Health Technology Review

Comparative Evidence Between Transdermal and Oral Estrogen as Part of Feminizing Hormone Therapy

Authors: Shariq Najeeb, Shannon E. Kelly, Nazmun Nahar, Melissa Brouwers, Becky Skidmore, Said Yousef Abdelrazeq, George A. Wells

This rapid review was conducted by the POst-market Drug Evaluation Team (PODET) through the Post-Market Drug Evaluation (PMDE) CoLab Network.

Key Messages

What Is the Issue?

• Hormone therapy may be prescribed to support individuals identifying as transgender, nonbinary, and gender-nonconforming who would like to align their bodies or appearance with their gender identity.

• For individuals seeking feminizing hormone therapy (FHT), estrogen is an established treatment.

• Various administration routes (ways to take estrogen) are available for FHT with estrogen, including oral (taken as a pill) and transdermal (absorbed through the skin). However, the comparative clinical efficacy, effectiveness, and safety of transdermal and oral administration routes are unclear.

• Decision-makers are interested in whether transdermal estrogen therapy should be considered for public reimbursement (funding) as a first treatment option (first-line option), as an alternative to oral estrogen therapy, in the context of gender-affirming care.

What Did We Do?

• We evaluated the evidence of the clinical efficacy, effectiveness, safety, and cost-effectiveness (value from a human or health system perspective) of transdermal versus oral estrogen in gender-affirming care using a rapid review approach.

• We searched for evidence-based guidelines on the use of transdermal or oral estrogen in gender-affirming care.

What Did We Find?

• We identified 1 systematic review, 3 primary studies, and 4 evidence-based guidelines relevant to this review. No relevant health technology assessment (HTA) reports or cost-effectiveness studies were identified.

• The systematic review reported no preidentified clinical efficacy or effectiveness outcomes and did not formally compare the safety of transdermal estrogen to oral estrogen, which limits any related conclusions regarding the safety of these products in the context of gender-affirming care.

• The primary studies suggest that transdermal estrogen therapy may have lower cardiometabolic risks (conditions that affect the heart and metabolism, such as heart attack, obesity, and diabetes), have similar effects on bone health, and have similar feminizing effects (breast development, changes in body fat composition) compared to oral therapy. However, important patient outcomes such as quality of life and adverse effects remain unexamined.

• Current guidelines, largely based on expert opinion, recommend transdermal estrogen therapy for patients older than either 40 or 45 years or those with a higher cardiovascular risk, starting at a lower dose and gradually increasing as necessary.

What Does This Mean?

• Both transdermal and oral formulations appear safe, but it is unclear if transdermal estrogen offers the same or greater benefits in gender-affirming care.

• Those making reimbursement decisions may consider individual risk for venous thromboembolism (VTE) (blood clots in the veins) or other harms that have been identified by those who are concerned about the risks associated with oral therapy.

Introduction and Rationale

Background

Gender-Affirming Care

Gender-affirming hormone therapy (GAHT) mainly consists of either estrogen or testosterone.¹ Transgender and nonbinary people may take hormone therapy as part of their gender transition to help their bodies and appearance align with their gender identity.² The concept of GAHT has emerged to better address the health care needs of transgender, nonbinary, and gender-nonconforming individuals, moving beyond the traditional framework of hormone replacement therapy.³

Estrogen Therapy

Estrogen, along with antiandrogen therapy, is a key component of FHT, a form of GAHT, which involves administering hormones to suppress effects of masculinizing hormones and promote feminization. The reasons why transgender, nonbinary, and other gender-expansive people take estrogen hormone therapy varies from person to person. It can be used to reduce coarse body hair and facial hair and to develop breasts and hips.^4,5 Some people choose to take estrogen because it makes them feel right in their body.⁶ Estrogen therapy sometimes requires the additional suppression of androgens (testosterone) in the body.⁷ Studies also indicate that FHT with estrogen improves bone mineral density (BMD).⁸

Available estrogen products used in FHT are administered by several routes of administration, each with different benefits and considerations. They are used primarily to induce and maintain feminizing physical changes in transgender women (assigned male at birth but identifying as female) and nonbinary individuals seeking feminization. The most common routes include oral tablets,⁹ which are convenient but carry higher risks of cardiovascular (CV) complications such as VTE, myocardial infarction, and hyperlipidemia caused by first-pass metabolism in the liver.¹⁰ Studies on individuals in postmenopause suggest that transdermal estrogen, compared to oral estrogen, may carry a reduced CV risk, particularly among smokers.^11,12 Transdermal FHT involves the delivery of estrogen through patches, gels, or creams, which are applied directly to the skin and absorbed.¹³ There is speculation that transdermal estrogen products may have some advantages over oral products, including a potentially lower risk of CV adverse effects and VTE, and may be a more appropriate option over oral estrogen in certain patient groups, such as individuals with migraines and hypertension.^14-16 Studies also suggest that, compared to oral FHT, transdermal FHT may result in lower CV risk, such as lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) and healthier triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL) lipid profiles. They may additionally lower CV risks associated with total cholesterol (TC) and body mass index (BMI).¹⁷

Policy Issue

There are 2 transdermal formulations of estrogen available in Canada: topical gels (e.g., EstroGel)¹⁸ and topical patches (e.g., Estradot).¹⁹ Multiple factors can influence the selection of an alternative hormonal therapy drug, including cost, adherence to regimen, and patient preference. Drug plans now seek more robust and current evidence comparing transdermal and oral estrogen therapy in the context of gender-affirming care. Therefore, the rationale for this rapid review arises from the need for a clear understanding of the clinical efficacy, safety, and cost-effectiveness of transdermal versus oral estrogen therapy to guide reimbursement decision-making.

Policy Question

Should transdermal estrogen be reimbursed in the first-line setting, as an alternative to oral estrogen, in the context of gender-affirming care?

Purpose

The objective of this project is to compare the efficacy, effectiveness, safety, and cost-effectiveness of transdermal estrogen therapy versus oral estrogen therapy in the context of gender-affirming care.

Research Questions

The following research questions will be used to address the policy question:

1. What is the clinical efficacy, effectiveness, and safety of transdermal estrogen compared to oral estrogen in the context of gender-affirming care?

2. What are the evidence-based guideline recommendations regarding the use of transdermal estrogen in the context of gender-affirming care?

3. What is the cost-effectiveness of transdermal estrogen compared to oral estrogen in the context of gender-affirming care?

Methods

We conducted a rapid review of the clinical efficacy and safety of transdermal estrogen in the context of gender-affirming care and of the evidence-based guidelines and cost-effectiveness literature.

Literature Search Methods

An experienced medical information specialist developed and tested the search strategies through an iterative process in consultation with the review team. Another senior information specialist peer-reviewed the MEDLINE strategy prior to execution using the Peer Review of Electronic Search Strategies (PRESS) Checklist.²⁰ Using the multifile option and deduplication tool available on the Ovid platform, we searched Ovid MEDLINE® ALL, Embase Classic+Embase, APA PsycInfo, and the Cochrane Central Register of Controlled Trials. We applied a combination of controlled vocabulary (e.g., “health services for transgender persons,” “hormone replacement therapy,” “administration, topical”) and keywords (e.g., “trans female,” “HRT,” “transdermal”), adjusting the vocabulary and syntax as necessary across the databases. Robust design and economic filters were used in all databases but CENTRAL, which is prefiltered for randomized and controlled clinical trials. We did not restrict by language but did limit results to the publication years 2017 to the present and, where applicable, removed animal-only and opinion pieces. We performed all searches on August 26, 2024, and updated them on October 1, 2024.

We downloaded and deduplicated the records using EndNote version 9.3.3 (Clarivate Analytics) and uploaded them to Covidence (Veritas Health Innovation Ltd.).

We conducted a focused search for relevant HTAs by exploring potentially relevant documents published by international organizations or country-specific HTA agencies in Canada, the US, the UK, Australia, and New Zealand. This search was guided by the Canada’s Drug Agency Grey Matters Checklist, using keywords relevant to our research questions. A single reviewer systematically screened reports and publications from these HTA websites, retrieving any potentially relevant full-text documents for further evaluation to assess their eligibility for inclusion in the review.

A targeted search of various clinical guideline developers was conducted to identify guidelines for the use of FHT using transdermal estrogen published since 2017. Practice guideline developers specializing in GAHT (including FHT), both within Canada and internationally, as well as reputable generalist organizations, were selected. The targeted list of developers included the Canadian Professional Association for Transgender Health, Trans Care British Columbia, Alberta Health Services, the AIDS Committee of Toronto, Rainbow Health Ontario, Nova Scotia Health Authority, Australian Professional Association for Trans Health (AusPATH), World Professional Association for Transgender Health (WPATH), Endocrine Society, American College of Obstetricians and Gynecologists, British Medical Association, National Health Service England, Royal College of General Practitioners, and European Society for Sexual Medicine. We searched the guideline producer and organizations' websites to locate the most current version of any relevant guidelines.

FHT Marketed in Canada

In Canada, various estrogen products are available for FHT, as listed in Table 1.

Table 1: Selected Estrogen Products Marketed in Canada²¹

DIN = Drug Identification Number.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 2.

Table 2: Selection Criteria

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 2, were duplicate publications, or were published before 2017. Abstracts, non-English articles, letters to the editor, opinion pieces, narrative reviews, books, and book chapters were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included systematic reviews. Guidelines that did not meet the PICO (population, intervention, comparator, outcomes) criteria or did not consider the route of administration were also excluded.

Critical Appraisal of Individual Studies

All studies were critically appraised by 1 reviewer. The included systematic review was critically assessed using the AMSTAR (A MeaSurement Tool to Assess systematic Reviews) 2 tool.²² The included primary studies were critically appraised using a modified version of the ROBINS-I (Risk Of Bias In Nonrandomized Studies of Interventions) checklist, which focused on study validity confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results.²³ Evidence-based guidelines were appraised using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument,²⁴ focusing on the rigour of development and editorial independence domains. Each included publication’s strengths and limitations were described narratively.

Patient Engagement

Three individuals receiving transdermal or oral estrogen for gender-affirming care were confidentially interviewed before the literature search to share their lived and living experiences. These individuals offered personal perspectives on treatment priorities, research questions, and outcomes outlined in the selection criteria.

All individuals had several years of experience receiving hormone therapy in the context of gender-affirming care; 1 individual started oral estrogen therapy, 1 individual started on oral estrogen therapy and switched to transdermal estrogen therapy, and 1 individual started on transdermal estrogen therapy and switched to oral estrogen therapy.

Two individuals with lived and living experience reviewed the draft report to provide feedback on content and language.

A summary of the patient engagement report using the Guidance for Reporting Involvement of Patients and the Public (GRIPP2) framework is provided in Appendix 1, Table 3.

Summary of Evidence

Quantity of Research Available

A total of 384 citations were identified in the literature search. Following the screening of titles and abstracts, 344 citations were excluded, and 40 potentially relevant reports from the electronic search were retrieved for full-text review. In addition, 7 potentially relevant guidelines were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 8 publications met the inclusion criteria and were included in this review. These comprised 1 systematic review¹⁷ and 3 primary studies (2 prospective cohort studies,^25,26 1 retrospective cohort study²⁷) and 4 evidence-based guidelines.^9,28-30 No HTA reports or cost-effectiveness studies were identified. Figure 1 in Appendix 2 presents the PRISMA flow chart of the study selection.

Study Characteristics

Systematic Review

The systematic review, published in 2022, included 5 studies, of which 4 (3 prospective studies and 1 retrospective study) met the inclusion criteria of this report.¹⁷ The review provided a narrative synthesis of primary study findings, and no meta-analysis or any other statistical comparison was performed. The included studies were published up to 2016. The details of the systematic review are provided in Table 4 in Appendix 3.

Patient Population

The primary studies included in the systematic review were carried out in various countries in Europe, including the Netherlands, the UK, and Austria.¹⁷ Overall, 203 of 259 (78%) patients received transdermal or oral estradiol as FHT. The remaining patients received injectable FHT, which was not relevant to this review. None of the studies included information on ethnicity or other demographic details of the included patients.

Interventions and Comparators

The interventions in the systematic review primarily focused on the administration of hormone therapy through both non-oral (transdermal patches and intramuscular injections) and oral routes.

Across 4 studies included in the review, transdermal 17-beta estradiol was administered to more than 84 patients (the actual number of patients receiving transdermal FHT was not reported) at a dose of 100 mcg every 2 weeks for 2 to 60 months. Additionally, 23 patients received transdermal estradiol hemihydrate at a dose of 40 mcg or 50 mcg every 24 hours for 40 months. All transdermal FHTs were administered using patches. No information about the titration of doses was provided.

Comparators included various oral estrogen therapies. In 1 included study, oral ethinyl estradiol was administered to 15 patients who received 100 mcg every 24 hours for 2 to 4 months. In a second study, 57 patients received conjugated equine estrogen with doses ranging from 1.25 mg to 5 mg every 24 hours over a period of 6 to 40 months. Forty patients in the third study received oral estradiol valerate at a dose of 4 mg every 24 hours for 12 months. Lastly, in the fourth included study, 41 patients received oral 17-beta estradiol, with doses ranging from 2 mg to 4 mg every 24 hours for between 3 and 60 months.

Efficacy and Effectiveness Outcomes

The systematic review’s focus was on safety and, as such, did not report any efficacy or effectiveness outcomes of interest to the rapid review.

Safety Outcomes

The systematic review included outcomes focusing on cardiovascular risk across different routes of estrogen therapy administration. All included primary studies reported outcomes for cardiovascular events, which included LDL, HDL, TG, and TC levels. Two of the primary studies included in the review also assessed SBP and DBP measurements. However, the review did not specify or cite the studies reporting these outcomes, making it difficult to infer overall conclusions about cardiovascular risks associated with transdermal FHT versus oral FHT. None of the included primary studies reported data on all-cause or cardiovascular mortality.

Primary Studies

No RCTs were identified. Among the 3 primary studies included in this review,^25-27 2 studies were described as prospective cohort studies,^25,26 and 1 as a retrospective cohort study.²⁷ None of the primary studies were included in the systematic review identified. The details of the primary studies are described in Table 5 in Appendix 3.

Countries Where the Studies Were Conducted

One study was conducted in Australia²⁷ and 2 were conducted in the Netherlands.^25,26

Patient Population

The number of patients included in the primary studies ranged from 49 to 231.^25-27 One study examined the effects of estrogen administered through both transdermal and oral routes in a cohort of 212 patients.²⁶ In 1 study, testosterone or estrogen was administered to 430 patients, with 231 patients receiving transdermal or oral estrogen.²⁵ In 1 study, 55 patients received estrogen via transdermal or oral administration or a combination of these routes.²⁷ After the exclusion of patients undergoing combination therapy, 49 patients who received transdermal or oral estrogen were included from this study in this review.²⁷

All patients were adults, with median ages ranging from 28.0 to 52.8 years.^25-27 Median ages of individual treatment groups were reported in 2 studies, with the transdermal group being older (median age 43.0 and 59.1 years) than those receiving oral FHT (median age 22.0 and 52.5 years).^26,27 The ethnicity of the patients was reported in only 1 study, in which 97.4% of the included 430 patients were white,²⁵ and the other 2 studies did not include ethnicity or other demographic information of patients specific to transdermal or oral FHT.^26,27 In 1 study, patients were included if they had received FHT for 6 months or more,²⁷ and in 2 studies, patients were excluded if they had previously received FHT.^25,26

Interventions and Comparators

In Wiepjes et al., 99 patients received transdermal estradiol patches (50 mcg to 100 mcg twice weekly) combined with cyproterone (50 mg to 100 mg daily), and 63 patients received oral estradiol (2 mg to 4 mg daily) with cyproterone.²⁵ The Balcerek et al. study included 32 patients on oral estradiol (median 4 mg) and 17 patients on transdermal estradiol (via patches with a median of 62.5 mcg or gels with a median dose of 1.0 mg to 1.25 mg).²⁷ The Tebbens et al. study included 88 patients in the transdermal estradiol group (50 mcg to 100 mcg for 24 hours, twice weekly) and 124 patients in the oral estradiol group (2 mg to 6 mg daily).²⁶ The 2 prospective studies by Wiepjes and colleagues and Tebbens and colleagues were carried out for 1 year, which was also the duration of transdermal and oral FHT.^25,26 In 1 study, the median duration of transdermal FHT was 48 months,²⁷ and the median duration of oral FHT was 78.3 months.²⁷

None of the studies compared the efficacy of patches and gels to each other.

Efficacy and Effectiveness Outcomes

The included primary studies reported a limited number of outcomes relevant to this review. One study each reported BMD,²⁵ change in BMI,²⁷ and feminizing effects (change in body fat percentage and breast development).²⁶

Safety Outcomes

Safety-related outcomes were reported in only 1 study, which reported the differences in cardiovascular risk factors in patients receiving transdermal estradiol compared to oral estradiol.²⁷ Specifically, the following outcomes were assessed: BMI, number of patients with ischemic heart disease (IHD), number of VTE events, number of patients with obesity (defined by BMI > 30), dyslipidemia (increased lipid levels from baseline), and new cases of diabetes.

Evidence-Based Guidelines

Four evidence-based guidelines were identified.^9,28-30 These guidelines were developed by the multinational Endocrine Society (last updated in 2017),²⁸ AusPATH in Australia (published in 2019),²⁹ Standards of Care by WPATH (version 8, last updated in 2022),⁹ and Rainbow Health Ontario (last updated in 2023).³⁰ Rainbow Health Ontario is a government-funded program dedicated to improving transgender and nonbinary patients’ health outcomes.³¹ Detailed characteristics of the evidence-based guidelines are provided in Table 6 in Appendix 3.

Critical Appraisal

Summaries of the critical appraisal of the systematic review, primary studies, and evidence-based guidelines are presented in Table 7, Table 8, and Table 9, respectively.

Systematic Review

The AMSTAR 2 assessment of the systematic review by Miranda and colleagues¹⁷ highlighted several strengths, including a clearly focused research question based on PICO criteria, a predefined review method registered on PROSPERO (International Prospective Register of Systematic Reviews), and a comprehensive literature search across multiple databases. Study selection and data extraction were conducted by 2 reviewers independently, and the risk of bias was assessed using the Newcastle-Ottawa Scale. The review also had limitations such as a lack of details of the study designs of the primary studies, incomplete reporting of excluded studies, and insufficient details about the populations studied. The heterogeneity of outcomes prevented a meta-analysis, which limited the ability to assess quantitatively both the risk of bias and potential publication bias. No efficacy outcomes related to FHT were included in the PICO and hence were not extracted from the primary studies.

Although the review had only 1 critical flaw (excluded studies not listed), its utility in this rapid review is limited given it did not report the overall outcomes of FHT specific to transdermal routes (the injectable and transdermal routes were combined as non-oral and compared to the oral route in the descriptive analysis) making it difficult to draw meaningful conclusions specifically about the safety of transdermal FHT.

Primary Studies

All eligible studies clearly addressed the focused research question.^25-27 One study controlled for potential confounding factors such as age, vitamin D supplementation, body weight, smoking, and alcohol use,²⁵ and another study controlled for baseline age, BMI, and estradiol concentrations.²⁶ One study did not adjust for any confounding factors.²⁷ Two studies did not report on patients lost to follow-up or those who discontinued due to adverse effects, making it challenging to evaluate potential attrition bias that these patients may systematically differ from those who remain in the study.^26,27 Additionally, a major limitation across these studies was the lack of safety data or adverse effect reporting as well as the absence of major efficacy outcomes for FHT.^25-27 One study had a small sample size of patients (49 patients) receiving FHT.²⁷ None of the studies recorded whether patients discontinued FHT due to adverse effects, and important patient outcomes such as feminizing effects (breast development and changes in body fat) were reported by only 1 study²⁶ and entirely omitted by the other 2 studies.^25,27 Although 1 retrospective study described the treatment period as almost 6 years,²⁷ neither of the prospective studies had a follow-up period beyond 12 months.^25,26 Therefore, these limitations hinder the ability to fully assess the comparative safety, efficacy, and long-term impact of transdermal FHT versus oral FHT.

Evidence-Based Guidelines

The Endocrine Society²⁸ guidelines referenced systematic review methods but lacked detailed information on how these were applied. It also provided limited detail on how the criteria for selecting evidence were determined, as a PICO was not clearly defined. The strengths and limitations of the evidence were discussed to some extent, with the guideline using its own grading scale. In contrast, AusPATH²⁹ and Rainbow Health Ontario³⁰ guidelines based their findings on pre-existing systematic reviews, expert opinion, and observational studies; did not elaborate on the PICO criteria; and failed to address the strengths and limitations of the evidence in detail. WPATH, on the other hand, showed stronger rigour by implementing a good systematic review methodology and using an elaborate PICO, though it did not explicitly mention the PICO elements in the guidelines.⁹ Both WPATH and AusPATH used Grading of Recommendations Assessment, Development and Evaluation (GRADE)³² to evaluate recommendations, which enhanced the clarity around the strengths and limitations of the evidence.^9,29 Overall, there was variability in the transparency and depth of the methods used to formulate recommendations, with WPATH⁹ standing out for its thorough approach, whereas the other guidelines provide more limited explanations.

In terms of formulating recommendations, the Endocrine Society 2017²⁸ and Rainbow Health Ontario³⁰ offered minimal details about the process. The guidelines by AusPATH,²⁹ provided vague indications on how the recommendations were developed that lacked significant depth. In contrast, WPATH 2022⁹ provided a more thorough description, considering the benefits, side effects, and risks of different recommendations in the formulation process.

Findings

Findings from the included systematic reviews, primary studies, and evidence-based guidelines are presented in Table 10, Table 11, and Table 12 in Appendix 5.

Systematic Review

A summary of the findings in the Miranda et al. systematic review is presented in Appendix 5, Table 10.

Efficacy and Effectiveness Outcomes

The included systematic review did not report any efficacy and efficacy outcomes.

Safety Outcomes

Cardiovascular Risk

In their 2022 systematic review, Miranda and colleagues considered cardiovascular risk among 203 of 259 patients receiving transdermal or oral FHT across 3 retrospective studies and 1 prospective study.¹⁷ The review examined changes in baseline for BMI, SBP, DBP, HDL, LDL, TC, and TG levels in patients receiving transdermal FHT and oral FHT for up to 60 months. However, there were no statistical analyses conducted to measure within- or between-group differences in the review, limiting our ability to draw firm conclusions about the relative safety of each administration route.

Primary Studies

A summary of the findings from the 3 included primary studies is presented in Appendix 5, Table 11.

Efficacy and Effectiveness Outcomes

Body Mass Index

In 1 study,²⁷ there were no significant differences in the change from baseline in BMI between patients receiving FHT via transdermal patches (17 patients) or oral estrogen (32 patients). The median duration of therapy was 48.0 months for transdermal patches and 78.3 months for oral.²⁷

Feminizing Effects

In 1 study, there were no statistically significant differences in breast development or in changes in fat displacement in individuals receiving transdermal FHT or oral FHT.²⁶

Bone Mineral Density

In 1 study,²⁵ no statistically significant difference was observed between the total BMD measured in the lumbar spine, total hip, and femoral neck regions in patients receiving transdermal estradiol FHT via patches (63 patients) compared to oral FHT (99 patients) after 1 year of therapy.

Safety Outcomes

Cardiovascular and Metabolic Risk Factors

One study reported that no differences in the proportion of patients with diabetes, hypertension, obesity, IHD, cardiovascular disease, or venous thromboembolic disease were observed regardless of the route of estrogen received as part of gender-affirming care.²⁷ Nevertheless, the study reported that a significantly higher number of patients receiving transdermal estrogen had dyslipidemia (increased levels of lipids from baseline) compared to patients receiving oral estrogen.²⁷

Evidence-Based Guidelines

For individuals either older than 40 years or older than 45 years, or those at higher risk of VTE or cardiovascular events, all 4 guidelines recommend transdermal estradiol over oral formulations as a safer option.^9,28-30 The guidelines provide varied recommendations for the dosage and regimen of transdermal estradiol in GAHT. Estradiol patches typically range from 50 mcg to 200 mcg per day, with applications suggested either every 3 to 5 days or twice weekly.^9,28-30 Estradiol gel begins at a daily dose of 2.5 g (150 mcg estradiol), with a maximum of 6.25 g (375 mcg), though application area may limit higher doses.^9,28-30 The details of the regimens are provided in Table 12 in Appendix 5.

The strength of the recommendations ranged from weak (reflecting uncertainty or variability in the balance between benefits and risks, often due to lower-quality evidence, patient preferences, or differing contexts) to strong (indicating high confidence that the intervention’s benefits clearly outweigh its risk).^9,28-30 The quality of evidence ranged from low — based on observational studies, case series, or case reports — to moderate — typically derived from well-conducted observational studies or RCTs with some limitations, such as small sample sizes, incomplete follow-up, or methodological flaws.^9,28-30 Some recommendations were informed by studies on menopause in cisgender people in addition to individuals receiving FHT.^9,29,30

Cost-Effectiveness of Transdermal FHT Compared to Oral FHT

No relevant evidence regarding the cost-effectiveness of transdermal FHT compared to oral FHT was identified in any of the included systematic reviews, primary studies, the guidelines, or other publications.

Limitations

Several limitations should be considered in this rapid review comparing transdermal versus oral estrogen for gender-affirming care. A key limitation of this report is the limited number of studies included. Only 1 systematic review and 3 primary studies met the eligibility criteria. Moreover, none of the primary studies were RCTs; they were observational studies, which are more prone to confounding, selection bias, and difficulties in establishing causality.^25-27 Based on the decision to balance rigorous methodology with timeliness when conducting a rapid review, inherent methodological constraints (such as a limited search strategy, a less comprehensive risk of bias assessment, and a restricted inclusion criteria) were unavoidable.

Systematic Review

A major limitation of the systematic review included in this report is that, in reporting the individual outcomes from studies of transdermal versus oral routes, the authors combined outcomes for transdermal and intramuscular FHT as non-oral routes in their overall synthesis, diluting the specificity of the comparative evidence of interest.¹⁷ Furthermore, although outcomes from individual studies were reported, no comparisons were made between routes of adminsitration.¹⁷ Additionally, the reviewed studies lacked clear definitions for key population characteristics, such as ethnicity and prior treatment history, further limiting the generalizability and applicability of the findings to specific patient groups. Overall, it was difficult to infer meaningful conclusions from this systematic review.

Primary Studies

In 2 of the 3 primary studies included in this review, patients receiving transdermal FHT were older (aged 59.1 and 43.0 years) than those receiving oral FHT (aged 52.5 and 22.0 years),^26,27 and in 1 study the median or mean age of patients receiving either transdermal or oral FHT were not reported.²⁵ The differences in age within the treatment groups may have impacted estrogenic effects on outcomes, and this makes it challenging to inform treatment decisions for diverse age groups. One study provided the ethnicity information and included mostly participants who were white. Only 1 study was a multicentre study²⁵ (while 1 was conducted at 1 clinic²⁶ and, in the other study, patients were recruited from 2 clinics)²⁷ and all studies were conducted in either the Netherlands or Australia, limiting the external validity and applicability of their results in diverse clinical settings and populations.^25-27 Two of the included studies did not report if any patients were lost to follow-up or to adverse effects, which could have led to attrition bias in these studies.^26,27 Two of the 3 primary studies did not exclude individuals who had received FHT before the start of the study, which may limit the applicability of the findings to inform the use of transdermal FHT as a first-line option for gender-affirming care. Although 1 study included feminizing effects such as breast development and change in body fat percentage,²⁶ other feminizing effects such as those associated with hair, skin, testes, prostate, sexual anatomic function, sexual desire, or libido were not reported, further limiting the ability to draw comprehensive conclusions about the feminizing effects of transdermal FHT. None of the included studies reported quality of life as an outcome. The number of patients receiving FHT ranged from 49 to 231,^25-27 but with only 1 study of 49 patients included in the comparison of BMI and cardiovascular risk between transdermal and oral routes, the robustness of any definitive conclusions for this outcome was limited.²⁷ As such, random variation in the results cannot be ruled out, and additional studies with similar sample sizes may provide different findings.³³ Additional studies with larger sample sizes are required to provide robust estimates for the outcomes of interest in this population. Moreover, variations in study design and bias mitigation, such as, but not limited to, adjusting for confounding variables, may have led to inconsistent or conflicting results, affecting the interpretability and comparability of outcomes. Together, selective reporting of outcomes and lack of standardized protocols likely contributed to variability in outcomes, thereby reducing the overall robustness of the evidence. Comparative RCTs are needed to better ascertain the clinical efficacy and safety of transdermal estrogen versus oral estrogen.

Guidelines

Although studies on treatments for menopause and postmenopause suggest that transdermal estrogen may be a safer option compared to oral estrogen,^10,34 the limited data on critical clinical outcomes in studies of individuals receiving transdermal estrogen for FHT — such as feminizing effects, cardiovascular safety, metabolic adverse effects, and quality of life — significantly impede the creation of clear, evidence-based guidelines for its use, particularly for younger and more diverse patient populations. A limitation common to all 4 included guidelines was an increased potential for bias due to their reliance on observational studies (or systematic reviews of observational studies).^9,28-30 In some cases, data were derived from studies conducted on cisgender individuals to inform their recommendations.^9,29,30 This may limit the applicability of the evidence to transgender populations because therapy goals, biology, and age ranges of individuals undergoing hormone therapy for the management of menopause are different from individuals who are receiving transdermal estrogen for gender-affirming care.

Patient Engagement

A notable limitation of this work relates to the patient engagement component of the rapid review. The engagement process involved 4 individuals who shared their lived and living experiences with FHT. However, the perspectives of these individuals cannot fully represent the lived and living experiences of the broader patient population. Additionally, no qualitative research or analysis of patient perspectives was conducted as part of this process.

Discussion and Implications for Decision- or Policy-Making

Conclusion

The objective of the rapid review was to summarize the evidence about the benefits and harms of transdermal estrogen therapy compared to oral estrogen therapy for gender-affirming care. We found 1 systematic review, 3 observational studies, and 4 evidence-based guidelines. No HTAs, RCTs, or pharmacoeconomic studies were identified.

Engaging with individuals who have experience with FHT was an important component of the rapid review. Through interviews, we gathered information regarding their perspective on relevant outcomes that should be considered in our review as well as their views on treatment priorities and access to treatment.

The interviewed participants identified feminization as the primary desired outcome of FHT so that their body aligns with their identity. They specifically mentioned breast development, facial features, skin, and body fat distribution as important outcomes. The evidence to date suggests that there are no statistically significant differences between the transdermal and oral formulations in changes in BMI or fat distribution or in breast development.

During the interviews, safety was raised as a main concern, and the participants indicated that transdermal FHT may have a better safety profile than oral therapy. Liver damage, cancer, and osteoporosis were all specifically mentioned as concerns. One observational study of 49 patients reported no statistically significant differences in the number of patients with diabetes, hypertension, obesity, IHD, or VTE. However, patients administered the transdermal formulation had a statistically significant increase in lipid levels. The largest observational study (231 patients receiving FHT) showed that there were no statistically significant differences in BMD.

The systematic review reported the changes from baseline for BMI, SBP, DBP, TG, TC, LDL, and HDL levels across individual studies, but no statistical analyses were conducted. It also did not conduct any statistical analyses of overall differences between transdermal and oral routes. Because of the lack of comparisons, no conclusions can be drawn from the systematic review.

Finding appropriate dosage levels of estrogen therapy was a challenge for all 3 interviewed participants. For individuals who switched from 1 formulation to another, the primary reason for switching was dosing challenges. Participants expressed a preference to start FHT with the safest, lowest-risk dosage. The guidelines offer various recommendations on the dosage regimen of transdermal estradiol in FHT.

Two observational studies included individuals receiving FHT aged 20 to 63 years, and the patients receiving transdermal estrogen were older than those receiving oral estrogen. Therefore, the results are not applicable to a younger population. One observational study reported that most patients included in the study were white, and ethnicity was not reported in the other 2 observational studies. Therefore, we cannot comment on the generalizability of the findings. Furthermore, the observational studies measured surrogate outcomes and not long-term clinical outcomes of concern to the participants.

Implications for Decision-Making

The policy question inquired as to whether transdermal estrogen should be reimbursed as first-line treatment, as an alternative to oral estrogen, in the context of gender-affirming care. The evidence considered in this review cannot adequately answer this question. While both transdermal and oral formulations appear to be safe, insofar as near-term cardiovascular risk among reasonably healthy adults, we cannot be certain if receiving transdermal estrogen for gender-affirming care confers similar or greater benefits than the oral formulation. Unlike orally administered estrogen, which undergoes first-pass metabolism in the liver, transdermal estrogen avoids this process, potentially reducing risks associated with hepatic metabolism, such as VTE. This distinction is especially critical for individuals with liver dysfunction or elevated VTE risk, who may benefit from transdermal over oral formulations. Expert guidelines recommend that the transdermal preparations be considered in certain groups of patients. All 4 evidence-based guidelines recommend transdermal FHT in those aged older than either 40 or 45 years, or those with cardiovascular or thromboembolic risk factors, and recommend starting with the lowest dosage and gradually increasing as necessary. Considering the evidence, it may be prudent to base decisions on the existing guidelines. Reimbursement policy-makers may consider individual risk for VTE or other harms among individuals who have concerns about the risks associated with oral estrogen therapy.

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Authors and Contributors

Authors

Shariq Najeeb contributed to screening studies; extracting data; analyzing and interpreting results, figures, and tables; verifying and assessing quality; and drafting and revising the report.

Shannon E. Kelly contributed to the conceptualization, methodology, and validation; the writing of the original draft of the report and the review and editing of its contents; and supervision and project administration.

Nazmun Nahar contributed to the full-text searches.

Melissa Brouwers contributed to supervision; funding acquisition; writing, editing, and review; and validation.

Becky Skidmore developed the search strategy in consultation with the review team; responded to PRESS feedback; translated and executed final strategies; deduplicated, packaged, and uploaded records to Covidence; and tracked PRISMA, provided search documentation, and wrote methods for the final manuscript.

Said Yousef Abdelrazeq contributed to the conception and design and the revision of the final report.

George A. Wells contributed to supervision; funding acquisition; writing, editing, and review; validation; and methodology.

Contributors

We thank Kaitryn Campbell, MLIS, MSc (Hamilton, ON) for peer-reviewing the MEDLINE search strategy.

This project was selected as part of a pilot for early engagement with patients and clinicians. We thank the contributors from these impacted groups for providing feedback and expertise throughout this project.

Patient Partners

We thank Alexis Egri, Alice Holland, Laura P., and 1 other person (who wishes to remain anonymous) for providing input into the direction of the research, drawing from lived experience, and providing valuable contributions to this report.

Clinical Experts

These individuals kindly provided comments on this report:

Sheila Wijayasinghe, MD, CCFP, MSCP

Family Physician, Medical Director, Primary Care Outreach

University of Toronto

Emma Gibbons, MD CCFP

Family Physician, Gender-Affirming Care Specialist

Conflicts of Interest

Said Yousef Abdelrazeq disclosed the following:

Involvement with projects or scientific advice

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RC1549 BRAF-MEK Inhibitors in Melanoma With Brain Metastasis

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

TR0016 Long-Acting Inhaled Agents for COPD

Shannon E. Kelly disclosed the following:

Involvement with projects or scientific advice

RE0048 Remdesivir for COVID-19 in the Inpatient Setting

HT0041 Remdesivir for COVID-19 in the Outpatient Setting

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RC1549 BRAF-MEK Inhibitors in Melanoma With Brain Metastasis

RC1552 Biologics for Inflammatory Bowel Disease

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

TR0016 Long-Acting Inhaled Agents for COPD

RD0076 Antiviral Drugs for the Treatment of Influenza

Nazmun Nahar disclosed the following:

Involvement with projects or scientific advice

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

Becky Skidmore disclosed the following:

Involvement with projects or scientific advice

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RC1549 BRAF-MEK Inhibitors in Melanoma With Brain Metastasis

RC1552 Biologics for Inflammatory Bowel Disease

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

TR0016 Long-Acting Inhaled Agents for COPD

RD0076 Antiviral Drugs for the Treatment of Influenza

Melissa Brouwers disclosed the following:

Involvement with projects or scientific advice

RE0048 Remdesivir for COVID-19 in the Inpatient Setting

HT0041 Remdesivir for COVID-19 in the Outpatient Setting

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RC1549 BRAF-MEK Inhibitors in Melanoma With Brain Metastasis

RC1552 Biologics for Inflammatory Bowel Disease

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

TR0016 Long-Acting Inhaled Agents for COPD

RD0076 Antiviral Drugs for the Treatment of Influenza

Pagebreak

Shariq Najeeb disclosed the following:

Involvement with projects or scientific advice

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RC1549 BRAF-MEK Inhibitors in Melanoma With Brain Metastasis

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

TR0016 Long-Acting Inhaled Agents for COPD

George A. Wells disclosed the following:

VBI Vaccines Inc. (2020–current): Coronavirus vaccine; Data Safety Monitoring Board, member

Thermedical (2021–current): Ablation system and catheter needle; design and analysis advice for preparation of FDA submission

VBI Vaccines Inc. (2020–current): Coronavirus vaccine; design and analysis advice for preparation of FDA submission

Involvement with projects or scientific advice

RE0048 Remdesivir for COVID-19 in the Inpatient Setting

HT0041 Remdesivir for COVID-19 in the Outpatient Setting

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RC1549 BRAF-MEK Inhibitors in Melanoma With Brain Metastasis

RC1552 Biologics for Inflammatory Bowel Disease

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

TR0016 Long-Acting Inhaled Agents for COPD

RD0076 Antiviral Drugs for the Treatment of Influenza

Kaitryn Campbell disclosed the following:

Involvement with projects or scientific advice

RE0043 Omalizumab for Chronic Idiopathic Urticaria

RC1549 BRAF-MEK Inhibitors in Melanoma With Brain Metastasis

RC1552 Biologics for Inflammatory Bowel Disease

RE0050 Immuno-oncology for Mutated Non–Small Cell Lung Cancer

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

TR0016 Long-Acting Inhaled Agents for COPD

RD0076 Antiviral Drugs for the Treatment of Influenza

Sheila Wijayasinghe disclosed the following:

Payments as advisor or consultant

Sanoling AI (2024): Virtual Care

Felix Virtual Care (2024): Virtual Care

McMaster Women’s Health Lecture on Menopause

Advisory Board for National Menopause Show

Walrus Talks Menopause

Involvement with projects or scientific advice

RD0073 Transdermal Versus Oral Menopausal Hormone Therapy

No other conflicts of interest were declared.

Appendix 1: Summary of Patient Engagement

Please note that this appendix has not been copy-edited.

Table 3: Reporting of Patient Engagement Using the GRIPP2 Framework

FHT = feminizing hormone therapy.

Appendix 2: Selection of Included Studies

Please note that this appendix has not been copy-edited.

Figure 1: PRISMA Flow Chart of Selected Reports

Appendix 3: Characteristics of Included Publications

Please note that this appendix has not been copy-edited.

Table 4: Characteristics of the Included Systematic Review

FHT = feminizing hormone therapy; NR = not reported.

^aData from one study excluded from this review because outcomes were compared between intramuscular injections and oral route.

^bOne study did not provide mean age.

^cData was only shown for transdermal route. Intramuscular injections outcome excluded this report.

^dTransdermal 17-beta estradiol reported in 4 studies and transdermal estradiol hemihydrate reported in one study.

^eIn all studies, cyproterone acetate (50 to 100 mg/24 hour or 48 hour) was used an antiandrogen regardless of route

^fOne study did not report number of patients undergoing transdermal therapy, so it was not possible to calculate the total number of patients undergoing transdermal therapy included in the systematic review.

Table 5: Characteristics of Included Primary Studies

BMD = bone mineral density; BMI = body mass index; CVD = cardiovascular disease; FHT = feminizing hormone therapy; IHD = ischemic heart disease; IQR = interquartile range; NR = not reported; VTE = venous thromboembolism.

^aPatients receiving transdermal or oral estrogen FHT.

^bExcluded from this report.

Table 6: Characteristics of Included Evidence-Based Guidelines

GRADE = Grading of Recommendations Assessment, Development, and Evaluation.

Appendix 4: Critical Appraisal of Included Publications

Please note that this appendix has not been copy-edited.

Table 7: Summary of the Critical Appraisal of the Included Systematic Review Using the AMSTAR 2 Tool

AMSTAR 2 = A MeaSurement Tool to Assess systematic Reviews 2; FHT = feminizing hormone therapy; PICO = population, intervention, comparator, outcomes; PROSPERO = International Prospective Register of Systematic Reviews.

^aDesignated as a critical item.

Table 8: Summary of the Critical Appraisal of Included Primary Studies Using the ROBINS-I Tool

BMD = bone mineral density; BMI = body mass index; ROBINS-I = Risk Of Bias In Non-randomized Studies of Interventions; vs. = versus.

Table 9: Summary of the Critical Appraisal of Included Evidence-Based Guidelines Using the AGREE II Tool

AGREE II = Appraisal of Guidelines for Research and Evaluation II; AusPATH = Australian Professional Association for Trans Health; COI = conflict of interest; CV = cardiovascular; GAHT = gender-affirming hormone therapy; PICO = population, intervention, comparator, outcomes; WPATH = World Professional Association for Trans Health.

^aThe term “women” is used by the study to define the population, and the extracted text is verbatim.

Appendix 5: Main Study Findings

Table 10: Outcomes Reported in the Systematic Review

BMI = body mass index; CIHR = Canadian Institutes of Health Research; DBP = diastolic blood pressure; FHT = feminizing hormone therapy; HDL = high-density lipoprotein; IQR = interquartile range; LDL = low-density lipoprotein, SBP = systolic blood pressure; TC = total cholesterol. TG = triglyceride.

^aThe review did not extract any statistically significant differences between transdermal and oral FHT from the primary studies and did not present any overall conclusions in the context of transdermal versus oral FHT. Only outcomes across individual studies were provided.

This table has not been copy-edited.

Table 11: Outcomes Reported in the Primary Studies

AE = adverse event; BMD = bone mineral density; BMI = body mass index; CVD = cardiovascular disease; FN = femoral neck; IHD = ischemic heart disease; IQR = interquartile range; LS = lumbar spine; NR = not reported; SAE = severe adverse event; TH = total hip; VTE = venous thromboembolism.

^aAdjusted for age, vitamin D supplementation, and alcohol use.

^bUnadjusted outcomes.

^cChange in fat adjusted for age and BMI; breast development adjusted for age, BMI, and blood estradiol concentration. Individual changes in treatment groups were not reported in this study.

^dMeasured using bioelectrical impedance analysis.

^eMeasured using 3-dimensional imaging.

^fMean difference between oral and transdermal estradiol users.

This table has not been copy-edited.

Table 12: Description of the Recommendations and Their Supporting Evidence for Gender-Affirming Hormone Replacement Therapy Using Transdermal Routes From Evidence-Based Guidelines

FHT = feminization hormone therapy; VTE = venous thromboembolism.

This table has not been copy-edited.

Appendix 6: References of Potential Interest but Not Meeting the Inclusion Criteria

Please note that this appendix has not been copy-edited.

Primary Studies

Irrelevant Study Design

Lim HY, Leemaqz SY, Torkamani N, et al. Global Coagulation Assays in Transgender Women on Oral and Transdermal Estradiol Therapy. J Clin Endocrinol Metab. Jul 1 2020;105(7)doi:10.1210/clinem/dgaa262 PubMed

Outcomes Out of Scope

Chantrapanichkul P, Ingsathit A, Chotai P, et al. Serum hormone concentrations in transgender individuals receiving gender-affirming hormone therapy: a longitudinal retrospective cohort study. Endocr Pract. 2021;27(1):27-33. PubMed

Salakphet T, Yodkoet P, Wattanayingcharoenchai R, et al. Hormone concentrations in transgender women who self-prescribe gender-affirming hormone therapy: a retrospective study. J Sex Med. 2022;19(5):864-871. PubMed

Sumerwell C, Johnson M, Lee A, et al. Serum hormone concentrations in transgender youth receiving estradiol. Endocr Pract. 2024;30(2):155-159. PubMed

Kariyawasam NM, Wylie K, Sumerwell C, et al. Comparison of estrone/estradiol ratio and levels in transfeminine individuals on different routes of estradiol. Transgender Health. 2024. In press. Available from: https://doi.org/10.1089/trgh.2023.0138

Guidelines

Not Evidence-Based

Oliphant J, Veale J, Macdonald J, et al. Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa New Zealand. Transgender Health Research Lab; 2018.