Inflammation as a Potential Mechanism Contributing to Sexual Functioning Following Initiation of Gender-Affirming Hormone Therapy

Abstract

Purpose of Review

Many transgender and gender non-conforming (TGNC) people seek gender-affirming hormone therapy (GAHT). While GAHT is generally safe and increases well-being, it is essential to accurately understand potential unintended effects and risk factors to better inform and manage treatment. This narrative review covers recent literature documenting changes in sexual function following the initiation of GAHT and explores inflammation as a potential mediator of these changes.

Recent Findings

Generally, the initiation of GAHT is correlated with increased sexual desire in transgender men and decreased sexual desire in transgender women, with time-limited effects that return to levels approaching baseline after about a year; there are also changes in inflammation markers that parallel this timeline. Findings on other aspects of sexual function (e.g., orgasm, pain, and sexual quality of life) are more limited. As there is evidence from cisgender populations that inflammation acts as a mechanism by which hormones influence sexual function, we propose applying this model to TGNC people taking GAHT.

Summary

Sexual function may change in TGNC patients receiving GAHT, and those changes may be influenced by inflammation. However, these changes often return to baseline as TGNC patients’ bodies adjust to a new hormonal equilibrium.

Introduction

The CDC estimates that 60–70% of transgender and gender non-conforming (TGNC) people in the United States receive some form of gender-affirming hormone therapy (GAHT; [1], see [2] for a community sample). Substantial research on GAHT demonstrates that it is generally safe and consistently effective at decreasing gender dysphoria and increasing well-being in TGNC patients [3••, 4–7, 8•, 9]. While GAHT is associated with relatively limited impacts on mortality and morbidity [3••, 10], understanding unintended effects and risk factors is crucial for appropriately advising TGNC patients as they consider their options. Sexual functioning is an often-overlooked facet of health, but many patients consider sexual wellbeing to be an important part of gender transition and overall wellbeing [11, 12•]. Broadly, sexual function can be impacted by both psychosocial changes accompanying gender transition, such as changing levels of gender dysphoria, and medical interventions, such as GAHT and surgical procedures [3••]. While much medical literature investigates post-surgical outcomes, there is insufficient research examining the direct and indirect impacts of GAHT on sexual function [13].

Inflammation has been explored as a potential etiological mediator in the growing literature on the impacts of endogenous and exogenous hormones on sexual functioning in cisgender (cis) men and women [14]. Applying this framework to the impact of GAHT on sexual function in TGNC patients may shed light on previously unstudied indirect effects that may be worth addressing in assessment and treatment of sexual dysfunction in both cis and trans populations. This narrative review brings together the findings from the limited work on hormone treatments, inflammation, and sexual function in TGNC populations; examines related work in cis people when relevant; and explores interrelationships as possible evidence for inflammation as a mechanism contributing to sexual function in GAHT care (Fig. 1).

Fig. 1.

A theoretical model of the mediating role of infammation in the relationship between sex hormones (endogenous and exogenous) and sexual function (e.g., desire, arousal, and pain). This relationship has been theorized previously in cisgender samples; we propose applying it to the use of GAHT in TGNC samples. Potential mediating may be direct (e.g., efects of sex steroids on infammatory actors), indirect (e.g., via changes in stress physiology), or a combination of both

Interpretive Notes on Applying Research Across Populations

In this review, we summarize physiological relationships between GAHT, inflammation, and sexual function. However, the process of gender transition should be considered in the context of the biopsychosocial model. TGNC people experience unique stressors (e.g., gender dysphoria, minority stress, and transphobic discrimination) that can dramatically impact many facets of health and wellbeing, including response to GAHT [15]. In the context of this paper, there are critical psychological and social processes associated with gender transition that impact all facets of the physiological relationships we discuss (Fig. 1). The link between GAHT and inflammation is influenced by the inflammatory nature of chronic stress, which TGNC people often experience as a result of discrimination, social exclusion, and stigmatization [13]. Similarly, the link between GAHT and sexual function is influenced by the substantial social and psychological changes associated with beginning a hormonal transition. For example, GAHT has been documented to increase serotonin reuptake transporter binding [16] and reduce cortisol levels [17], which are associated with reduced anxiety and enhanced mental health quality of life [18, 19•]—which in turn can greatly impact interest in sex. Another major mediator in this relationship is body satisfaction [12•]—changes in body composition associated with hormones may be desired or undesired, and that can also have a significant impact on willingness to engage in sex or sexual satisfaction.

Another aspect of this research that is difficult to disentangle is the significant proportion of TGNC people undergoing GAHT who also receive some form of gender-affirming surgery. The CDC estimates that 20–40% of TGNC people complete at least one surgical procedure as a part of their transition [1]. Existing research often examines sexual dysfunction in TGNC people but does not separate or specify if the sample has received surgery as well as GAHT—and more controlled studies may not be possible for ethical reasons. Additionally, when TGNC people do undergo genital surgery, their concepts of sexual function and dysfunction may change with their new body. Here, we attempt to focus on the impact of GAHT without considering the additional confounding factor of surgery.

Not all TGNC people receive GAHT, and not all people that receive GAHT are TGNC. As indicated previously, up to 40% of trans people do not receive GAHT [1], which includes people who choose not to transition hormonally, people who do not have access to providers that will prescribe GAHT (although see [20]), and people who risk increased discrimination if they begin presenting differently. Additionally, hormone treatments that improve alignment to one’s preferred gender expression is not only something that is accessed by TGNC people: cis people may receive similar hormone treatments as are included under the umbrella of GAHT for many reasons, such as increasing libido and ameliorating symptoms of menopause or hypogonadism—treatment which could be affirming for their gender identities. While this paper will describe GAHT treatments as “masculinizing” or “feminizing,” it should be noted that nonbinary and genderqueer people may desire hormone treatments to create physical changes that align with their perceptions of themselves. Nonbinary people are persistently excluded from research, even in research studying outcomes in trans people (e.g., [21•, 22••]), so caution should be taken when applying the findings reported here to nonbinary people, who are likely impacted by distinct biopsychosocial factors.

Additionally, many TGNC people may be disincentivized from reporting any side effects of affirming treatment for fear that negative effects could be used for political agendas to eliminate the option of affirming care. This factor could artificially suppress reports of adverse effects that are included in these studies. It is crucial to note that TGNC people deserve the right to accurately report the positive and negative effects of their gender affirming treatments without fear this will remove access to the treatment that is best for them.

Primers on Hormone Treatments and Inflammation

Hormone Treatments

Endogenous (natural) hormones act as chemical messengers, signaling target tissues to coordinate various bodily functions, while feedback systems regulate these signals to maintain homeostasis. Exogenous (administered) hormones are chemically similar to endogenous hormones and can act on the body’s feedback pathways, amplifying or reducing the physiological response of the target tissue [23–25]. This interaction can make it difficult to identify the specific effects of exogenous hormones on bodily processes, as effects may arise out of either direct action on hormone receptors, regulation of endogenous hormone systems, or both.

The method of exogenous hormone administration can influence the effectiveness and physiological impact of the hormones, partly due to differences in metabolism. Oral administration creates a bolus processed by the liver, stimulating hepatic factors that can lead to downstream cardiovascular inflammatory responses and changes to lipid metabolism [26]. For example, oral estrogens have been associated with elevated inflammation markers [27]. Alternatively, transdermal administration has not been observed to increase coagulation, inflammatory markers, or steroid binding proteins [27]. Both oral and transdermal administrations of sex steroids (like estrogens and androgens) can alter lipid storage at different dosages; as adipose tissue is a source of inflammation, these alterations in lipid storage may be an indirect means by which hormone treatments impact inflammation.

The site of administration also influences hormonal impacts on the body. Systematic administration (e.g., pills or buccal gel tablets taken orally) requires large dosages of hormones to reach target tissues and are thus subject to higher risk of side effects [23, 28]. In contrast, local administration that occurs at the site of the target tissue (e.g. intravaginal suppositories or rings; transdermal patches or sprays) allows for lower dosages of hormones, as they are absorbed directly into the tissue [29]. Moreover, hormones administered orally must pass through the digestive system where they are metabolized in the intestines, as well as hepatically metabolized in the liver. Transdermal medications avoid this firstpass effect and thus can be administered in lower doses with shorter half-lives [30, 31]. Hormones administered locally also create lower activity in the blood and are unable to pass through the blood–brain barrier at high rates, resulting in fewer neurological effects than hormones administered systematically [30].

Hormone replacement therapies (HRT) and GAHTs target reproductive hormone systems such as estrogens, androgens, and progestins, which primarily act upon the hypothalamic pituitary gonadal (HPG) axis. However, changes to the HPG axis can also lead to changes in activity of the hypothalamic pituitary adrenal (HPA) axis, which regulates the action of glucocorticoids like cortisol. Glucocorticoids have a significant effect on regulating inflammation, with potentially pro- or anti-inflammatory effects depending on concentration and timing of HPA activity [32•]. Sex steroids, such as estrogen, progesterone, and testosterone, have an inhibitory effect on the HPA axis. Cortisol also has an inhibitory effect on the HPG axis, with varied downstream effects depending on the specific sex steroid most concentrated in the individual; these downstream effects contribute to observed sex dimorphisms seen in inflammatory responses [33]. The addition of exogenous hormones leads to regulation at the level of the hypothalamus to control downstream production or inhibition of target hormones [34]. A reciprocal pattern of estrogen and luteinizing hormone (LH) inhibits the release of ACTH from the pituitary gland [35], leading to an inhibition of the anti-inflammatory effect of the HPA axis. Inversely, activation of the HPA axis under stress leads to inhibition of sex steroid hormones, with greater effects on androgens than estrogens [35–37]. This crosstalk between reproductive and stress systems is particularly important when considering how GAHT may impact sexual function, as gender dysphoria and discrimination are significant stressors that may be influenced by gender-affirming care.

Inflammation

Inflammation refers to a variety of processes the body employs to fight infection, repair injured tissue, stimulate tissue growth, and clear waste and debris. Clinically, elevated inflammation can be identified by biological markers such as C-reactive protein (CRP), proteins such as cytokines and chemokines, chemical signals such as histamine, and activation of immune cells such as phagocytes. Certain cytokines can be designated as pro-inflammatory or anti-inflammatory, depending on the specific cell growth or action they activate [38]. While their role is complex, elevated levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), or CRP are commonly considered to indicate increased inflammation. Histamine activates immune responses in the recruitment of phagocytes, which engulf invaders and promote apoptosis of damaged cells. Finally, as the formation of clots is mediated by inflammation, other common clinical indices of inflammation include fibrinogen and d.dimer, which are elevated in baseline testing in patients with chronic inflammatory conditions [39, 40].

Inflammation has direct effects on the nervous system and vascular system, as well as indirect effects on the endocrine system. At the level of vasculature, inflammation can directly interfere with vasodilation, which in turn can interfere with genital blood flow during arousal [41]. These effects have to date been observed primarily in the case of penile erection, but it is likely that inflammation could interfere with clitoral erection as well, given similar underlying mechanisms [42]. Additionally, other aspects of arousal (increased genital sensitivity, lubrication) are directly linked to increases in blood flow to the vagina and surrounding vasculature [43, 44]; as such, inflammation may interfere with arousal processes via decreased genital blood flow. It has also been demonstrated that brain regions involved in coordination of sexual desire and arousal like the mesolimbic reward system, cingulate cortex, and thalamus [45, 46] respond to cytokine signaling, both directly on neuronal receptors [47, 48] and indirectly through interactions with neurotransmitters [49–51]. Even at low levels, pro-inflammatory cytokines can interfere with neural processing surrounding motivation and reward, including sexual desire and pleasure [52, 53]. For example, direct administration of the proinflammatory cytokine IL-6 to healthy rats results in significantly decreased effort to access appetitive rewards and lower activity in the nucleus accumbens, an area of the brain important for sexual reward [52].

Exploring Relationships Between Hormones, Inflammation, and Sexual Function in Cisgender Samples

Relationships Between Hormones and Sexual Function

Reviewing the literature exploring relationships between hormones and sexual function in cis samples guides our interpretation of more limited findings in TGNC populations. The research in cis populations clearly demonstrates that gonadal hormones contribute significantly to sexual (dys)function but also highlights that the effects can be difficult to extricate from other aspects of the biopsychosocial model [54–56]. The differential impacts between androgens and estrogens can be difficult to ascertain because testosterone and other androgens can be aromatized (converted) into estrogen in many tissues [56–58]. Additionally, the impact of exogenous hormones will depend on whether treatment includes introducing hormones (e.g. estrogen), suppressing hormones (e.g., androgen blockers), or both. In this literature, sexual function is often divided empirically into sexual dysfunction (including dysfunction surrounding desire, arousal, orgasm, and pain [15, 59, 60]) and satisfaction/pleasure (for which impacts of sex hormones are largely unknown).

There is general consensus that androgens are positively associated with sexual function and pleasure [15, 61]. In cis men, endogenous testosterone is correlated with sexual function [21•, 55, 62, 63]. Exogenous testosterone treatment can increase low sexual desire in males with hypogonadism (low levels of endogenous sex hormones) [15, 64], effectively restoring normal hormonal functioning. The effects of exogenous testosterone on the sexual function of cis women are more varied [14, 15, 21•, 55, 58]. However, research tends to agree that treatment with testosterone can increase low libido in post-menopausal or hypogonadal cis women [65–67] (again, potentially restoring hormonal function), but does not have significant effects in eugonadal pre-menopausal cis women (i.e., those with sufficient existing levels of endogenous sex hormones) [57, 68, 69].

The effects of estrogen on sexual function are more complex. In cis men, endogenous estrogen does not appear to be linked to sexual desire [58, 70] but elevated estradiol may contribute to erectile dysfunction [71]. Exogenous estrogens may reduce desire in select circumstances (e.g., prostate cancer patients and sex offenders; [58]). In cis women, endogenous estrogens facilitate vaginal lubrication and peripheral blood flow during arousal, two critical components of the physiological arousal response [21•, 55, 72, 73]. Results vary widely surrounding the impacts of exogenous estrogen on sexual function in cis women—some report an increase in desire post-menopause and post-oophorectomy [74, 75], others report that high doses of estrogen may decrease desire [76], and some report no effect [77].

Both estrogen and testosterone can impact sexual pain (e.g., [78]), both directly via changes in pain sensation and perception [79, 80] and indirectly via changes to arousal processes such as lubrication, which protect against pain with penetration[81]. Here too, there are different effects of applying exogenous hormone treatments to eugonadal vs. hypogonadal patients, which should be considered in the context of evaluating the impact of GAHT on sexual pain. For example, while testosterone treatments have been found to relieve sexual pain in hypogonadal postmenopausal women [82], studies in eugonadal transmasculine patients have found testosterone either had no effect or worsened vaginal/vulvar pain [83, 84].

Exogenous hormone treatment can also indirectly impact sexual functioning via various biopsychosocial processes that in turn affect sexual function. For example, testosterone treatment is associated with mood fluctuations in cis men [85] and weight gain in cis women [86]—symptoms that can exacerbate sexual dysfunction. The indirect effect of interest in this paper is inflammation, explored below.

Relationships Between Hormones and Inflammation

Early research on the connections between gonadal hormones and inflammation presented simple relationships, with androgens characterized as anti-inflammatory and estrogens as pro-inflammatory [87]. More recent research has elucidated more nuance. The inflammatory impact of endogenous estrogen has been found to depend on its concentration—high levels can be anti-inflammatory, while low levels can be pro-inflammatory [88–91]. The impact of progesterone often depends on the concentration of cooccurring estrogen—it is generally considered to be weakly anti-inflammatory on its own but can work to inhibit inflammation at high concentrations of estrogen [89, 92]. In the other direction, inflammation can contribute to reductions in estrogen and progesterone synthesis—creating a regulatory feedback loop [88]. The impact of exogenous estrogen appears to depend significantly on the administration—oral estrogen increases CRP and other inflammatory markers, while transdermal administration is not associated with these effects [27].

The immune effects of endogenous testosterone, while previously believed to be exclusively immunosuppressant, also vary based on concentration—in cis women, concentration can be pro- or anti-inflammatory based on menstrual cycle phase or even level of sexual activity [14, 93, 94]. In the other direction, high levels of inflammation can reduce testosterone production [95, 96], and large concentrations of IL-6 and TNF-α can increase aromatization of testosterone to estrogen [97, 98].

As noted above, there is substantial cross-talk between gonadal hormones and stress systems (e.g., [99]). Cortisol and other glucocorticoids have a major function in regulating inflammatory processes in a biphasic pattern [100]. As such, estrogen and androgen treatments can indirectly influence regulation of inflammation via alterations of cortisol production and release.

Chronic inflammation is often studied as a core mechanism and predicting factor of cardiovascular disease (CVD) given its tremendous disease burden. In addition, significant research has examined the complex and sex-specific relationships between endogenous sex hormones and CVD risk (for a review, see [101]). In general, cis men have increased cardiovascular risk compared to cis women of the same age, and cis women experience a drastic increase in CVD risk after menopause, suggesting protective effects of estrogen [102]. The mechanism of chronic inflammation also plays a large role in sexual function, particularly erectile dysfunction [103].

Relationships Between Inflammation and Sexual Function

The relationship between inflammation and sexual function may be sex-specific. Preliminary evidence suggests that higher levels of inflammatory markers (CRP, IL-6, and TNF-α) are associated with lower sexual desire, arousal, and pleasure in cis women, but some reports of higher desire in cis men [104–109]. Chronic inflammation can also contribute to “sickness behaviors,” such as fatigue and inactivity, that may reduce interest in sexual activity to conserve resources during illness—and cis women may be differentially impacted as reproduction requires significantly more resources in females [110–116]. Additionally, inflammation may contribute to increased disgust sensitivity and avoidance of previously rewarding stimuli [117, 118], which substantially inhibit cis women’s desire and arousal [119]. Finally, inflammation is often associated with the sensation of pain, and cis women that report pain during sex do have increased levels of inflammation markers [120–131].

Overview of GAHT

The term GAHT covers a variety of treatments that can be prescribed in different ways depending on the specific goals of a patient’s gender transition and their health profile [7]. Typically, the goal of GAHT is induction of serum estradiol or serum testosterone in the reference range for the sex associated with the person’s gender identity [8•, 15]. These will generally be supraphysiologic doses (i.e., larger than normally produced by the body) relative to the sex assigned at birth—which may account for differential impacts on inflammation and sexual function when trans and cis people are prescribed the same hormones. However, these doses are not supraphysiologic to human bodies per se, and to adapt to this changed hormonal landscape, other bodily systems will react to attempt to re-establish homeostatic equilibrium. Thus, some physiological changes associated with GAHT (i.e., inflammation and sexual dysfunction) may arise with introduction of treatment but level out after a few months.

Masculinizing GAHT typically includes administration of exogenous testosterone (T). This administration can be transdermal (TD; testosterone gel or patch), oral (testosterone capsules), or parenteral—often intramuscular (IM) or subcutaneous (SC; testosterone enanthate or cypionate, testosterone undecanoate; [4, 8•, 15]).

Feminizing GAHT typically includes administration of exogenous bioidentical estrogen, generally some form of estradiol (E2). This administration can be oral (estradiol valerate), transdermal (estradiol patch), or parenteral (estradiol valerate or cypionate; [4, 8•, 15]). An earlier form of estrogen—ethinyl estradiol (EE)— is no longer recommended due to its less favorable safety profile and increased thrombotic risk [8•]. Feminizing GAHT often also includes antiandrogen treatment, which is administered orally (cyproterone acetate (CPA) or spironolactone) to block androgen receptor activity [4, 8•]. Antiandrogens are often required even when antiestrogens are not, because the levels of androgens are higher in people of all sexes relative to the levels of estrogen and thus may need to be differentially suppressed. There is some controversy surrounding including progestins in GAHT—they can be used in feminizing care to supplement estrogens and in masculinizing care to suppress menstruation—but are generally not recommended because of increasing risk of thromboembolism [8•, 13, 58].

TGNC adolescents may also receive gonadotropin-releasing hormone agonists, or “puberty blockers” to suppress or delay pubertal development, a treatment considered to be potentially lifesaving by international guidelines and standards of care [132, 133]. This review will not focus on this population, as a discussion of the nuance necessary to consider what is normative healthy sexual development in prepubescent TGNC youth is outside of our current scope.

Exploring Relationships Between Hormones, Inflammation, and Sexual Function in TGNC Samples

Relationships Between GAHT and Inflammation

As we have highlighted the substantial and growing literature on the relationships between sex hormones, inflammation, and sexual function in cis populations, we will now turn to exploring these same pathways (Fig. 1) in TGNC groups, albeit with more sporadic and limited research. Not only is this investigation crucial for making accurate medical recommendations to TGNC patients, but it is also an opportunity for theoretic clarity—in cis populations, it may be difficult to disentangle the impact of sex hormones from chromosomal influences, and thus, research with TGNC populations (who are more likely to have incongruence between chromosomes and hormones) may be able to shed light on differential impacts [7, 134]. See Table 1 for the summary of patient populations and forms of GAHT used in the studies referenced below.

Table 1.

General characteristics of cited studies, including number of participants in the sample and their genders, types of masculinizing and feminizing GAHT used, and whether participants also underwent gender affirming surgeries during the study

First author, year (Ref.)	Sample	Masculinizing GAHT	Feminizing GAHT	Also receiving affirming surgery
Defreyne, 2020 [3••]	356 trans men and 401 trans women (prospective study)	IM T undecanoate, IM T esters, TD T gel	Oral EV, TD E2 patches, TD E2 gel, CPA	Various masculinizing and feminizing surgeries (in the prospective study)
van Dijk, 2019 [148]	193 trans men and 205 trans women	TD T gel, IM T undecanoate, IM T esters	Oral EV, TD E2 patch, TD E2 gel, CPA, spironolactone	Not reported
Wierckx, 2014 [58]	138 trans men and 214 trans women	IM T esters, IM T undecanoate, TD T, oral T undecanoate	TD E2 gel, TD E2 patch, oral E2, oral estriol, oral EE	Various masculinizing and feminizing surgeries
Elaut, 2008 [146]	62 trans women and 30 ovulating cisgender women	Not applicable	TD E2 gel, oral EV, oral conjugated estrogens, oral EE	Various feminizing surgeries
Zaliznyak, 2023 [19•]	33 trans men and 130 trans women	IM (no information on hormone type)	Oral, IM, patch, gel, pellets (no information on hormone type)	No genital surgeries
Ristori, 2020 [21•]	141 trans men and 160 trans women (cross-sectional study); 36 trans men and 36 trans women (prospective study)	IM T undecanoate	Oral EV, TD E2 gel, CPA	No surgery
Bartolucci, 2015 [143]	36 trans men and 67 trans women	IM T, TD T gel	Oral EV, oral conjugated estrogen, TD E2 patches, CPA	No genital surgeries
Manieri, 2014 [144]	27 trans men and 56 trans women	TD T gel, IM T enanthate, IM T undecanoate	Oral E2, TD E2, CPA, spironolactone, dutas- teride	No surgery
Gieles, 2023 [12•]	145 transmasculine participants and 180 transfeminine participants	Not reported	No information reported	Various surgeries
Kerckhof, 2019 [150]	211 trans men and 307 trans women	Not reported	No information reported	Various surgeries
Lake, 2023 [137]	170 trans women	Not applicable	Oral EV, spironolactone	Not reported
Iannantuoni, 2021 [139]	157 trans men	IM T undecanoate	N/A	Not reported
Schutte, 2022 [32•]	47 trans men and 48 trans women	TD T gel	TD E2 patches, CPA	No surgery

Abbreviations include intramuscular (IM), transdermal (TD), testosterone (T), estradiol (E2), estradiol valerate (EV), ethinyl estradiol (EE), cyproterone acetate (CPA)

GAHT has both direct and indirect effects on inflammation. These effects have largely been studied in the context of CVD indicators, which assumes chronic exposure to GAHT, as atherosclerosis and endothelial dysfunction risk is elevated with chronic (but not acute) inflammation. Overall, research has documented increased risk of cardiovascular events (e.g., stroke and myocardial infarction) in TGNC people receiving GAHT, particularly trans women, and is the main cause of death for this population (for reviews, see [4, 135]). However, in research on feminizing GAHT, much of the CVD risk has been attributed to ethinyl estradiol (EE), which is therefore no longer recommended for primary treatment [4]. For masculinizing GAHT, there is less consensus in the literature, with some studies reporting no change in CVD risk and some reporting CVD risk in the reference range for cis men [4]. The literature on CVD risk in TGNC people suffers from a wide variety of methodological differences, including collapsing hormone type and route of administration, small sample sizes, and lack of adjusting for other cardiovascular risk factors [4, 135].

There is much unknown about the inflammatory effects of GAHT at more subtle levels (i.e., too low to cause CVD concern, but still potentially neuroactive and thus relevant for sexual functioning; for one review; see [7]). To explore this, we will review several studies that indicate changes in markers of inflammation during GAHT administration.

Older studies have found significantly elevated inflammation markers in trans women using high-dose estrogen treatments, particularly when those treatments are administered orally (e.g., [136]). In contrast, a more recent secondary analysis of 170 trans women found that participants displayed decreased d.dimer, a marker of inflammation related to blood clotting, after 6 and 12 months of GAHT [137]. Similarly, in another study, levels of CRP, IL-6, IL-8, IL-22, and VCAM-1 decreased in trans women after 12 months [32•]. These results agree with a recent systematic review showing potentially decreased inflammation associated with feminizing treatment [138]. The reductions in inflammatory markers in these samples of trans women taking GAHT that does not include EE suggest decreased inflammatory and CVD risk for these alternate formulations [32•].

In trans men, one study found that levels of IL-6 and TNF-α were increased after 12 weeks of GAHT [139]. Another found that levels of CRP increased after 12 months [32•]. An older study similarly found increased expression of inflammatory cytokine profiles (IFN-γ/IL-4 ratio) in trans men after four months of GAHT [140]. Taken together, these studies suggest temporarily increased inflammation associated with masculinizing treatment. The increased CRP levels in trans men are surprising compared to the general anti-inflammatory effect of testosterone observed in cis men [14, 141] and the smaller increase in CVD risk for trans men compared to trans women [4].

One study compared levels of B-cell activating factor (BAFF) and TNF-α in trans men and women and cis men and women, intentionally splitting inflammation associated with sex hormones and sex chromosomes [134]. They found that serum BAFF levels corresponded to sex hormones, as levels were highest in cis and trans women (and not statistically different from each other), followed by trans men and then cis men [134]. Stimulated TNF-α levels followed a similar pattern, whereas basal TNF-α appeared to be impacted both by chromosomal and hormonal sex [134].

One indirect effect of hormones on inflammation is changing exposure to (and potentially reactivity to) discrimination stress. Discrimination, stigma, and threats of violence are extremely prevalent for TGNC people [2, 22••, 142], and these experiences can cause psychological distress that impacts many bodily systems [142]. One study found that in 65 healthy trans men undergoing testosterone therapy, there was significantly higher CRP in participants reporting stress associated with “passing” as men than participants without “passing” stress [142]. Additionally, chronic stress increases risk of CVD and mortality [142]—making it even more difficult to extricate CVD and inflammatory risk of GAHT from other biopsychosocial aspects of TGNC experiences. One study of trans children and young adults found that higher scores on the Gender Minority Stress and Resilience Scale (measuring greater gender-based stress and lack of gender-based supports) were correlated with higher CRP, even in a sample of youth and young adults with access to gender affirming care [22••]. This exposure to changing levels of discrimination would theoretically apply to all GAHT, but likely not (to the same degree) to cis people taking the same hormones, potentially explaining some empirical differences between these populations.

Relationships Between GAHT and Sexual Function

Overwhelmingly, the research on gender affirming care of all kinds notes improvements in overall sexual quality of life [143, 144]. However, this section will focus primarily on treatment-emergent changes in sexual function, to better understand the changes potentially impacted by inflammation and provide guidance for treatment of sexual concerns. Most studies examining sexual function during or after GAHT focus on desire; findings on other aspects of sexual function and dysfunction, such as orgasm, pain, distress, satisfaction, and sexual quality of life, are more sporadic and varied. Significantly, while many researchers have attempted to establish correlations between serum sex steroid levels and desire or dysfunction, most have been unable to do so [3••, 15, 145, 146], potentially due to methodological limitations [3••].

GAHT and Sexual Desire

Research on masculinizing GAHT has generally documented increased sexual desire in trans men, while work in feminizing GAHT shows decreased desire in trans women [58, 145, 147]—but these changes are temporal and typically peak within three months, with levels of desire returning roughly to baseline at about 12 months [3••, 21•, 148]. Broadly, these effects follow the same pattern as described in studies of inflammation in GAHT, with most effects (pro or antiinflammatory) in the first 3–4 months followed by a stabilization period and leveling off.

One recent cross-sectional and prospective study found that for trans women, dyadic (partnered) desire, solitary desire, and total scores on the Sexual Desire Inventory (SDI-2) decreased after three months of GAHT, but increased steadily thereafter, settling at levels higher than baseline after three years [3••]. In an almost directly opposite pattern, trans men reported increases in total, dyadic, and solitary SDI scores at the three-month mark, which decreased slowly and settled at levels not statistically different from baseline at 3 years [3••]. Interestingly, this study also found that removal of gonads (orchiectomy in trans women and hystero-oophorectomy in trans men) was associated with prospective increases in SDI scores after 24 months, despite the concomitant decreased production of sex steroid hormones that are thought to contribute to the significantly decreased desire observed in cis people following similar procedures [3••]. This contrast may arise due to reduced production of the hormones that were causing gender dysphoria.

Corroborating these results, another prospective study found that trans men reported an increase in desire peaking at three months after GAHT initiation, and decreasing slightly to levels still higher than baseline at 12 months [148]. Trans women reported decreased desire peaking at three months and improving slightly to levels still lower than baseline at 12 months [148]. These studies expanded upon and added a temporal element to earlier studies concluding that GAHT increased sexual desire (as well as other related components such as masturbation, sexual fantasies, and arousal) in trans men [145, 147, 149], also noting that desire was reported as being more urgent and less controllable during GAHT [147]. A graphical representation of the general consensus from these studies can be found in Fig. 2.

Fig. 2.

A conceptual diagram depicting the consensus findings of the impact of GAHT initiation on sexual desire in trans men and women. Around 3–4 months after beginning treatment, trans men report an increase in desire and trans women report a decrease in desire; desire begins to level out closer to baseline after around 12 months. This graph is conceptual only and does not represent specific clinical data

In addition to measuring levels of sexual desire, some studies address differential rates of Hypoactive Sexual Desire Disorder (HSDD) in this population, often using the Sexual Function Health Council guidelines. One study reported an HSDD prevalence in trans women on GAHT of about 22%—a rate higher than is observed in cis women, and a prevalence in trans men of about 5%—a rate similar to cis men [58]. In contrast, another study compared HSDD in trans women and cis women, finding that there were no significant differences between SDI-2 scores or rate of HSDD diagnoses (about 1/3 of participants) in both groups [146].

Other Effects on Sexual Function

Regarding orgasm, several studies indicate that TGNC participants report difficulty reaching orgasm as a primary concern [12•, 150]. One recent study asked participants to retrospectively compare their current orgasms from masturbation with orgasms prior to starting GAHT; trans women reported an increase in lead-time necessary to reach orgasm, orgasm duration, and orgasm satisfaction, as well as orgasms in new body places and having multiple peaks in their orgasms, while trans men reported an increase in orgasm duration and orgasm satisfaction [19•]. Since these comparisons were retrospective and all participants had been on GAHT for over a year, it is difficult to know if there would have been gendered differences at the three-month mark as seen with desire.

One construct to address in future research is pain associated with sex after GAHT. This literature is complicated by difficulties disentangling the effects of genital surgeries (see [15] for some considerations regarding differences in sexual behaviors in TGNC people depending on genital structures). The current literature mentions certain symptoms of sexual pain including an increase in clitoral pain in trans men six months after GAHT initiation and breast tenderness in trans women starting after three months [148]. This is worth exploring further, especially with respect to the temporal aspect. Post operative pain would be expected, but pain that lasts for months after wound healing could be associated with chronic inflammation, which may be impacted by GAHT.

Effects on Sexual Distress, Dysfunction, and Quality of Life

One study focusing specifically on sexual distress found that GAHT decreased sexual distress in both trans men and women but that trans men showed a reduction in distress at all timepoints, whereas trans women only showed reductions at timepoints after three months [21•], reflecting the temporal aspects of desire mentioned earlier. Regarding general sexual dysfunction, another study found that 69% of sexually active trans women and 54% of sexually active trans men reported at least one sexual dysfunction (the majority of the sample received surgery and GAHT; [150]). This study demonstrates much higher rates of sexual dysfunction in trans men and women then in cis counterparts but included items that are not always considered sexual dysfunctions (e.g., difficulty initiating sexual contact; [150]). They also highlight that many participants experienced dysfunction without associated distress—in people who reported low desire, 25% did not report associated distress [150].

On the opposite side of the spectrum of sexual distress and dysfunction is sexual quality of life (QOL), which has been studied often in TGNC populations (for a review, see [151]). One study found that half of the sample said they were dissatisfied or very dissatisfied with their sexual lives but that having received GAHT was associated with better sexual QOL [143]. Another study found that trans women reported significantly increased sexual QOL after one year of GAHT [144]. Despite its obvious relevance to sexual QOL, there has been almost no research on sexual pleasure in TGNC populations [12•, 150]. One study found that their sample of trans participants had lower scores on the Amsterdam Sexual Pleasure Index than cis reference populations, but that lower age, current happiness, and genital body satisfaction were all associated with higher pleasure [12•].

Limitations of Research on GAHT and Sexual Function

There are several limitations to mention in drawing conclusions from this literature. These studies often have small sample sizes (e.g., [144, 145, 147]) and collapse different types of hormones and routes of administration for analysis. Researchers examining GAHT are unable to conduct randomized trials due to obvious ethical issues [21•] and thus often use cross-sectional and retrospective (e.g., [145, 147, 150]) and occasionally prospective methods (e.g., [3••, 21•, 148, 149]). As mentioned previously, while some studies only include participants receiving GAHT, many include participants who have received various gender affirming surgeries (e.g., [3••, 146, 147]). This can be valuable analysis to capture the reality of many TGNC people who intend to receive both GAHT and surgery but makes it difficult to tease apart the unique impacts of GAHT on sexual function. An additional methodological concern is that there are very few measurements that are validated for use in trans populations [15, 133, 150]. Some authors adapt validated scales to make them appropriate for TGNC participants [21•, 150], and some create new non-validated questionnaires to address trans-specific experiences [149], but differences in adaptations may affect results.

Another potentially large concern is the lack of standardization in controlling or accounting for other variables. For example, TGNC populations are disproportionally affected by sexual assault [2, 152] and are likely to have high rates of SSRI use due to increased mental health disparities [153]—two characteristics that can significantly impact both sexual function and potential mediators such as inflammation [15, 56, 133, 154]. In addition to non-standardized controls, there is no consensus on reference populations. Most studies compare trans women to cis women and trans men to cis men but do not specify any other characteristics of the reference groups. One study compared trans men to cis gay and bisexual men [147], which may be justified given external perceptions and minority stress. Clinics that assess and treat this population are rare—over half of all studies cited in this section use data collected from the European Network for the Investigation of Gender Incongruence study or their participating clinics in the Netherlands, Belgium, Germany, Norway, and Italy [3••, 12•, 21•, 58, 145, 146, 148, 150]. TGNC people in those countries may not reflect TGNC people around the world, and geographically diversifying research with this population is certainly needed.

Finally, many researchers measure sexual dysfunction symptoms such as low desire or vaginal pain with penetrative insertion but do not subsequently ask if respondents are distressed by this symptom. This may be a particularly salient distinction in TGNC groups, as some symptoms of “dysfunction” may be desired (e.g., some trans women may find erections dysphoric and welcome loss of erectile “function”). There is a pervasive need for more analysis of sexual dysfunction that considers standardized assessments of subjective distress, particularly in TGNC populations, to more accurately allocate treatment resources.

Conclusions

There is evidence for and against the potential mediating role of inflammation in the sexual changes observed during initiation of GAHT. On the one hand, as reviewed here, there is little question that hormone treatments impact inflammation in both cis and TGNC populations. Also as reviewed here, there is growing evidence for the role of inflammation in the effects of hormones on sexual function, both as an indirect mediator and as moderator of more direct estrogenic and androgenic effects. And the temporal parallels across changes in hormones, inflammation, and sexual function following initiation of GAHT—that is, showing the largest effects within the first 3–4 months followed by a period of stabilization and eventual reestablished equilibrium—points to shared pathways across effects.

On the other hand, existing data in cis populations suggest that elevated inflammation is associated with decreased sexual desire (particularly for women), as well as decreased arousal and pleasure. But recent research in patients receiving GAHT suggests that those patients who show elevations in inflammation markers—i.e., trans men—show concurrent increases in sexual desire, while those who experience anti-inflammatory effects of GAHT—i.e., trans women—show concurrent decreases in sexual desire. That is, the directionality of effects of inflammation on sexual function does not align with that which has been observed in cis populations.

There are several potential explanations for this discrepancy. There may be complex interactions between chromosomal sex and hormone treatments that contribute to different immunologic effects of the same hormones in cis and TGNC populations. Indeed, a recent study comparing cis and trans men and women found significant differences in the effects of sex steroid hormones on immunoregulatory cell activity across groups, suggesting sex-by-gender effects of hormones on inflammatory processes [155]. There may also be differences in the associations between sex hormones and inflammation in people who are vs are not under chronic stress [156], which as noted above may be particularly relevant for TGNC populations experiencing discrimination and minority stress. Possibly, the introduction of exogenous hormones during GAHT alters endogenous hormone production in ways that counteract the expected inflammation effects on sexual function. And finally, it is possible that the co-incidence of changes in sexual function, hormone levels, and inflammation during GAHT initiation is just that: a coincidence.

Overall, the reviewed research on the relationships between GAHT, inflammation, and sexual function in TGNC people reveals findings that are complex, inconsistent with established patterns in cis people, and clearly impacted by many external factors. As we see that the effects of GAHT on sexual functioning significantly decrease or return to baseline levels after around 12 months, we must consider the ways in which hormone effects are not irrespective of the body in which those hormones are operating. Particularly relevant in this case, by design, GAHT changes one’s appearance in ways that correspond with one’s identity, which can in turn have impacts on sexual function. Although the focus of the current paper has been to explore effects in TGNC samples, these findings should also raise questions about these same processes in cis populations. We often assume that if hormone levels are increased and sexual behavior or function is altered in parallel, that behavioral change results from direct action of the hormone on the nervous system. But it is just as likely that hormone treatments impact how cis people see their own gender and sexual identities. Put another way, it is not simply that hormone treatments have a physiologic effect in cis people and a social effect in TGNC people—rather, hormone treatments can have both physiologic and social impacts in everyone. As such, there is a need for one cohesive model that highlights the many complex mechanisms of hormonal effects on sexual function across all genders.

Still, the collection of these studies has significant clinical implications for GAHT providers. Patients considering GAHT should be appropriately counseled about potential sexual dysfunction side effects, but providers should clarify that it is unlikely that they will last forever and that patients should contact providers if they last longer than several months. Providers should ensure that patients feel comfortable bringing up sexual side effects, not just because steps should be taken to try to ameliorate their effects to allow for sexual satisfaction and pleasure, but also because, even if they are not distressing, there may be implications for underlying chronic inflammation. Recognizing the potential effects of inflammation on sexual function could also aid in general risk assessment—potentially noting chronic sexual dysfunction as an indicator for CVD risk. While further research on these relationships is certainly necessary, we should be monitoring inflammation alongside sexual function and dysfunction in GAHT.

Data Availability

No datasets were generated or analyzed during the current study.