d-b36c6a009471","order_by":7,"name":"Matthias Blüher","email":"","orcid":"","institution":"Leipzig University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Blüher","suffix":""},{"id":419167009,"identity":"896d039d-3331-4c60-9085-de16ea9fb842","order_by":8,"name":"Michael Stumvoll","email":"","orcid":"https://orcid.org/0000-0001-6225-8240","institution":"University of Leipzig","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Stumvoll","suffix":""},{"id":419167010,"identity":"f59be398-ef5f-4bf2-96e0-b983f192eca0","order_by":9,"name":"Sascha Heinitz","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sascha","middleName":"","lastName":"Heinitz","suffix":""}],"badges":[],"createdAt":"2025-02-05 17:40:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5967812/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5967812/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-026-01420-0","type":"published","date":"2026-02-07T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":78357298,"identity":"edd11a22-5760-43d9-8aba-9a1988133337","added_by":"auto","created_at":"2025-03-12 11:41:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":126173,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerum testosterone and estradiol concentrations under hormone therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTestosterone (nmol/l) and estradiol (pmol/l) concentrations in trans women, cis men, trans men and cis women grouped by assigned sex at birth. Median + interquartile range. Statistical testing: Durbin-Skillings-Mack test to analyze changes over the time, mixed model analysis for analysis between subgroups. ****: p≤0.0001, ***: p≤0.001, *: p≤0.05.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5967812/v1/fae28361c9ba2f94c3d3ffd4.png"},{"id":78357303,"identity":"abbb88d4-5e76-450e-9a52-34487c1c1148","added_by":"auto","created_at":"2025-03-12 11:41:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":208323,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuantitative sensory testing for temperature perception\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTemperature detection thresholds (°C) a) grouped by assigned sex at birth and b) in trans women, cis men, trans men, cis women. Median + interquartile range. Statistical testing: a) Mann-Whitney-U test b) Durbin-Skillings-Mack test. Abbr.: AMAB: assigned male at birth, n=22, AFAB: assigned female at birth, n=30. MtF= male-to-female transgender, FtM= female-to-male transgender, **: p≤0.01, *: p≤0.05.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5967812/v1/adb5f3103f7111f90eca91b1.png"},{"id":104777040,"identity":"01788ddf-d861-434a-9125-4e80df96955c","added_by":"auto","created_at":"2026-03-17 07:07:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1061243,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5967812/v1/f870150f-cd87-46b9-8d93-70f559657748.pdf"},{"id":78357300,"identity":"4f1dedd8-9e1f-4370-b8b4-cfd92b860818","added_by":"auto","created_at":"2025-03-12 11:41:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":184306,"visible":true,"origin":"","legend":"Supplemental Material","description":"","filename":"Supplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-5967812/v1/1bea7b3875f3f45cdab84d34.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nHaiko Schlögl received third party funding for this study from Besins Healthcare. Matthias Blüher received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors have no conflicts of interest.","formattedTitle":"Changes in temperature perception in transgender persons undergoing gender-affirming hormone therapy","fulltext":[{"header":"Highlights","content":"\u003cp\u003e- We found an improvement in temperature detection ability during gender-affirming hormone therapy (GAHT) over 6 months in trans women (male-to-female transgender)\u003c/p\u003e\u003cp\u003e- In persons assigned female at birth in the absence of hormone treatment, temperature detection thresholds were lower than in persons assigned male at birth\u003c/p\u003e\u003cp\u003e- We neither found differences in cold and heat pain thresholds between sexes nor significant changes during GAHT in trans women or trans men\u003c/p\u003e\u003cp\u003e- We neither found differences in subjective temperature sensation between sexes nor significant changes during GAHT in trans women or trans men\u003c/p\u003e\u003cp\u003e- Sex hormones testosterone and estradiol might be relevant factors for sex differences in temperature perception and sensation. Further studies in larger cohorts are necessary.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eTemperature perception is an important part of body homeostasis. Correct temperature sensing is needed to keep body temperature, a co-regulator of all physiological processes, in the optimal range\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Furthermore, thermal stimuli to the skin play an important role in thermal comfort\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Women have lower thermal detection thresholds than men and are therefore more sensitive in thermal detection\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Also, women show higher cold-wetness perception at the skin, which is associated with thermal discomfort\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, and have higher unpleasantness and pain intensity ratings for extreme temperatures\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The reasons for sex differences in temperature and pain sensation, perception and thermoregulatory responses are still unknown and it is unclear, which roles the sex hormones testosterone and estrogen play\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMultiple levels of temperature signaling may be involved. Free nerve endings of C-fibers and Aδ-fibers with temperature sensitive channels/receptors (such as TRPV1, TRPM2 and TRPM8) transmit temperature signals to the dorsal horn of the spinal cord, from where spinothalamic and spinoparabrachial projections ultimately relay signals to subcortical targets in thalamus and hypothalamus. The latter sends efferent signals to effector organs to keep temperature homeostasis, e.g., via shivering, sweating or behavioral changes\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Study results on the effects of sex hormones on these pathways are contradictory. Animal data suggest that the activity of cold receptor TRPM8 is directly modulated by testosterone\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, and castration of male mice increased sensitivity to mild cold\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. While the effects of testosterone have been investigated more in depth, animal data on the molecular mechanisms mediating the action of estradiol on TRPM8 is scarce and it is not yet clear if estradiol affects receptor function\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Few studies investigated the influence of sex hormones on TRPM2 receptors, which are involved in warm perception, in elaborated animal and \u003cem\u003ein vitro\u003c/em\u003e models\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, but which have limited significance for physiology in healthy humans. To our knowledge, no human study so far investigated direct effects of sex hormones on thermosensation\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOne reason of this unsatisfactory state of knowledge is that performing prospective interventional studies with sex hormones in healthy persons is not possible. Using a cohort undergoing gender-affirming hormone therapy (GAHT) offers the unique opportunity to prospectively assess direct effects of testosterone and estrogen during therapy intraindividually when being applied to the respective other assigned sex at birth (i.e., biological sex). During GAHT, the sex hormone concentrations of the assigned sex at birth are changed to match the perceived gender. This approach helps not only to disentangle the role of sex hormones in temperature perception and sensation in human physiology, but also to gain a better understanding of the effect of GAHT, which is highly relevant for the increasing number of trans persons seeking hormonal treatment\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe hypothesized that with quantitative sensory testing and a temperature sensation questionnaire we could detect changes in temperature perception and sensation in transgender persons undergoing GAHT in the magnitude of known differences between men and women\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. We show for the first time that during GAHT in trans women temperature perception improved and suggest that sex hormone concentrations influence thermosensation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy cohort: Transgender persons and control group\u003c/h2\u003e \u003cp\u003ePatients with gender incongruence (diagnosis number after the international statistical classification of diseases and related health problems [ICD]-10 F64.0, ICD-11 HA60) were recruited at the endocrinological outpatient clinic of the University Hospital Leipzig. Measurements were performed between 01/2021 and 10/2023, as a part of a larger trial monitoring various effects of GAHT (clinicaltrials.gov registration number NCT04838249). Twelve trans women (male-to-female transgender) and 17 trans men (female-to-male transgender) participated in the study. The study is observational, the decision for GAHT was solely based on patient\u0026rsquo;s demand and clinical need, and independent from the study. The control group of persons without gender incongruence were recruited through both analog and online advertisements and were measured between 01/2021 and 10/2023, comprising 13 cis women and ten cis men. Baseline characteristics of the four groups are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Inclusion criteria for patients and control persons were age\u0026thinsp;\u0026ge;\u0026thinsp;18 years and for patients a signed informed consent about the GAHT. Exclusion criteria for both groups included serious medical conditions (e.g., uncontrolled high blood pressure, heart insufficiency, history of stroke, malignant diseases, or chronic infections), uncontrolled endocrine diseases (e.g., hypercortisolism, pituitary disease, hypo- or hyperthyroidism) and previous GAHT. All study participants consented to participating in the study.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics and laboratory data of the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eAssigned male at birth\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c8\" namest=\"c5\"\u003e \u003cp\u003eAssigned female at birth\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCharacteristics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eTrans women (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eCis men\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;10)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003ep\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eTrans men (n\u0026thinsp;=\u0026thinsp;17)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eCis women\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(n\u0026thinsp;=\u0026thinsp;13)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003ep\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.8 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.6 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.8 (4.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.4 (16.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.9 (10.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71.5 (20.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65.7 (16.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody Mass Index (kg/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.5 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.7 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.9 (7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23.0 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody surface (m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.92 (0.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.98 (0.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.83 (0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.76 (0.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody fat mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.1 (14.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.7 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.5 (13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17.4 (7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody fat free mass (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59.1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.75 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47.7 (7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47.8 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTestosterone concentration\u003c/p\u003e \u003cp\u003e(nmol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.40 (5.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.47 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.06 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.98 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstradiol concentration (pmol/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90.3 (36.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105.5 (75.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e222.0 (234.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e\u0026sect;\u0026nbsp;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e87.0 (269.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eMedian (interquartile range) and Mann-Whitney-U test for not-normally distributed data. \u003csup\u003e\u0026sect;\u003c/sup\u003en\u0026thinsp;=\u0026thinsp;9: 4 cis women, who took hormonal contraceptive with ethinylestradiol were excluded for this specific calculation; \u003csup\u003e\u0026dagger;\u003c/sup\u003emissing data of one participant.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eGender-affirming hormone therapy\u003c/h3\u003e\n\u003cp\u003eTreatment was performed following international guidelines\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, with trans women receiving estradiol and cyproteroneacetate and trans men receiving testosterone. Medication was controlled and adjusted following regular checks of blood concentrations of testosterone and estradiol. The employed preparations and concentrations are listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePreparations and concentrations used in the study for gender-affirming hormone therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 Months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 Months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTrans women\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003en\u0026thinsp;=\u0026thinsp;12\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003en\u0026thinsp;=\u0026thinsp;11\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstradiol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstradiol gel\u003c/p\u003e \u003cp\u003e0,6 mg/g, 1.25\u0026ndash;5 g/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstramon patch\u003c/p\u003e \u003cp\u003e75 \u0026micro;g/24 h\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyproteroneacetate\u003c/p\u003e \u003cp\u003e10 mg \u0026minus;\u0026thinsp;12.5 mg/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTrans men\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003en\u0026thinsp;=\u0026thinsp;17\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003en\u0026thinsp;=\u0026thinsp;13\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTestosterone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTestosterone undecanoate injection\u003c/p\u003e \u003cp\u003e1000 mg, approx. every 3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTestosterone gel\u003c/p\u003e \u003cp\u003e16.2 mg/g, 1.25\u0026ndash;2.5 g/d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eHormone therapy was performed following international guidelines\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. In trans women, estradiol was given transdermally via gel or patch, in trans men testosterone was applied transdermally via gel or intramuscularly via injection following patient\u0026rsquo;s preferences. Cyproteroneacetate was given as tablet.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eExperimental design\u003c/h3\u003e\n\u003cp\u003eBaseline measurements in patients were obtained immediately before the start and after 3 and 6 months of ongoing GAHT. In the control group, measurements were conducted at the same time intervals and study protocol was identical for both patients and controls: In the morning anthropometric data was assessed and a fasting blood draw was performed. Body surface was calculated by Mosteller formula\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Body composition (body fat mass, body fat free mass) was determined using body impedance analysis\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. At approximately 11 am, participants had lunch and at approximately 12:30 pm quantitative sensory testing was performed in the outpatient clinic of the Clinic for Neurology at the University Hospital Leipzig. Room and skin temperature at the hand were measured after entering the room. If the skin temperature was below 28\u0026deg;C, participants were instructed to hold their hands under warm water for 20 seconds, after which the temperature was measured again. After that, participants had to complete a questionnaire addressing temperature sensation (\u003cem\u003esee\u003c/em\u003e Temperature sensation questionnaire). Then, quantitative sensory testing was started, performed as described below, and skin temperature of the hand was measured again after removing the thermode.\u003c/p\u003e\n\u003ch3\u003eQuantitative sensory testing\u003c/h3\u003e\n\u003cp\u003eQuantitative sensory testing was performed using the Main Station Neurosensory Analyzer Model TSA-II (2001), Medoc, Ramat Yishay, Israel with its standard 30 x 30 mm thermode (Peltier-element) with temperature sensors and an accuracy of 0.3\u0026deg;C\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The thermode was placed at the palm as suggested by previous literature\u003csup\u003e\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e of the non-dominant hand and fixed with velcro tape. Participants were instructed to press a button with their dominant hand, as soon as they detected a change in temperature at the site of thermal stimulation. In the first set of measurements, the thermode\u0026rsquo;s temperature decreased according to the method of limits with a rate of 0.3\u0026deg;C/sec from its baseline temperature set at 32\u0026deg;C until the participant pressed the button. In the second set of measurements, the thermode\u0026rsquo;s temperature increased accordingly. Four measurements for cold perception and four for warm perception were conducted and the respective means were calculated and used for further analyses. Before the next sets of measurements, participants were instructed to press the button as soon as they felt a heat or cold induced pain. Again, starting from the skin indifference temperature of 32\u0026deg;C, the thermode\u0026rsquo;s temperature decreased/increased at a rate of 1.5\u0026deg;C/sec until the button was pressed or the lowest possible temperature of 0\u0026deg;C/highest possible temperature of 50\u0026deg;C was reached\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eTemperature sensation questionnaire\u003c/h3\u003e\n\u003cp\u003eParticipants answered an 18 question long questionnaire based on \u0026ldquo;The experienced temperature sensitivity and regulation survey\u0026rdquo;\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Statements regarding temperature sensation were rated by participants on a numeric rating scale ranging from zero to ten. The questions were designed to assess temperature sensations in everyday situations and to quantify the experience of hot and cold flushes. All questions and possible answers, as well as how questions were grouped for calculation of the two summary scores are listed in the Supplemental material.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFour cis women, who were treated with hormonal contraceptives with ethinylestradiol during the measurements were excluded for the analysis of estradiol concentrations, as ethinylestradiol suppresses endogen estradiol secretion and is not detected by our used estradiol laboratory assay (leaving nine participants in this subgroup). Due to small group sizes (\u0026lt;\u0026thinsp;20 persons) we used non-parametric tests throughout the measurements (Mann-Whitney-U test, mixed model analyses with GraphPad Prism 10.0.2, Durbin-Skillings-Mack\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e test and Conover pairwise rank comparison\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e with XLSTAT, version 2023.3.1\u0026ndash;1416). In comparison to these tests, we performed Friedman\u0026rsquo;s and Dunn\u0026rsquo;s test under exclusion of participants with missing data and results are reported in the supplement. Correlation analyses between temperature detection thresholds and age, body mass index (BMI), fat mass, fat free mass, room temperature and average monthly temperature were performed with GraphPad Prism 10.0.2 using Spearman correlation including all baseline measurements. Correlation analyses of fat mass and fat free mass were separately calculated for assigned female and male sex at birth due to sex differences in body composition.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAnthropometric and laboratory parameters\u003c/h2\u003e \u003cp\u003eBaseline characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. As expected, testosterone serum concentrations decreased in trans women during 6 months of GAHT (p\u0026thinsp;\u0026le;\u0026thinsp;0.0001) (Conover\u0026rsquo;s procedure: 0 vs. 3 months p\u0026thinsp;\u0026le;\u0026thinsp;0.05, 0 vs. 6 months p\u0026thinsp;\u0026le;\u0026thinsp;0.05, 3 vs. 6 months p\u0026thinsp;\u0026ge;\u0026thinsp;0.05) and estradiol concentrations increased (p\u0026thinsp;=\u0026thinsp;0.001) (Conover\u0026rsquo;s procedure: 0 vs. 3 months p\u0026thinsp;\u0026le;\u0026thinsp;0.05, 0 vs. 6 months p\u0026thinsp;\u0026le;\u0026thinsp;0.05, 3 vs. 6 months p\u0026thinsp;\u0026ge;\u0026thinsp;0.05). In trans men, testosterone concentrations increased (p\u0026thinsp;\u0026le;\u0026thinsp;0.0001) (Conover\u0026rsquo;s procedure: 0 vs. 3 months p\u0026thinsp;\u0026le;\u0026thinsp;0.05, 0 vs. 6 months p\u0026thinsp;\u0026le;\u0026thinsp;0.05, 3 vs. 6 months p\u0026thinsp;\u0026ge;\u0026thinsp;0.05), while serum estradiol concentrations did not change (p\u0026thinsp;=\u0026thinsp;0.602). Neither testosterone concentrations in cis men and cis women (p\u0026thinsp;=\u0026thinsp;0.471 and p\u0026thinsp;=\u0026thinsp;0.743), nor estradiol concentrations (p\u0026thinsp;=\u0026thinsp;0.762 and p\u0026thinsp;=\u0026thinsp;0.725) changed. In the interaction analysis between trans women and cis men there were differences in testosterone (p\u0026thinsp;\u0026le;\u0026thinsp;0.0001) and estradiol (p\u0026thinsp;=\u0026thinsp;0.03) concentration-changes over the study period, between trans men and cis women there were differences in testosterone concentration-changes (p\u0026thinsp;\u0026le;\u0026thinsp;0.0001), but not in estradiol concentrations (p\u0026thinsp;=\u0026thinsp;0.58, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eQuantitative sensory testing for temperature perception\u003c/h2\u003e \u003cp\u003eCorrelation analyses including all baseline measurements showed no significant correlations between \u0026ldquo;cold\u0026rdquo; and \u0026ldquo;warm\u0026rdquo; detection thresholds and age, BMI, fat mass, fat free mass and the average monthly temperatures at the time of the measurements (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Room temperature correlated with \u0026ldquo;warm\u0026rdquo; detection thresholds (r=-0.32, p\u0026thinsp;=\u0026thinsp;0.028) (Suppl. Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e), but not with \u0026ldquo;cold\u0026rdquo; detection thresholds (r\u0026thinsp;=\u0026thinsp;0.17, p\u0026thinsp;=\u0026thinsp;0.26).\u003c/p\u003e \u003cp\u003eIn quantitative sensory testing, median (interquartile range) threshold values for discriminating \u0026ldquo;cold\u0026rdquo; and \u0026ldquo;warm\u0026rdquo; at baseline measurement were in persons assigned female at birth lower (-1.04 [0.73] and 1.31 [0.74] \u0026deg;C) than in persons assigned male at birth (-1.50 [1.34] and 1.83 [0.81] \u0026deg;C) (p\u0026thinsp;=\u0026thinsp;0.006 and p\u0026thinsp;=\u0026thinsp;0.01; Cohen\u0026rsquo;s d 0.73 and 0.74) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003eIn trans women, over the period of 6 months of GAHT, the thresholds for both \u0026ldquo;cold\u0026rdquo; (p\u0026thinsp;=\u0026thinsp;0.004) and \u0026ldquo;warm\u0026rdquo; (p\u0026thinsp;=\u0026thinsp;0.045) detection decreased (both p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 in \u003cem\u003epost-hoc\u003c/em\u003e tests). There were no changes in temperature detection thresholds in trans men (p\u0026thinsp;=\u0026thinsp;0.75 and p\u0026thinsp;=\u0026thinsp;0.82), cis women (p\u0026thinsp;=\u0026thinsp;0.95 and p\u0026thinsp;=\u0026thinsp;0.19), and cis men (p\u0026thinsp;=\u0026thinsp;0.10 and p\u0026thinsp;=\u0026thinsp;0.29) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). In the interaction analysis, neither between trans women and cis men there were significant differences in \u0026ldquo;cold\u0026rdquo; and \u0026ldquo;warm\u0026rdquo; threshold-changes (p\u0026thinsp;=\u0026thinsp;0.89 and p\u0026thinsp;=\u0026thinsp;0.98), nor between trans men and cis women (p\u0026thinsp;=\u0026thinsp;0.54 and p\u0026thinsp;=\u0026thinsp;0.58).\u003c/p\u003e \u003cp\u003eMann-Whitney-U and Wilcoxon test, respectively, did not show statistically significant differences in room temperature at measurements between assigned sexes at birth at baseline and in trans women over the three measurements in 6 months (data not shown).\u003c/p\u003e \u003cp\u003eTemperature threshold for pain sensation (i.e. \u0026ldquo;cold pain\u0026rdquo; or \u0026ldquo;heat pain\u0026rdquo;) did not differ between the assigned sexes at birth, nor were there changes in this measure in any of the four study groups over the study period (data not shown).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTemperature sensation questionnaire\u003c/h2\u003e \u003cp\u003eCorrelation analyses showed no correlations between \u0026ldquo;summary score cold\u0026rdquo; and age, BMI, fat mass, fat free mass, current room temperature and the average monthly temperatures at the time of the measurements (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). \u0026ldquo;Summary score warm\u0026rdquo; showed no correlation with age, fat mass, fat free mass, current room temperature and the average monthly temperatures at the time of the measurement (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), but a positive correlation with BMI (r\u0026thinsp;=\u0026thinsp;0.32, p\u0026thinsp;=\u0026thinsp;0.022) (Suppl. Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe did not find differences in summary scores for cold and warm feelings in daily situations at baseline between persons assigned female and male at birth, and no changes during the period of 6 months of GAHT in neither group (data not shown).\u003c/p\u003e \u003cp\u003eWe did not find differences in the occurrence of cold and hot flushes as reported by questionnaires at baseline between persons assigned female and male at birth (p\u0026thinsp;=\u0026thinsp;0.95 and p\u0026thinsp;=\u0026thinsp;0.06). Trans men reported over the period of 6 months of GAHT an increase in sudden feelings of coldness (p\u0026thinsp;=\u0026thinsp;0.034, post-hoc: non-significant in Conover\u0026rsquo;s procedure), but no changes in hot flushes (p\u0026thinsp;=\u0026thinsp;0.56). No changes in sudden feelings of coldness and heat were detected in trans women (p\u0026thinsp;=\u0026thinsp;0.77 and p\u0026thinsp;=\u0026thinsp;0.56), cis men (p\u0026thinsp;=\u0026thinsp;0.24 and p\u0026thinsp;=\u0026thinsp;0.32) and cis women (p\u0026thinsp;=\u0026thinsp;0.94 and p\u0026thinsp;=\u0026thinsp;0.55) (data not shown).\u003c/p\u003e \u003cp\u003eResults of the evaluation of the room temperature and all statistical analyses calculated with Friedman- and Dunn\u0026rsquo;s Test under exclusion of participants with missing data are presented in the Supplemental material. These control analyses qualitatively supported the results from the main analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWhen measuring temperature detection thresholds using quantitative sensory testing, we saw 1) lower warm and cold detection thresholds in persons assigned female at birth compared to male at birth, which is in accordance with previous literature\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e and 2) a threshold reduction over the observation period of six months in persons assigned male at birth treated with estrogen and testosterone blockers.\u003c/p\u003e \u003cp\u003eA possible mechanism leading to the observed effects is that testosterone interacts with the androgen receptor and TRPM8 and reduces the channel activity of the cold receptor TRPM8. This is supported by a study in mice where hypogonadism was induced in male animals through castration and they became more sensitive to mild cold\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, data on the effects of testosterone on TRPM8 is inconclusive; e.g., in a cell culture study, testosterone activated the cold receptor TRPM8 and opened it completely in lipid layers\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Also, estrogen may influence receptor signaling\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. E.g., in the luteal phase of the female menstrual cycle when progesterone and estrogen concentrations are higher than in the follicular phase, the threshold for cold perception is lower\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. However, data on the effects of estradiol on temperature receptors are scarce and it is not yet clear if the molecule affects receptor function\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnother mechanism that could contribute to the improvement of temperature detection thresholds in trans women undergoing GAHT may be the skin softening effect of therapy. In cis persons, skin thickness is different in men vs. women\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. After start of GAHT, softening of skin is observable already after three to six months of GAHT\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. In a study using a thermal model describing the temperature evolution in skin, thicker skin seemed to decrease thermal perception\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. However, another study investigating only male participants did not find associations between skin thickness at the fingertip and thermotactile perception\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Having investigated the first 6 months of GAHT, we cannot say whether the changes in temperature perception in trans women will persist during lifelong treatment, increase, or vanish after adaption to the new hormonal situation. Bodily changes in trans women under GAHT, e.g., breast growth, redistribution of body fat or decrease of the growth rate of body hair have a visible onset after three to six months after the start of GAHT and reach their maximum after two to five years of GAHT\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn trans men who were treated with testosterone, we did not see significant changes in temperature perception. In this group, testosterone serum concentrations increased from the female reference range to within the male reference range through therapy. However, usually during the first 6 months of treatment with testosterone, the hypothalamic-pituitary-gonadal axis is not yet suppressed and still gonadotropin releasing hormone, luteinizing/follicle stimulating hormone and consequently estradiol are secreted. The process of hypothalamic-pituitary-gonadal axis suppression though testosterone therapy with inhibition of ovulation and menstrual bleeding, and accompanying decease of ovarian estrogen secretion in many patients takes longer\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Also in the sample of trans men studied here, median estrogen concentrations after 6 months of treatment were not yet reduced compared to baseline measurements.\u003c/p\u003e \u003cp\u003eLimitations to our study include that, first, our group sizes are relatively small for conducting a clinical study. However, the median temperature detection thresholds in our group were 0.3\u0026deg;C lower in persons assigned female at birth than in persons assigned male at birth, which was in the range of 0.2\u0026ndash;0.4\u0026deg;C described before in the cohort of 1252 participants\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Second, as our results did not withstand the interaction analysis we cannot be sure that GAHT was causal for observed effects, but measurements in trans persons may have changed over the study period for different reasons (e.g., habituation to the study procedures). Nevertheless, this study tried to minimize this limitation as control groups underwent the same measurements in the same time intervals.\u003c/p\u003e \u003cp\u003eOur findings are especially of importance, since there is an increase in the prescription of GAHT\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e in transgender persons and our study helps to gain further knowledge of changes in body physiology in persons undergoing GAHT. Considering that thermosensation also influences body temperature regulation\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, a better understanding of how sex hormones influence temperature sensation is also important for persons exposed to more extreme temperatures due to climate change. To investigate underlying mechanisms which are causal for the observed changes in temperature perception, subsequent studies are necessary.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eTaken together, in our study we show for the first time, that temperature perception thresholds decreased in persons with male testosterone serum concentrations during treatment with estrogen and testosterone blockers, and thus transitioned to a female hormonal situation. With our study setup and methods, in trans women under GAHT we found changes over time in temperature perception that were comparable to the differences between assigned sexes at birth. Future studies are needed to assess the mechanisms behind these changes to gain a better physiological understanding of how sex hormones affect temperature perception.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure statements:\u0026nbsp;\u003c/strong\u003eHaiko Schl\u0026ouml;gl received financial support for this study from Besins Healthcare. Matthias Bl\u0026uuml;her received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGrants or fellowships supporting the writing of the paper:\u0026nbsp;\u003c/strong\u003ePauline Zimmermann and Franziska Labinski received a 6 months scholarship from the German Diabetes Society (\u003cem\u003eDeutsche Diabetes Gesellschaft e.V\u003c/em\u003e.) during their medical studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e NCT04838249.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). The Ethics Committee of the University of Leipzig approved this research project (approval no. 023/20-ek), according to the national research ethics regulations. All participants gave their written consent for all study procedures.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and material\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due patient confidentiality. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eHaiko Schl\u0026ouml;gl received financial support for this study from Besins Healthcare. Matthias Bl\u0026uuml;her received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePauline Zimmermann and Franziska Labinski received a 6 months scholarship from the German Diabetes Society (\u003cem\u003eDeutsche Diabetes Gesellschaft e.V\u003c/em\u003e.) during their medical studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePZ: data analysis, conduction of the study, writing, reviewing and editing of the manuscript; MK: conduction of the study, reviewing and editing of the manuscript; TB: conduction of the study, reviewing and editing of the manuscript; LM: conduction of the study, reviewing and editing of the manuscript; FL: conduction of the study, reviewing and editing of the manuscript; FE: reviewing and editing of the manuscript; MB: funding acquisition, resources, reviewing and editing of the manuscript; MS: funding acquisition, resources, reviewing and editing of the manuscript; SH: conceptualization, conduction of the study, reviewing and editing of the manuscript; HS: conceptualization, funding acquisition, data analysis, conduction of the study, project administration, writing, reviewing and editing of the manuscript. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all participants for their partaking in the study. We thank Jens Przybilla and Paul Czechowski for statistical advice. We thank Natalia Schischkarjow, Bj\u0026ouml;rn Drechsler-Kryst, Lotte Oldenburg and Antonia Stengler for helping to conduct the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGreenfield, A. M., Alba, B. K., Giersch, G. E. W. \u0026amp; Seeley, A. D. Sex differences in thermal sensitivity and perception: Implications for behavioral and autonomic thermoregulation. Physiol. Behav. 263, 114126 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagashima, K., Tokizawa, K. \u0026amp; Marui, S. Thermal comfort. Handb. Clin. 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Physiol. 119, 771\u0026ndash;780 (2019).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Transgender, gender-affirming hormone therapy (GAHT), sex differences, temperature perception, temperature sensation, quantitative sensory testing (QST)","lastPublishedDoi":"10.21203/rs.3.rs-5967812/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5967812/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTemperature perception differs between the two biological sexes male and female with lower thermal detection thresholds found in women compared to men. \u0026nbsp;However, underlying mechanisms of these differences and the influences of sex hormones are not yet sufficiently understood.\u003c/p\u003e\n\u003cp\u003eTo assess the effects of sex hormones on temperature perception, we measured temperature detection and pain thresholds with quantitative sensory testing and subjective temperature sensation in transgender patients undergoing gender-affirming hormone therapy (GAHT). We included 12 trans women (male-to-female transgender) and 17 trans men (female-to-male transgender) before and 3 and 6 months after start of GAHT. As a control group, we also measured 13 cis women and 10 cis men without hormone treatment at the same timepoints.\u003c/p\u003e\n\u003cp\u003eTemperature detection thresholds in persons assigned female at birth at baseline were lower than in persons assigned male at birth. Accordingly, in trans women, temperature detection thresholds improved with feminizing GAHT. Pain detection thresholds did not differ between assigned sexes at birth and did not change with time.\u003c/p\u003e\n\u003cp\u003eIn a group of trans women undergoing GAHT with estrogen and cyproteroneacetate, for the first time we could show that the ability to detect changes in temperature detection improved, which is in congruence with a higher temperature sensitivity of women compared to men. Future studies need to assess at which neurobiological processing stages the relevant changes occur and what molecular mechanisms play a role.\u003c/p\u003e","manuscriptTitle":"Changes in temperature perception in transgender persons undergoing gender-affirming hormone therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-12 11:41:54","doi":"10.21203/rs.3.rs-5967812/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b7623cab-5279-439a-948c-fbc49d482118","owner":[],"postedDate":"March 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":44694904,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases"},{"id":44694905,"name":"Health sciences/Neurology/Neurological disorders"},{"id":44694906,"name":"Biological sciences/Physiology"}],"tags":[],"updatedAt":"2026-03-17T07:07:31+00:00","versionOfRecord":{"articleIdentity":"rs-5967812","link":"https://doi.org/10.1038/s43856-026-01420-0","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2026-02-07 05:00:00","publishedOnDateReadable":"February 7th, 2026"},"versionCreatedAt":"2025-03-12 11:41:54","video":"","vorDoi":"10.1038/s43856-026-01420-0","vorDoiUrl":"https://doi.org/10.1038/s43856-026-01420-0","workflowStages":[]},"version":"v1","identity":"rs-5967812","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5967812","identity":"rs-5967812","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}