Gender-Affirming Hormone Therapy: Physical and Sociopsychological Effects, Impact and Satisfaction

Background Gender dysphoria treatment includes gender-affirming hormone therapy (GAHT). Studies are still lacking on how to characterize its effects and impact on transgender people's lives more effectively. Aim To study the physical and psychological effects of GAHT on transgender individuals, assess its impact on their lives, and rate their overall satisfaction. Methods Participants (n = 114; ages 18-62 years; median age 24.0 (21.0 - 33.0) years) included transgender adults residing in Portugal who were undergoing or had undergone hormonal therapy for at least one uninterrupted year. Participants completed an original questionnaire. For most items, an ordinal Likert-style scale ranging from 0 (worst result) to 6 (best result) was used. Descriptive statistics and non-parametric tests, including Pearson's chi-squared test, Wilcoxon signed-rank test, and Mann-Whitney U test were used to analyze categorical and continuous variables, with a significance level set at 0.05. Outcomes The outcomes included desired physical changes rating (perception and satisfaction with changes); side effects of GAHT; the sociopsychological impact of GAHT (on self-esteem, body image, psychological wellbeing, social and family relations); overall satisfaction (with treatment results and medical follow-up). Results The changes classified as the most perceptible in those undergoing masculinizing treatment (Group M) were amenorrhea (6 (5.0-6.0) points) and clitoris enlargement (6 (5.0-6.0) points). These were also the ones rated as the most satisfactory (6 (6.0-6.0) points for amenorrhea and 6 (4.0-6.0) points for clitoris enlargement). On those undergoing feminizing therapy (Group F), the alteration voted as the most perceptible was sperm production decrease (6 (2.0-6.0) points), and the ones classified as the most satisfactory were sperm production decrease (6 (4.0-6.0) points) and spontaneous erections decrease (6 (5.0-6.0) points). Side effects were reported by 89.7% of Group M (mood swings were the most common) and 96.3% of Group F (decreased libido was the most frequent). The sociopsychological impact of hormonal treatment was significantly positive in all analyzed variables (p<0.001). Overall satisfaction with treatment results and medical follow-up were rated with 5 points and 4.5 points, respectively. Clinical implications This study provides clinicians with more evidence that GAHT may improve the physical, psychological and social health of transgender people seeking medical transition. Strengths and limitations The strengths of the current study include a high participant count relative to the target population, the acquisition of data on previously unexplored variables, and the significance of being one of the few investigations of its kind conducted in Portugal. However, the study has limitations, including differences in participant characteristics, a small sample size for some variables, potential bias due to the retrospective nature of the study, individualized treatment regimens, and the inclusion of participants from different countries, which limit the generalization of the results. Conclusions This study provides further evidence that GAHT is effective, and that its physical effects are satisfactory while resulting in mostly non-severe nor life-threatening side effects. GAHT is an important therapy in gender dysphoria and has consistent results in improving numerous sociopsychological variables.


Introduction
Gender dysphoria (GD) is characterized by clinically significant distress or impairment in important areas of functioning, that can arise in many transgender people as a consequence of the incongruence between the experienced gender and the one assigned at birth [1].
In Portugal, being transgender is legal and protected under anti-discrimination laws [2]. Transgender individuals have the right to change their name and gender on legal documents, and gender-affirming healthcare is available through the public health system [2]. In the last years, there has been an increasing acceptance of gender diversity and transgender rights, and Portugal's Gender Identity Law of 2011 is a significant aspect of this change, allowing individuals to change their gender marker on identification documents without the need for medical procedures [2,3]. However, despite the legal protections in place, there is still discrimination and stigmatization of transgender people in society, particularly in relation to employment, education, and access to healthcare [2]. Although more public hospitals are offering genderaffirming treatments, there are still long waiting lists for these services, indicating the need for further improvements [4]. The prevalence of transgender individuals in Portugal is unknown, but national data shows that, between 2011 and 2021, 1227 transgender Portuguese changed their gender marker in the Civil Registration System [3].
GD treatment consists of social transition, psychotherapy, hormone therapy, and surgery [5]. Studies have shown that these therapies are effective in treating GD and can lead to improvements in mental health issues [6]. While the treatment plan is personalized, hormone therapy is often the initial medical intervention and is based on individual objectives, risk-benefit analysis, the presence of comorbidities, and socio-economic factors [5]. Masculinizing therapy is typically achieved through testosterone while feminizing hormone therapy involves a combination of estrogen and an androgen blocker, which is usually more complex [5].
The timing of appearance of the desired physical changes is highly variable: some features might take as little as one month to be noticeable, while others can take up to six or more months, and even years to reach their peak [7]. The main expected effects of masculinizing therapy are amenorrhea, clitoris enlargement, and voice deepening while feminizing therapy most markedly induces breast development, softer/less oily skin, and a decrease in semen production, spontaneous erections, and testicle size [7]. Also, masculinizing therapy is expected to increase body and facial hair, decrease body fat mass and increase lean mass, on the other hand, feminizing hormone therapy is expected to have the opposite effects [7].
The first aim of our study was to evaluate how significant the perception of the desired physical changes was and the consequent satisfaction with such changes after at least one year of uninterrupted GAHT in transgender individuals.
Our second aim was to explore the impact of GAHT on trans people's lives regarding sociopsychological variables such as self-esteem, body image satisfaction, psychological well-being, and social and familial relations, by rating them with a pre-and post-therapy score.
The third and last objective was to rate participants' overall satisfaction with both therapy results and medical follow-up during treatment.
With this study, we hope to get better enlightenment on GAHT's benefits and risks so that physicians can provide more evidence-based care to transgender patients. It is also our desire to encourage other investigators to conduct studies in this under-researched area.

Participants and procedure
We performed a cross-sectional study in March 2021.
The participants of this study were adult transgender individuals, residing in Portugal, currently undergoing or had undergone GAHT, regardless of the timeframe in which the treatment was conducted.
Data was collected through an original non-validated questionnaire that was sent to the participants via email. The authors developed the questionnaire in collaboration with Portuguese psychologists specializing in the healthcare of transgender individuals. The questionnaire was based on questions from several validated questionnaires freely available online, such as the Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults (GIDYQ-AA), the Trans Woman Voice Questionnaire (TWVQ) and the Body Image Scale (BIS). To identify potential participants for the study, we collaborated with 12 Portuguese LGBTQI+ associations and organizations. These groups helped us by accessing their databases and sending an invitation to all their registered transgender associates, inviting them to participate in the study. The invitation contained the questionnaire Google Forms' link and all transgender associates who did GAHT were invited to participate. We obtained a total of 147 responses, of which 142 were valid: two were excluded because they were duplicated, and three were excluded because the answers weren't congruent throughout the questionnaire.
Having the aim of this article in mind, only the answers of participants who took GAHT for at least one uninterrupted year were included (regardless of still being on GAHT or not), resulting in a total of 114 relevant answers to the questionnaire, of which 87 were from individuals on masculinizing therapy (Group M) and 27 from people undergoing feminizing treatment (Group F). All data was registered anonymously, respecting participants' data protection.
This study was approved by the local ethics committee ("Ethics Committee CHUP/ICBAS -DEFI"). Informed consent was explained at the beginning of the questionnaire, and participants had to give consent to proceed with the questionnaire.

Measures
The study's questionnaire was created by the authors using the Google Forms platform, consisting of 60 different questions, 19 of each addressing demographics, GAHT physical and sociopsychological effects, impact, and consequent satisfaction with both results and medical follow-up. Other questions aimed to evaluate how the treatment was being oriented, participants' knowledge about the transition process, therapy regimen safety, adhesion, and compliance. For this article's aim, only the answers to the first 19 questions are presented and discussed.
To answer some of the items on the questionnaire, an ordinal Likert-style scale ranging from 0 (worst result) to 6 (best result) was used.
For the first aim, regarding GAHT effects, participants rated their perception of physical changes development from "0 -no changes" to "6 -very significant changes" and their satisfaction with them from "0 -not satisfied" to "6 -totally satisfied". Participants also indicated the physical and psychological adverse effects that they experienced by choosing them from a list presenting the most common side effects, explained with common nonmedical language, while also having the option of writing down any other one not listed.
The third goal was accomplished by rating the general satisfaction with GAHT's results and with the medical follow-up received during the treatment with a scale ranging from "0 -not satisfied" to "6 -totally satisfied".

Statistical analysis
Categorical variables were presented as frequency distribution and compared using Pearson's chi-squared test. For each continuous variable, normality was tested by histogram observation and the Kolmogorov-Smirnov test and, since the almost totality of continuous variables had a non-normal distribution, results were presented as medians (followed by interquartile ranges). Samples were compared using nonparametric tests, such as Wilcoxon signed-rank test for paired variables and the Mann-Whitney U test for independent variables, with a significance level set at 0.05. Data analysis was performed using the SPSS Statistics v. 27 software (IBM Corp., Armonk, NY).

Demographics
Respondents' age ranged from 18 to 62 years and their median age was 24.0 (21.0 -33.0) years. Participants' median age of recognition of self-gender identity was 8.0 (8.0 -14.0) and initiation of public expression of their experienced gender was 18.0 (14.5 -22.5) years of age. Participants initiated hormonal therapy at a median age of 21.0 (18.0 -27.0). Figure 1 presents this data organized in stacked bar charts.
Regarding side effects, 89.7% of the participants from Group M experienced some adverse effect from GAHT, whilst 96.3% of the respondents from Group F reported at least one side effect.  As shown, the most frequently stated side effects from participants in masculinizing therapy (Group M) were mood swings (56.3%), acne (52.9%), and alopecia (37.9%), while respondents who underwent feminizing therapy (Group F) mostly reported decreased libido (66.7%) and mood swings (63.0%). Table 4 shows the sociopsychological impact of GAHT's effects. 2023  All analyzed variables had a statistically significant improvement (p<0.001) with GAHT, both in the total sample and in Group M. In Group F, all variables improved significantly, except for psychological well-being (p=0.406).

Satisfaction
These participants (who underwent at least one year of uninterrupted GAHT) rated their overall satisfaction with treatment results with a median of 5.0 (M|F=5.0) points and their satisfaction with received medical follow-up with a median of 4.5 (M=4.0; F=5.0) points. The difference between the medians of the scores attributed to the received medical follow-up by Groups M and F was not statistically significant (p=0.681).

Discussion
The 2015 U.S. Transgender Survey, conducted by the National Center for Transgender Equality, revealed that among transgender individuals using GAHT, 39% reported using testosterone, while 64% reported using estrogen and/or progesterone, evidencing a much greater number of people seeking feminizing treatments [8]. In contrast, our study demonstrated an inverse relationship, with a larger proportion of individuals seeking masculinizing hormone treatments. This correlation was likewise observed in two additional studies conducted on the transgender population in Portugal, suggesting that this might be characteristic of the Portuguese context [4,9]. While there is no current explanation for this, we suggest that cultural and societal factors, as well as differences in healthcare access and availability of hormone therapy options, may contribute to the observed disparities. Sample size, recruitment methods, and study design are important considerations that may also influence these findings. Further research is needed to better understand the underlying factors that may explain these differences.
Our study results were consistent with other international studies that have shown the significant physical changes induced by GAHT [10][11][12][13][14][15][16][17][18]. Our study reinforces the findings of others that side effects are mostly mild, with acne and libido loss being among the most frequent in transgender individuals receiving masculinizing or feminizing hormone therapy, respectively, and that severe adverse alterations, such as erythrocytosis, venous thromboembolism or even important hepatic toxicity seem to be rare [16][17][18][19].
Previous research has demonstrated the positive impact of GAHT on body image and self-esteem in transgender individuals, with findings similar to ours. GAHT can improve gender-body conformation, meaning that transgender individuals who undergo GAHT tend to experience a greater sense of alignment between their gender identity and their physical appearance [13,[20][21][22][23]. This, in turn, can reduce body image dissatisfaction and increase satisfaction with appearance, as well as overall self-esteem [13,[20][21][22][23]. These positive effects on body image and self-esteem can have significant implications for mental health, as body dissatisfaction and low self-esteem are risk factors for depression and anxiety [13,[20][21][22][23].
The results here presented, similarly to the ones of other studies, also demonstrated improvements in psychological well-being and reduced risk of suicidal ideation following GAHT. A probable explanation for this is that making the body characteristics more congruent with the experienced gender reduces dysphoria and even potentially decreases marginalization, allowing better results in mental health, which considerably diminishes the risk of suicide attempt [24][25][26]. Psychological well-being did not improve in a statistically significant way in Group F, possibly because of the greater social stigma that trans women face, in comparison to trans men, even after transition. A study from Verbeek et al. (2020) showed that trans women deal with higher social stigma, not only because of misogyny itself but also for being perceived as a threat to cisgender women [27].
Our study also revealed an improvement in social and family relations after hormone therapy, as suggested by other researchers. Although individual experiences may vary, since not all transgender individuals have supportive families and peers, and some may experience rejection or hostility, several studies have found that gender-affirming treatment can result in positive changes in relationships [20,21,28,29]. A study by Gorin-Lazard et al. (2017) found that transgender individuals who underwent hormone therapy reported improvements in their family relationships, including increased acceptance and support from family members [20]. This may occur because gender-affirming treatments seem effective in reducing gender dysphoria and improving overall well-being in transgender people, which can have positive effects on relationships with family members and other social connections [20,21,28,29].
Other studies have also reported significant improvements in the quality of life of transgender individuals who undergo GAHT. Our study similarly found that individuals who received GAHT reported a high level of satisfaction with the results, which suggests that hormone therapy can have a positive impact on the overall well-being of transgender individuals. The aforementioned improvements in various areas of transgender individuals' lives may collectively contribute to the substantial enhancements in their reported quality of life [20,30].
All these findings are in line with the growing body of evidence that supports the use of GAHT as a crucial component of gender-affirming care.

Strengths and limitations
The current study has several notable strengths that contribute to the field of research. Firstly, the study achieved a high participant count relative to the expected size of the target population, indicating a strong level of engagement and interest from individuals within the studied population. Secondly, the study was able to acquire data regarding variables that had not been previously explored in related investigations, providing new insights into the topic under investigation. Additionally, the study represents one of the few investigations of its kind conducted in Portugal, emphasizing the significance of its contribution to the field. Together, these strengths highlight the value of the current study and provide an additional foundation for future research in this area.
Nonetheless, several potential limitations should be taken into account when interpreting the results. Firstly, differences between the number and characteristics of the participants from each group, as well as a small sample size for some variables, participant selection procedures and limited data comparison and analysis may have influenced the study's findings. In addition, the individualized nature of GAHT regimens, different treatment duration for each participant, the uncertainty of medication adherence, and the inclusion of participants from various countries with potential interpopulational and biological differences should also be acknowledged. Furthermore, the cohort mainly consisting of participants from Portugal limits the generalization of the results. Moreover, due to the retrospective nature of the study and the lack of a validated questionnaire, participants' evaluation of pre-treatment variables may have been less accurate. Finally, the potential for bias in participants' responses due to the "sunk cost fallacy," along with other factors such as concurrent treatment or personal life events that may have influenced the results, were not controlled for in the study. As a result, caution should be exercised when generalizing the findings to other populations or settings.
Gender dysphoria is a recently acknowledged issue, and it has only recently gained recognition in the field of medicine. There is still a dearth of large-scale, prospective studies that are necessary to optimize its management and to provide individuals who identify as transgender with the best possible treatment options. To address this gap in knowledge, it is critical to undertake research that employs more standardized methods of data collection and that follows clearly delineated treatment protocols.

Conclusions
This study provides further evidence that GAHT is effective, and several expected satisfactory changes can be observed after at least one uninterrupted year of hormonal therapy. The adverse effects reported were also mostly non-severe and non-life-threatening. For transgender people who seek transition, GAHT is consistently associated with improvements in self-esteem, body image satisfaction, psychological wellbeing, and social and family relations. Our study also revealed that there is general satisfaction with both therapy results and medical follow-up.
This study brings new evidence to physicians that GAHT seems to be important to increase the physical, psychological and social health of transgender people seeking medical transition, probably associated with the improvement in the quality of life verified in other studies.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee CHUP/ICBAS -Education, Training, and Research Department (DEFI) issued approval 2021.041(033-DEFI/034-CE). "The Board of Directors of "Centro Hospitalar Universitário do Porto" (CHUP) authorizes the aforementioned study to be carried out at the Endocrinology Service of this institution and having Rafael Santos, an "Instituto de Ciencias Biomédicas Abel Salazar" (ICBAS) student, as Principal Investigator. The study was previously analyzed by the Ethics Committee of CHUP/ICBAS, by the Clinical Investigation Service, by the Management of the Department of Education, Training and Research at CHUP and by the President of the Board of Directors, having obtained a favorable opinion". Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.