Evaluation of Transdermal Testosterone Replacement Therapy on Endocrine, Cardiovascular, and Neurocognitive Outcomes in Women with Turner Syndrome

The primary objective of this study is to evaluate the **endocrine**, physiological, cardiovascular, neurocognitive, and genomic effects of transdermal testosterone replacement therapy (TRT) as a supplement to estrogen replacement therapy (ERT) in women with Turner Syndrome. This investigation is clinically relevant as it aims to elucidate the comprehensive impact of TRT on multiple physiological systems in this specific patient population, potentially informing treatment protocols and improving patient outcomes.

The clinical trial focuses on evaluating the effects of transdermal testosterone replacement therapy (TRT) as a supplement to estrogen replacement therapy (ERT) in women diagnosed with **Turner Syndrome**. The study population comprises females aged between 18 and 50 years, all of whom are currently receiving estrogen replacement therapy. Participants are required to speak Danish. The trial does not include male subjects or vulnerable populations. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria emphasize the inclusion of all karyotypes of Turner Syndrome, ensuring a comprehensive assessment of the therapy's impact across the specified age range.

The clinical trial is designed to evaluate the effects of **testosterone replacement therapy** (TRT) in women with **Turner Syndrome**. This study is a randomized, double-blind, controlled trial, conducted over a period of 18 months, with an estimated recruitment start date of March 3, 2025, and an estimated end date of September 1, 2026. The trial aims to assess the endocrine, physiological, cardiovascular, neurocognitive, and genomic effects of transdermal TRT as a supplement to estrogen replacement therapy (ERT) in the target population. Participants will be randomly assigned to receive either the active treatment or a placebo, ensuring the study's double-blind nature.

Study visits are structured to include an initial screening visit, multiple follow-up visits, and a final end-of-study visit. The inclusion visit will involve screening for eligibility criteria, which include a confirmed diagnosis of Turner Syndrome, age between 18 and 50 years, current ERT, and proficiency in Danish. Follow-up visits will be scheduled at regular intervals to monitor changes in primary and secondary endpoints, such as body composition, quality of life, inflammatory markers, and neurocognitive function. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of all study parameters.

Participants are expected to be involved in the trial for the entire duration of 12 months, with the possibility of early termination if they experience adverse effects, fail to comply with the study protocol, or withdraw consent. The trial's primary endpoint focuses on changes in body composition, assessed through dual-energy x-ray absorptiometry (DXA) scans, while secondary endpoints include a range of physiological and cognitive measures. The study's methodology and design ensure rigorous evaluation of TRT's potential benefits in women with Turner Syndrome, contributing valuable insights into its therapeutic efficacy.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **ISOPROPYL MYRISTATE** is utilized in the form of an ointment, with a maximum daily dose of 2.7 mg and a total maximum dose of 990 mg over a 12-month period. The route of administration is transdermal, and it serves as a chemical agent in the study. Participant compliance is monitored to ensure adherence to the dosing schedule.

**ANDROGEL 25 mg, gel transdermique**, containing the active substance **TESTOSTERONE**, is administered as a transdermal gel. The maximum daily dose is 0.55 g, with a total maximum dose of 201 g over the course of 12 months. This product is provided by BESINS HEALTHCARE and is used as a standard-of-care therapy in the trial. The transdermal route is employed to facilitate the absorption of testosterone, and compliance is closely monitored.

**CARBOMER 980** is included in the study as an eye gel, with a maximum daily dose of 4.5 mg and a total maximum dose of 1650 mg over 12 months. It is used transdermally and functions as a gelling agent. The administration schedule is designed to ensure consistent application, and participant adherence is tracked throughout the trial.

**SODIUM HYDROXIDE** is administered as a solution for infusion, with a maximum daily dose of 26.4 mg and a total maximum dose of 9636 mg over a 12-month period. It is used transdermally as a neutralizer. The dosing schedule is structured to maintain consistent exposure, and compliance is monitored to ensure proper administration.

**ETHANOL (96 PER CENT)** is utilized in the form of a cutaneous solution, with a maximum daily dose of 0.4 g and a total maximum dose of 146 g over 12 months. It serves as a solvent and absorption enhancer, administered transdermally. The study protocol includes measures to monitor participant compliance with the dosing regimen.

The efficacy of the clinical trial titled "Testosterone Replacement Therapy in Women with Turner Syndrome – Endocrine, Cardiovascular, Physiological, Neurocognitive and Genomic effects" will be assessed using a combination of primary and secondary endpoints. The primary endpoint focuses on changes in body composition, which will be evaluated through total body dual-energy x-ray absorptiometry (DXA-scan). This includes measurements of bone mass, visceral and subcutaneous fat mass, lean muscle mass, abdominal circumference, and weight.

Secondary endpoints will encompass a range of physiological and psychological parameters. These include changes in quality of life, inflammatory markers, sexual function, intramuscular sex hormone levels, blood volume, **hemoglobin** mass, coagulation parameters, metabolic parameters, neurocognitive function, hypothalamus structure, and physical performance metrics such as VO2-max, physical activity, muscle function, and strength. The trial is designed to explore the comprehensive effects of transdermal testosterone replacement therapy (TRT) as a supplement to estrogen replacement therapy (ERT) in women with Turner Syndrome.