Estradiol and Testosterone Concentrations Among Thai Transgender Women in a Transgender-Led,Integrated Gender-Affirming Care and Sexual Health Clinic: A Real-World Analysis

Introduction

Gender dysphoria refers to discomfort or distress that is caused by a discrepancy between a person's gender identity and sex assigned at birth. ¹ Feminizing hormone therapy (FHT) is among the options, and the recommended pharmacological method, to mitigate such discrepancy among transgender women. The goal of FHT is to induce secondary sex characteristics of the female gender and reduce sex characteristics of the male gender. ² Although there are several regimens of FHT, they can be broadly categorized into three groups: estrogen (e.g., estradiol valerate and estradiol hemihydrate [EH]), antiandrogens (e.g., cyproterone acetate, spironolactone, GnRH agonists—goserelin, buserelin, and triptorelin—and 5-alpha reductase inhibitors—finasteride and dutasteride), and progestins. ¹ Differences in accessibility to hormone regimens between regions, diversities in individual's goal, and lack of clinical trials data have contributed to various hormone regimens. ¹

In Thailand, both over- and under-the-counter hormones for off-label purposes are easily accessible. ³ As many Thai transgender women may seek social acceptance through physical beauty, it is unsurprising that most Thai transgender women have been using FHT for an average of 10 years.^4,5 Unfortunately, transgender women usually take FHT based on their transgender peers' experiences without proper monitoring.

FHT can increase the risk of diseases or conditions such as venous thrombosis, cholelithiasis, transaminitis, and hypertriglyceridemia. ¹ Therefore, it is recommended that transgender women who used FHT should be routinely monitored.^1,2 The target hormone concentrations for transgender women who are using FHT are testosterone concentrations below the upper limit of normal cisgender women (CGW) range (<50 ng/dL) and estradiol (E2) concentrations within a premenopausal CGW range (100–200 pg/mL), with an emphasis on avoiding supraphysiological concentrations, which may lead to increased risk of adverse events. ⁶

To add to limited data around FHT efficacy among Asian transgender women, we aimed to determine the proportion of Thai transgender women who were using FHT who had hormone concentrations within target ranges in a real-world clinic setting.

Methods

Results

Hormone concentrations at follow-up visit

A total of 302 (19.7%) transgender women came to at least one follow-up visit, and had both E2 and TT concentrations tested. Transgender women who came to follow-up visits were significantly more likely to identify themselves as female (16.6% vs. 4.5%, p<0.001) or to be unemployed (14.4% vs. 8.9%, p=0.02); and less likely to have undergone orchiectomy (0.7% vs. 2.9%, p=0.02) or have HIV infection (1.9% vs. 5.8%, p=0.01) at baseline. There were no significant differences in the proportion of transgender women who had any hormones within target concentrations at baseline between those who came and did not come to follow-up visits.

During 12 months of follow-up visit, 165 (54.6%) transgender women were able to achieve or maintain either hormone within target concentrations: 21 (7.0%) had both hormones, 9 (3.0%) had only E2, and 135 (44.7%) had only TT within target concentrations. All 137 transgender women who achieved neither hormone within target concentrations during follow-up period had normal male testosterone concentrations, and 7 transgender women (5% of 137) had supraphysiological E2 concentrations.

Among 187 transgender women who had neither hormone within target concentrations at baseline and came to at least one follow-up visit, 84 (44.9% of 187) were able to achieve any hormones within target concentrations during follow-up. Overall, there was an increasing trend of E2 concentrations and a decreasing trend of TT concentrations toward target concentrations during follow-up visits (Fig. 1).

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FIG. 1.

Linear trend changes of E2 (a) and TT (b) concentrations over follow-up visits at each follow-up visit categorized by those who had any hormones within target levels and had neither hormone within target concentrations at baseline. E2, estradiol; TT, total testosterone.

Discussion

In a real-world clinic setting, we demonstrated that one-third of Thai transgender women who had been using nonmedically supervised FHT had any hormones within target concentrations, and that E2 concentrations of the majority of transgender women were suboptimal rather than supraphysiological. Hematocrit, hemoglobin, and creatinine concentrations were the only metabolic parameters significantly different from those who had any hormones within target concentrations and those who did not. During a 12-month follow-up period, both E2 and TT showed a positive trend toward target concentrations, and approximately half were able to achieve or maintain at least one hormone concentration within target ranges, suggesting a positive effect from attending a comprehensive transgender-specific health care facility.

An estrogen-based regimen, either single or as part of a combined regimen, was the most common hormone regimen among Thai transgender women in our study (62.4%). From our experience, this is likely due to its low price. For example, the two most common regimens in our study (ethinyl estradiol + cyproterone acetate and estradiol valerate) cost <0.5 USD/pill in Thailand. In comparison, an antiandrogen such as cyproterone acetate costs 2 USD/pill, approximately four times higher than the estrogen-based regimen. Many Thai transgender women also take over-the-counter hormones based on their transgender peers' experience and recommendation, possibly leading to the continuing trend of using the estrogen-based regimen.

Because many Thai transgender women rarely seek medical advice on FHT use, this raises concerns about improper hormone concentrations, particularly supraphysiological concentrations. Our study highlighted that although two-thirds of transgender women did not achieve target concentrations before attending a health care facility, only 2% had supraphysiological E2 concentrations. On the contrary, more than half of transgender women endured suboptimal hormone concentrations at baseline. Although this is a less concerning matter from the safety perspective, it is plausible that many Thai transgender women would not reach the physical changes they are expecting and consequently unable to mitigate gender dysphoria.

Previous studies have reported the effect of FHT on metabolic laboratory values in transgender women. Decrements in hematocrit and hemoglobin concentrations among transgender women who were using FHT are well documented,^9–13 and our findings are consistent with previous reports. These changes occur due to the influence of androgen on the erythrocytosis rate. The role of estrogen in erythropoiesis is less understood, but a strong impact is unlikely. ¹⁴ Hematocrit can decrease to CGW physiological concentrations. ¹¹ These changes can occur as fast as 3 months after FHT initiation before reaching its stable levels.^9,13 We demonstrated a 3% hematocrit difference between those who had hormones and those who had neither hormone within target concentrations, comparable with the previously reported 4% decrement. Although transgender women who were using FHT reported elevated platelet counts,^12,13 the concentrations were still in the cisgender reference range. ¹⁴ Our study found higher platelet counts among those who had any hormones than those who had neither hormone within target concentrations, though the difference was not significant.

In contrast to the impact of FHT on hematocrit and hemoglobin concentration, the effect on creatinine concentration is less established. Studies showed decreased creatinine concentrations among transgender women who were using FHT.^11–13 However, the changes were minimal, and the concentrations were between the CGM and CGW reference range. ¹¹ Comparably, we found significantly lowered creatinine concentrations among those who had any hormones within target concentrations compared with those who had neither. Because total body muscle mass impacts creatinine concentrations, ¹⁵ a decrement is expected among transgender women who were using FHT, especially those who achieved physical responses. However, we were unable to confirm this due to missing data. The clinical implication is still an issue, particularly for calculating glomerular filtration rate, which requires sex and creatinine concentration in the formulation. Therefore, the results must be interpreted with caution.

A study consisting of 16 transgender women in a U.S. community clinic showed that all transgender women managed to achieve target E2 concentrations, and 67% managed to achieve target TT concentrations 6 months after FHT initiation. ¹⁶ In contrast, approximately half of our participants managed to achieve or maintain either hormone within target concentrations. Differences between clinical trials and real-world settings and the number of participants may have contributed to such results. Regardless, our findings demonstrated a positive trend toward target concentrations of both E2 and TT at follow-up visits, suggesting a positive effect from attending a comprehensive transgender-specific health care facility.

By using clinical data from a service-based real-world clinic setting rather than through a clinical trial, we encountered many missing data such as physical feminizing effects from FHT, dosages of the FHT, metabolic parameters, as well as losses to follow-up visits. These led us to an inability to conclude the longitudinal metabolic effect and clinical efficacy of FHT. Many transgender women who underwent orchiectomy were not included in the analysis because testosterone was not measured. Finally, other hormonal concentrations (e.g., free testosterone, sex hormone-binding globulin, luteinizing hormone, and follicle-stimulating hormone) were not measured. However, to our knowledge, this is among the largest studies to report information on hormone concentrations and related issues among transgender women who were using FHT in a real-world clinic setting.

Conclusion

Our real-world setting study demonstrated that one-third of Thai transgender women who were using FHT had any hormones within target concentrations at baseline. Most transgender women who had neither hormone within target concentrations had suboptimal rather than supraphysiological E2 concentrations. At follow-up visits, there was a positive trend of both E2 and TT concentrations toward target concentrations. More than half managed to achieve or maintain at least one hormone concentration within target concentrations, suggesting a positive effect from attending a comprehensive transgender-specific health care facility.