Abstract
Background
The risk of inflammatory diseases is sex-dependent, but it remains unknown whether this is due to the impact of sex hormones or sex chromosomes. Transgender individuals represent a unique cohort for studying the relative influence of endocrine and chromosomal factors. Here we compared serum levels of B-cell activating-factor (BAFF) and tumor necrosis factor (TNF) in transgender men (TM), transgender women (TW), cisgender women (CW) and cisgender men (CM).
Methods
BAFF and TNF were measured in the serum of 26 CW, 30 CM, 27 TM and 16 TW individuals. To determine the responsiveness of immune cells, TNF was measured in bacterial lipopolysaccharide (LPS)-treated peripheral leukocytes.
Results
BAFF was higher in CF (998 pg/mL) and TW (973 pg/mL) compared to CM (551 pg/mL) (P < 0.0001) and TM (726 pg/mL) (P < 0.0001). No difference in BAFF levels was shown between subjects grouped according to the number of X chromosomes. TNF was higher in CM (174 pg/mL) than TW (2.3 pg/mL) (P = 0.027) and TM (27.4 pg/mL) (P = 0.028). LPS-induced TNF was higher in CM (2524 pg/mL) and TM (2078 pg/mL) than in CW (1332 pg/mL) (both P < 0.0001) and TW (1602 pg/mL) (both P = 0.009).
Discussion
Sex hormones and sex chromosomes have different impacts on cytokines involved in the sex-dependent inflammatory response. The concentration of BAFF and LPS-stimulated TNF secretion depended on sex hormone levels, whereas basal TNF was regulated by both sex hormone-dependent and -independent factors.
Introduction
Low-grade systemic inflammation is associated with multiple conditions including cardiovascular disease, metabolic disease and osteoporosis and is the result of sustained activation of immune cells. The contribution of sex and sex hormones in immune responses and inflammatory diseases has been well established. Women are more prone to autoimmune/autoinflammatory diseases than men (1, 2).
Several factors have been suggested as causes of the differences among men and women in immune responses and susceptibility to autoimmunity and inflammatory diseases. B-cell activating factor (BAFF) also known as tumor necrosis factor (TNF) ligand superfamily member 13B is a cytokine of the TNF family that is causally linked to the development of autoimmunity as polymorphisms in the gene encoding for BAFF have been associated with the risk for systemic lupus erythematosus and multiple sclerosis (3). BAFF is expressed at higher levels in healthy women than in men and has been suggested to be regulated by sex hormones. BAFF suppression by testosterone has been demonstrated in animal studies and indirectly in humans when comparing men with high and low testosterone levels (4). In contrast, estrogens have been demonstrated to induce BAFF expression both in cells originating from males and females in murine and human cell culture models, but in male-derived cells, the induction was lower than that observed in female-derived cells, suggesting a contribution of factors other than sex hormones in its regulation (5, 6). The extent to which hormones and sex chromosomal complement contribute to BAFF expression has not been elucidated.
TNF, a pleiotropic cytokine elevated in most inflammatory conditions, has – in contrast to BAFF – been found at lower levels in cisgender women (CW) than cisgender men (CM), and its induction in acute inflammatory conditions is lower in females than males (7). In the context of obesity and metabolic syndrome, serum TNF was higher in CM than in CW, indicating gender dimorphism in its regulation (8). Nevertheless, both estrogens and testosterone directly suppress TNF production from immune cells (9), and testosterone deficiency has been associated with elevated serum TNF levels (10, 11).
Thus, whereas the roles of BAFF and TNF in the pathogenesis of autoimmunity and low-grade systemic inflammation are well established, the extent of the contribution of genetically vs hormonally determined gender has only been investigated in animal models, whereas the evidence from studies in humans is only indirect.
Transgender individuals are characterized by incongruence between gender identity and visible sexual anatomy and may identify as a different gender from the one assigned at birth (i.e. a binary identity – male or female) or a non-binary identity. Some transgender individuals undergo hormonal treatment and sex-affirming surgery to make their physical appearance more congruent with their gender identity (Olsson et al. 2003). Transgender men (TM) on masculinizing hormone therapy receive gender-affirming hormone treatment with testosterone in the same dose regimens as CM with hypogonadism. Transgender women (TW) on feminizing hormone therapy receive androgen-depriving or blocking therapy (cyproterone acetate, gonadotrophin-releasing hormone (GnRH)-analogs or aldosterone antagonists) in addition to estrogens.
The aim of the present work was to elucidate the role of sex chromosomes and sex hormones in the regulation of BAFF and TNF expression, two cytokines of the TNF family that have been associated with sex hormone regulation. For this purpose, we analyzed serum samples collected from a cohort consisting of healthy CM and CW as well as healthy TM and TW with no diagnosed inflammatory diseases, the two latter groups receiving hormonal treatment for at least 3 years.
Subjects and methods
Individuals included in the study
Inclusion criteria: healthy TW or TM aged 30–55; hormonal treatment with estrogens (TW) or testosterone (TM) for at least 3 years; gonadectomy at least 3 years prior to the study. All TW subjects were previously shown to be 46,XY, whereas the karyotype for all TM was 46,XX. Only transgender individuals desiring full masculinization or feminization were included in the study.
Exclusion criteria: Smoking, cortisone or interferon treatments in the last 3 months, recent infections or inflammatory diseases, HIV infection anti-diabetic/insulin therapy, opioids, glucocorticoids or any other anti-inflammatory medication.
TW and TM healthy individuals were recruited among individuals followed at the Reproductive Medicine Center at Skåne University Hospital, Malmö, Sweden.
A total of 87 TM individuals were contacted by telephone and 31 were interested in participating. Twenty-seven TM individuals were finally recruited for the study. Among the remaining 60 subjects, weight, blood lipids and hormone data were available on 22 for comparison with those from participants.
A total of 59 TW individuals were contacted, 19 were interested and 16 were finally included in the study. Among the non-participants, data from 16 were available.
Baseline characteristics among participants and non-participants are included in Table 1.
Comparison of baseline characteristics of participants and non-participants among transgender individuals. Values presented with mean (s.d.).
| TW | TM | |||
|---|---|---|---|---|
| Participants (n = 16) | Non-participants (n = 16)a | Participants (n = 27) | Non-participants (n = 22)b | |
| Age (years) | 41.6 (10.5) | 38.2 (8.1) | 33.4 (8.3) | 37.1 (7.17) |
| Weight (kg) | 76.7 (13.2) | 76.9 (10.4) | 73.14 (12.37) | 78.3 (13.4) |
| Cholesterol (mmol/L) | 4.55 (0.83) | 4.25 (0.84) | 4.39 (1.06) | 5.06 (1.08) |
| Triglycerides (mmol/L) | 0.96 (0.42) | 1.45 (1.52) | 1.19 (0.71) | 2.1 (1.61) |
| LDL (mmol/L) | 2.96 (0.71) | 2.78 (0.94) | 3.06 (1.05) | 3.33 (1.04) |
| LH (IU/L) | 17.04 (16.4) | 13.8 (14.6) | 6.10 (8.86) | 6.14 (8.27) |
| FSH (IU/L) | 25.23 (24.8) | 23.5 (31.9) | 10.1 (21.9) | 7.21 (12.40) |
| TSH (mIU/L) | 2.19 (1.46) | 2.62 (1.72) | 1.87 (0.98) | 2.39 (1.06) |
| Testosterone (nmol/L) | 0.70 (0.72) | 0.74 (1.23) | 26.0 (10.02) | 19.9 (9.4) |
| Estradiol (pmol/L) | 487 (539) | 586 ( 533) | 182.3 (85.8) | 183.9 (69.9) |
| SHBG (nmol/L) | 64.3 (31.7) | 70.7 (41.32) | 30.9 (12.4) | 31.2 (7.2) |
aNot included due to smoking (n = 3), refusal to participate (n = 1), dropout (n = 5), lives in distant region of the country (n = 1), cortisone treatment (n = 1), not orchidectomized (n = 4) and low compliance with hormone therapy (n = 1).
bNot included due to smoking (n = 3), refusal to participate (n = 2), dropout (n = 8), lives in distant region of the country (n = 5), ongoing glucocorticoid therapy (n = 2) and ongoing infection (conjunctivitis, n = 1 and sinusitis, n = 1)
FSH, follicle-stimulating hormone; LDL, low density lipoproteins; LH, luteinizing hormone; SHBG, sex hormone binding globulin; TM, transgender men; TSH, thyroid-stimulating hormone; TW, transgender women.
A group of 30 age-matched healthy CM and 26 age-matched healthy CW was also included in the study as control comparison groups. They were recruited among healthy individuals who participated in two previous studies (11, 12) and called to participate and provide fresh samples for this study. Selection in the control comparison groups was made according to the inclusion and exclusion criteria for the study group without taking into account information available from earlier studies. Furthermore, for the CW control group, inclusion criteria included within reference values of estradiol, and for the CM comparison group, no history of infertility and not receiving any fertility treatment or currently being treated for serious medical illness.
Information on current medication, BMI and waist circumference was collected.
The research project was approved by the Ethical Committee of Lund University/Swedish Ethical Review Authority, approval number 76/2017-2Mar2017. All participants signed an informed consent form after receiving written and oral information about the project.
Hormone therapy
Background characteristics are presented in Table 1. TM group received testosterone in form of injection (Nebido®) except three individuals who received it in the form of gel (Tostrex®). In the TW group, two subjects received per oral estradiol (Estradot®), four received estradiol both per orally and as gel (Estradot® and Divigel®), five received estradiol phosphate injections (Estradurin®) and five received Divigel® alone.
Sample collection and analysis
Fasting blood samples were collected before 10:00 h. Fasting plasma glucose was assessed with an automated hexokinase method and fasting insulin levels in serum were measured with an immunometric sandwich assay (Clinical Chemistry Laboratory, SUS, Malmö, using COBAS Roche system). In order to ensure that the TM, TW and comparison groups did not differ as considers insulin sensitivity, which may be associated with metabolic inflammation, HOMA-IR (homeostatic model assessment for insulin resistance) was calculated using the formula HOMA-IR = (Glucose) × (Insulin)/22.5, where glucose and insulin were expressed in molar units.
Serum total testosterone (TT) concentration was measured by a two-step competitive immunoassay using a luminometric technique (Electro ChemiLuminiscence Immunoassay (ECLI); lowest detection level 0.087 nmol/L; imprecision (CV%), 2.4% at 1.9 nmol/L and 4.0% at 25.5 nmol/L). Luteinizing hormone levels were determined with a one-step immunometric sandwich assay using a luminometric technique (ECLI); lowest detection level 0.10 IU/L; CV%, 2.0% at 5.0 IU/L and 2.2% at 55.2 IU/L; FSH levels were measured with a one-step immunometric assay (ECLI); lowest detection level 0.10 IU/L; CV%, 1.8% at 1.2 IU/L and 1.5% at 50.4 IU/L (Cobas, Roche); estradiol concentrations in serum were measured by an immunofluorometric method (DELFIA Estradiol, Wallace OY; lowest detection level 8 pmol/L; CV%, 20% at 30 pmol/L and 10% at 280 pmol/L. BAFF (lowest detection level 1.01 pg/mL; CV 6.5% at 433 pg/mL) and TNF (lowest detection level 1 pg/mL; CV 5.5% at 93 pg/mL) were measured by ELISA (purchased from R&D Systems for BAFF and from OriGene for TNF, Cat No EA100365). All measured specimens gave values within the detection range with the exception of basal TNF levels in some samples, being below the lowest detection limit of the assay. For these samples, the lowest detection limit value was attributed to allow statistical analysis.
To determine the direct contribution of sex hormones on the responsiveness of peripheral blood cells to a pro-inflammatory stimulus such as this from Gram (−) bacterial lipopolysaccharide (LPS), we stimulated whole blood with 100 ng/mL LPS and measured the production of TNF. For this purpose, peripheral blood was collected in EDTA tubes (BD-Vacutainer, 3 mL of blood, one tube per participant) and stimulated ex vivo with E. coli LPS (Sigma, serotype O111:B4, cat. #L2630) for 4 hours at 37°C with constant agitation on a rotating shaker at 5–10 rpm. Following incubation, plasma was collected by centrifugation at 850 g for 10 min and TNF was measured. Plasma was diluted in 1:10 in the sample dilution buffer provided by the manufacturer (OriGene, Rockville, MD, USA).
Statistical analysis
The group-specific values are presented as mean ± s.d. For statistical analysis, the TNF values below lowest detection limit were assigned a value of 0.5 pg/mL. Pairwise comparisons (CM, CW, TM, TW) were performed using linear regression models adjusted for age. Additionally, comparisons were made between gender groups defined by hormonal (CM + TM vs CW + TW) as well as chromosomal (46,XX vs 46,XY) status (CM + TW vs CW+TM), respectively. The condition for using parametric methods was validated by showing the normal distribution of the residuals. Correction for multiple comparisons was not performed due to the fact that the analyses were hypothesis-driven (i.e. markers were not randomly chosen). For statistical analysis, SPSS Statistics version 25.0 (IBM) was applied.
Results
Background characteristics
The characteristics of the cohort are shown in Table 2. HOMA-IR was similar among the groups analyzed. In addition, TT levels differed between CM and TM groups being twice as high in the TM group (P < 0.0001) whereas estradiol serum levels did not differ between CW and TW groups (Table 2).
Background characteristics of participants.
| CW mean (95% CI) | CM mean (95% CI) | TW mean (95% CI) | TM mean (95% CI) | |
|---|---|---|---|---|
| Age | 35.9 (32.5–39.2, n = 22) | 46.0 (43.6–48.4, n = 30) | 41.6 (36.1–47.3, n = 14) | 33.4 (30.1–36.6, n = 23) |
| BMI | 23.51 (23.02–23.99, n = 22) | 26.15 (23.1–29.2, n = 30) | 24.94 (22.6–27.3, n = 16) | 26.04 (24.7–27.4, n = 27) |
| Total testosterone (nmol/L) | ND | 13.5 (11.2–15.8, n = 30) | 0.7 (0.3–1.08, n = 16) | 25.3 (21.3–29.4, n = 27) |
| LH (IU/L) | 11.5 (6.4–16.5, n = 21) | 4.7 (3.9–5.4, n = 30) | 16.0 (7.2–24.7, n = 16) | 5.7 (2.2–9.0, n = 27) |
| FSH (IU/L) | 9.2 (4.06–14.4, n = 21) | 5.4 (4.0–6.7, n = 30) | 25.2 (11.6–38.5, n = 16) | 10.1 (1.4–18.7, n = 27) |
| Estradiol (pmol/L) | 525.7 (308–742, n = 21) | ND | 487 (144–748.2, n = 16) | 182.3 (141.7–209.7, n = 27) |
| HOMA-IR | 1.6 (1.5–1.7, n = 22) | 1.7 (1.2–2.2, n = 25) | 2.1 (1.5–2.7, n = 16) | 2.0 (1.7–2.4, n = 27) |
CM, cisgender men; CW, cisgender women FSH, follicle-stimulating hormone; HOMA-IR, homeostatic model for insulin resistance; LH, luteinizing hormone; ND, not determined; TM, transgender men; TW, transgender women.
BAFF serum levels
BAFF serum levels were significantly associated with hormonally defined sex being highest in CW and in TW, followed by TM and CM presenting with the lowest concentrations. The two former groups did not differ statistically significantly from each other, whereas the difference between the two latter was statistically significant (P = 0.012) (Fig. 1A and Table 3), following adjustment for age.
BAFF serum levels were higher in the CW and TW groups (A) and were dependent on sex hormones (B) but not on sex chromosomes (C). BAFF was measured in serum samples collected from the different participating cohorts. No difference was observed when groups were divided based on genetically determined sex. CM, cis men; CW, cis women; NS, not statistically significant; TM, transgender men; TW, transgender women; median with 95% CI is shown; ****P < 0.0001.
Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0456
Inter-group comparison of levels of basal levels of BAFF and TNF as well as LPS-stimulated TNF. For each group, mean values and 95% confidence intervals are given. Furthermore P-values for comparison between the groups.
| Factor | CW mean (95% CI, n) | CM mean (95% CI, n) | TW mean (95% CI, n) | TM mean (95% CI, n) | |
|---|---|---|---|---|---|
| BAFF (pg/mL) | 988 (898–1078, n = 19) | CW | |||
| TNF (pg/mL) | 80.7 (23–184, n = 22) | ||||
| LPS–TNF (pg/mL) | 1332 (863–1802, n = 22) | ||||
| CM | |||||
| BAFF (pg/mL) | <0.0001 | 551 (468–634, n = 29) | |||
| TNF (pg/mL) | NS | 174 (84–264, n = 30) | |||
| LPS-TNF (pg/mL) | <0.0001 | 2524 (2117–2931, n = 30) | |||
| TW | |||||
| BAFF (pg/mL) | NS | <0.0001 | 973 (866–1079, n = 14) | ||
| TNF (pg/mL) | NS | 0.027 | 2.3 (0–125.4, n = 16) | ||
| LPS–TNF (pg/mL) | NS | 0.009 | 1602 (1045–2159, n = 16) | ||
| TM | |||||
| BAFF (pg/mL) | <0.0001 | 0.012 | 0.001 | 726 (634–819, n = 23) | |
| TNF (pg/mL) | NS | 0.028 | NS | 27.4 (0 –122.3, n = 27) | |
| LPS–TNF (pg/mL) | 0.023 | NS | NS | 2078 (1649–2508, n = 27) |
BAFF, B-cell activating factor; CM, cisgender men; CW, cisgender women; LPS, lipopolysaccharide; NS, not statistically significant; TM, transgender men; TNF, tumor necrosis factor; TW, transgender women.
Aggregated group of CW + TW presented with statistically significantly higher values than CM + TM (P < 0.0001) (Fig. 1B). In contrast, no difference was observed between 46,XX vs 46,XY subjects (Fig. 1C).
Basal serum TNF levels
For basal serum TNF, the order of mean values, from highest to lowest, was CM, CF, TM and TW. Statistical significance (P = 0.028) was observed between TM as well as TW (0.028 and 0.027, respectively) and CM but not between other comparisons of groups (Table 3, Supplementary Fig. 1A, see section on supplementary materials given at the end of this article).
For comparison of the hormonally and chromosomally defined gender groups, the results did not reveal any statistically significant difference between groups aggregated based on sex hormones or sex chromosomes (Table 3, Supplementary Fig. 2B and C).
LPS-induced TNF levels
To determine the contribution of sex hormones on the responsiveness of peripheral blood cells to a pathogenic stimulus, peripheral blood was stimulated with LPS and the production of cytokines was measured in the plasma. LPS-induced TNF production was highest in CM and TM groups, whereas both CW and TW exhibited lower levels. CM and TM did not differ from each other, but the values were statistically significantly higher than CW (P < 0.0001) as well as TW (P = 0.009). No statistically significant difference was seen between CW and TW or between TW and TM (Table 3, Fig. 2A).
TNF levels in the plasma from LPS-stimulated whole blood samples. TNF was measured in the plasma following incubation with 100 ng/mL LPS for 4 hours. LPS-induced TNF was higher in CM and TM groups (A) and it depended on sex hormones (B) but not on sex chromosomes (C). CM, cis men; CW, cis women; NS, not statistically significant; TM, transgender men; TW, transgender women; median with 95% CI is shown; ****P < 0.0001; ***P < 0.001; **P < 0.01.
Citation: Endocrine Connections 12, 3; 10.1530/EC-22-0456
For comparison of the hormonally and chromosomally defined gender groups, the pattern of differences was identical to that seen for BAFF (Table 3, Fig. 2B and C).
Discussion
The association of gender with inflammatory and autoimmune diseases has been long acknowledged, but the significance of the contribution of sex hormones to this end has been documented only indirectly. Herein, we utilized a cohort of healthy CM, CW, TW and TM individuals to delineate the impact of sex hormones and sex chromosome background in regulating two key immunomodulatory cytokines, BAFF and TNF. Our study showed that hormonally rather than chromosomally defined sex is most prominently associated with BAFF serum levels as well as with the capacity of peripheral blood cells to produce TNF in response to LPS. In contrast, regulation of basal TNF levels appeared more complex, since estrogens contributed to lower levels within the 46,XY background, but testosterone was not associated with basal TNF within the 46,XX genetic background.
Recent evidence from mouse studies and hypogonadal men has shown an effect of testosterone to suppress BAFF expression (4). Estrogens have been shown to induce BAFF expression (3) in mouse splenocytes and macrophages (6), and estrogens in the serum of women have been positively associated with BAFF expression (3). Thus, our results were in accordance with these observations demonstrating stronger association of serum BAFF levels with the sex hormone status than with chromosomally defined sex. The results also are in line with the limited evidence regarding the prevalence of autoimmunity such as systemic lupus erythematosus in TW (4, 13, 14).
Testosterone levels in men have been strongly associated with cardiovascular diseases and elevated inflammatory cytokines, including TNF (15, 16, 17, 18). Sex hormones have been shown to directly regulate the capacity of immune cells to produce TNF in culture. Estrogen treatment suppresses TNF production in mice (9, 19) and the effect is dose-dependent (20). Testosterone also potently suppresses TNF production from immune cells (21). Our findings showed that TNF was higher in CM when compared to TW or TM groups, indicating that supplementation with estrogens in the TW group may contribute to reduced serum TNF. TNF increases after menopause and its increase is associated with the development of cardiovascular disease, osteoporosis and other inflammatory-driven diseases (22, 23). Nevertheless, testosterone seemed to suppress TNF, since TM subjects, having testosterone levels significantly higher than the CM group, presented with statistically lower concentrations of this cytokine. This finding, which is in accordance with previous reports (11, 20), suggests that testosterone supplementation to physiological levels as reached in the TM group may suppress basal inflammation. The fact that CM had higher basal TNF levels compared to TM suggests that additional factors that do not depend on sex hormones contribute to the regulation of the basal levels of this cytokine. Even though multiple cytokines have been reported to be affected by sex hormones, our study focused on TNF as a widely studied and representative cytokine of inflammatory status.
The magnitude of immune responses to pathogens and damage signals differs between sexes and females produce less TNF in response to TLR stimuli (1, 24). Our study focused on the response of peripheral blood cells to LPS, a TLR4 ligand, being highly expressed in antigen-presenting cells such as monocytes, macrophages and dendritic cells and the major source of TNF in response to a Gram (−) bacterial challenge. The results showed that LPS-induced TNF was dependent on sex hormones, being higher in CM and TM groups compared to CW and TW groups. Therefore, even though basal TNF is controlled by both sex hormone-dependent and independent factors, responsiveness to an acute inflammatory signal depends on sex hormones, with estrogens known to have the capacity to suppress inflammatory responses. In a recent study, peripheral blood mononuclear cells from TM receiving testosterone in the process of transitioning to TM became gradually more responsive to LPS (25). Therefore, upon infection CM and TM groups are more likely to exhibit an augmented response than CW and TW. For example, in the context of infectious pneumonia, men produced higher TNF than women and were more prone to developing sepsis (26), and in the context of trauma and sepsis survival of women was greater than men (27). Also, in SARSCoV-2 infections, men develop more severe symptoms and are more prone to the development of cytokine storm than women, suggesting that sex hormones or sex chromosomes contribute to the responsiveness of immune cells to infectious stimuli (28).
Strengths of this study include its unique design, allowing analyses of the contribution of sex hormones as well as sex chromosomes for the regulation of inflammatory markers. Comparison of weight, levels of blood lipids and hormones between participants and non-participants does not indicate any selection bias. The main weakness is the small number of participants, why the risk of type 2 error cannot be excluded. An additional weakness is the difference in the age of the participants, and for this reason, we corrected the analyses for age. Sex hormones and 46,XY background may affect the cellularity and ratio of different populations of peripheral blood, which has not been investigated in this study and may partly contribute to the observed differences. Furthermore, although a multivariate analysis including sex hormone levels and number of X-chromosomes as independent and BAFF/TNF as dependent variables might shed additional light on the relative impact of hormonal and chromosomal factors on the regulation of levels of those inflammatory markers, such analysis was not possible due to lack of data on estradiol levels in CM and testosterone levels in CW.
In conclusion, the present study confirms associations between sex hormones and sex chromosomes on BAFF and TNF, two cytokines that are mediating autoimmunity and inflammatory diseases. The results also provide evidence for the immunomodulatory effect of hormonal replacement therapies in transgender individuals.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-22-0456.
Declaration of interest
The authors have no conflict of interest to disclose.
Funding
This study was supported by ReproUnion (Grant number 20200407), funded by EU Regional Development Program V, The Danish Region of Capital, Region of Scania and Ferring Pharmaceuticals.
Acknowledgements
The authors would like to thank Dr. Katarina Link for contributing in patient recruitment, Prof. Y. L. Giwercman for contributing in study design and Dorota Tryzbulska for technical support.
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