Comparative Analysis of Oral Versus Transdermal Estradiol Replacement Therapy on Endocrine and Cardiovascular Outcomes in Turner Syndrome Patients

The primary objective of this study is to evaluate the **endocrine**, metabolic, cardiovascular, and thromboembolic risk factors in individuals with Turner syndrome following a washout period. Additionally, the study aims to compare the effects of oral versus transdermal estrogen replacement therapy (ERT) in women with Turner syndrome. The long-term effects of ERT administered through these two routes will be examined, focusing on endocrine, metabolic, cardiovascular, physiological, and thromboembolic risk endpoints. This research is clinically relevant as it seeks to optimize hormone replacement strategies in Turner syndrome, potentially improving patient outcomes by minimizing associated risks and enhancing therapeutic efficacy.

The clinical trial focuses on women diagnosed with **Turner syndrome**, aged between 18 and 50 years, who are already receiving estrogen treatment. The study also includes healthy female controls within the same age range, who are previously healthy, not on any medication, and not using contraceptive pills. The trial exclusively involves female participants, with no male subjects included, and does not target a vulnerable population. The sponsor has not provided information regarding the total number of participants. The trial aims to clarify endocrine, metabolic, cardiovascular, and thromboembolic risk factors in Turner syndrome and compare the effects of oral versus transdermal estrogen replacement therapy. Participants' lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the long-term effects of oral versus transdermal **estrogen replacement therapy** (ERT) in women with **Turner syndrome**. This is a phase IV, randomized, double-blind, controlled trial. The study aims to clarify endocrine, metabolic, cardiovascular, and thromboembolic risk factors in Turner syndrome after a washout period and to compare the effects of oral versus transdermal ERT. The trial will also examine the long-term effects of ERT via the two routes on various risk endpoints. The trial is expected to run from January 1, 2022, to December 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Turner syndrome, age between 18-50 years, and current estrogen treatment. Healthy controls must be female, previously healthy, not on medication, and not using contraceptive pills. The primary endpoints include assessments of body composition, blood test values, cardiovascular status, muscle quality, quadriceps strength, hand strength, fitness, bone mineral density, and jumping height. Secondary endpoints involve self-reported health-related quality of life and subjective assessment of the medication after six months of each treatment route.

The trial involves a maximum treatment period of seven days for each ERT route, with participants expected to be involved for the entire duration of the study unless conditions arise that necessitate early termination. Such conditions may include adverse reactions to the treatment or withdrawal of consent. The study will include follow-up visits to monitor the participants' health and response to the treatment, culminating in an end-of-study visit to assess the final outcomes and gather comprehensive data for analysis.

The clinical trial involves the administration of two experimental medications, both containing the active substance **estradiol**. The first medication is "Estrofem, filmovertrukne tabletter," which is a **film-coated tablet** form of estradiol. This medication is manufactured by Novo Nordisk A/S and is authorized in Denmark. The tablets are administered orally with a maximum daily dose of 10 mg and a maximum total dose of 2100 mg over a treatment period of 7 days. The pharmaceutical form ensures controlled release and absorption of the active substance through the gastrointestinal tract.

The second experimental medication is "Divigel 1 mg gel," a **gel** formulation of estradiol produced by Orion Corporation and authorized in Sweden. This medication is applied via transdermal use, allowing the active substance to be absorbed through the skin. Similar to the oral formulation, the maximum daily dose is 10 mg, with a total maximum dose of 2100 mg over a 7-day treatment period. The transdermal route is intended to provide a steady release of estradiol into the systemic circulation, potentially offering different pharmacokinetic and pharmacodynamic profiles compared to the oral route.

Both medications are used to compare the effects of oral versus transdermal estrogen replacement therapy (ERT) in women with Turner syndrome. The trial aims to evaluate the endocrine, metabolic, cardiovascular, physiological, and thromboembolic risk factors associated with each route of administration. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial data. Participant compliance with the dosing schedule will be monitored to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of estrogen replacement therapy (ERT) in women with Turner syndrome. The primary endpoints include measurements of body composition using bioimpedance, changes in blood test values related to metabolism, endocrinology, cardiovascular function, and coagulation, as well as cardiovascular status assessed through 24-hour ambulatory blood pressure monitoring and arterial stiffness using SphygmoCor. Muscle quality will be evaluated by magnetic resonance (MR) scans of the quadriceps to measure muscle cross-sectional area and fat content, alongside maximal isometric muscle strength tests. Additional primary endpoints include isometric hand strength tests, maximal oxygen uptake (VO2max) tests for fitness, bone mineral density assessed by DEXA scans, and maximal jumping height measurements.

Secondary endpoints focus on self-reported health-related quality of life and functioning using the SF-36 and WHOQoL-Bref questionnaires, as well as subjective assessments of the medication after six months of oral and six months of transdermal treatment. These endpoints will be measured and collected at specified intervals throughout the trial to ensure comprehensive data analysis. The trial aims to compare the effects of oral versus transdermal ERT on these parameters, providing insights into the long-term effects of ERT on endocrine, metabolic, cardiovascular, physiological, and thromboembolic risk factors in this population.