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

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. 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. 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. 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.