Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women

Doll, Elizabeth; Gunsolus, Ian L.; Thorgerson, Abigail; Tangpricha, Vin; Lamberton, Nathan; Sarvaideo, Jenna

doi:10.1016/j.eprac.2021.11.081

Cited by 8 publications

(3 citation statements)

References 18 publications

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“…We chose sublingual estradiol to test the hypothesis that pulses of serum estradiol would suppress testosterone production and that 2 pulses of estradiol might be more effective than 1 larger pulse of estradiol. Previous studies have demonstrated peak serum estradiol levels as high as 500 pg/mL with 1 mg sublingual estradiol, with rapid decreases over 2 to 4 hours [ 13 , 19 ]. Few studies have investigated if the number of estradiol peak levels obtained with sublingual estradiol are more effective at suppressing endogenous testosterone production than oral administration.…”

Section: Discussionmentioning

confidence: 99%

“…17-beta estradiol is currently the preferred estrogen formulation, which can be provided as tablet, patch, and injection. Sublingual administration of estradiol tablets achieves higher peak serum levels and, in theory, bypasses the first-pass metabolism within the liver; therefore, sublingual administration has been proposed to have advantages over oral estradiol [ 13 ]. However, few studies have explored the effect of peaks achieved through pulsed sublingual estradiol dosing (once vs twice daily) vs the more continuous blood levels offered via oral estradiol or transdermal drug delivery on suppression of the hypothalamic-pituitary-gonadal axis including testosterone production [ 14 , 15 ]…”

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confidence: 99%

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Effectiveness and Safety of Different Estradiol Regimens in Transgender Females: A Randomized Controlled Trial

Cortez,

Moog,

Lewis

et al. 2024

Journal of the Endocrine Society

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Background A goal of gender-affirming hormone therapy (GAHT) for transgender women is to use estradiol to suppress endogenous production of testosterone. However, the effects of different estradiol regimens and route of administration on testosterone suppression is unknown. This is the first open-label randomized trial comparing different GAHT regimens for optimal estradiol route and dosing. Objective To evaluate 1 month and 6 months testosterone suppression <50 ng/dL with pulsed (once- or twice-daily sublingual 17-beta estradiol) and continuous (transdermal 17-beta estradiol) GAHT. Methods This study was conducted at an outpatient adult transgender clinic. Thirty-nine transgender women undergoing initiation of GAHT were randomly assigned to receive either once-daily sublingual, twice-daily sublingual, or transdermal 17-beta estradiol. All participants received spironolactone as an antiandrogen. Doses were titrated at monthly intervals to achieve total testosterone suppression <50 ng/dL. Results Transdermal 17-beta estradiol resulted in more rapid suppression of total testosterone, lower estrone levels, with no differences in estradiol levels when compared to once-daily and twice-daily sublingual estradiol. Moreover, there was no difference in the mean estradiol dose between the once-daily and twice-daily sublingual 17-beta estradiol group. Conclusion Continuous exposure with transdermal 17-beta estradiol suppressed testosterone production more effectively and with lower overall estradiol doses relative to once or twice daily sublingual estradiol. Most transgender women achieved cisgender women testosterone levels within 2 months on 1 or 2 0.1 mg/24 hours estradiol patches. Given no difference between once- or twice-daily sublingual estradiol, pulsed 17-beta estradiol likely provides no benefit for testosterone suppression.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effectiveness and Safety of Different Estradiol Regimens in Transgender Females: A Randomized Controlled Trial

Cortez,

Moog,

Lewis

et al. 2024

Journal of the Endocrine Society

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“…Studies have demonstrated that transgender individuals on hormone therapy have higher rates of adverse cardiovascular events (myocardial infarction, venous thromboembolism, and ischemic stroke), highlighting the importance of investigating surrogate markers such as changes in lipoproteins, estrone, glucose, and insulin-sensitivity based on the estrogen preparation used during GAHT [8,[15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial

Cortez,

Moog,

Lewis

et al. 2023

JMIR Res Protoc

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Background Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. Objective This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. Methods This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. Results This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. Conclusions The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. Trial Registration ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707 International Registered Report Identifier (IRRID) DERR1-10.2196/53092

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Are the Pharmacokinetics of Sublingual Estradiol Superior or Inferior to Those of Oral Estradiol?

Safer

2022

Endocrine Practice

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Pharmacokinetics of Sublingual Versus Oral Estradiol in Transgender Women

Cited by 8 publications

References 18 publications

Effectiveness and Safety of Different Estradiol Regimens in Transgender Females: A Randomized Controlled Trial

Effectiveness and Safety of Different Estradiol Regimens in Transgender Females: A Randomized Controlled Trial

Effectiveness and Safety of Different Estradiol Regimens in Transgender Women (TREAT Study): Protocol for a Randomized Controlled Trial

Are the Pharmacokinetics of Sublingual Estradiol Superior or Inferior to Those of Oral Estradiol?

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