Evaluation of Dose Equivalence Between Oral and Transdermal Estradiol Administration in Turner Syndrome Patients

The primary objective of this study is to determine the **equipotency** of two different **estradiol** regimens, specifically comparing oral administration using Estrofem film-coated tablets and transdermal administration using Divigel gel, in women with **Turner syndrome**. This is achieved by evaluating various **estradiol-dependent surrogate markers**. The clinical relevance of this objective lies in optimizing hormone replacement therapy for Turner syndrome, ensuring effective and safe dosing regimens that can improve patient outcomes by balancing efficacy and minimizing potential side effects.

The clinical trial involves a study population consisting exclusively of **female** participants, with an age range of 18 to 50 years. The trial focuses on individuals diagnosed with **Turner syndrome**, as well as healthy controls. Participants with Turner syndrome are already receiving estrogen treatment, while healthy controls are previously healthy, not on any medication, and not using contraceptive pills. The trial excludes individuals with mental or psychiatric disorders. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is not part of a vulnerable group, and the trial does not include male subjects. The primary objective is to assess the equipotency of two different **estradiol** regimens, comparing oral versus transdermal administration, using various estradiol-dependent surrogate markers.

The clinical trial is designed to evaluate the **equipotency** of two different **estradiol** regimens, specifically oral versus transdermal administration, in women with **Turner syndrome**. This is a randomized, double-blind, controlled trial, categorized as a phase IV study. The trial aims to measure levels of luteinizing hormone and follicle-stimulating hormone at different doses to determine the primary endpoint of equipotency. The trial is expected to run from January 1, 2022, to December 31, 2026, with participant involvement lasting up to 14 days, corresponding to the maximum treatment period.

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 free from mental or psychiatric disorders. Following the screening, participants will be randomized to receive either oral or transdermal **estradiol**. Follow-up visits will be scheduled to monitor hormone levels and assess any adverse effects. The end-of-study visit will conclude the trial, where final assessments and data collection will occur.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to comply with the study protocol, or withdraw consent. The trial's design ensures that all procedures are conducted under strict ethical guidelines, with the safety and well-being of participants as a priority. The study's findings are anticipated to provide valuable insights into the optimal administration route for **estradiol** in managing **Turner syndrome**.

The clinical trial involves the administration of two **estradiol**-based treatments to evaluate their equipotency in managing Turner Syndrome. The first experimental medication is **Estrofem**, a **film-coated tablet** containing **estradiol** as the active substance. This pharmaceutical form is designed for **oral** administration. The dosage regimen allows for a maximum daily dose of 10 mg, with a total maximum dose of 140 mg over a treatment period of 14 days. The tablets are manufactured by **Novo Nordisk A/S** and are not formulated for pediatric use. Compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen.

The second experimental treatment is **Divigel**, a **gel** formulation also containing **estradiol**. This product is intended for **transdermal use**, providing an alternative route of administration. Similar to Estrofem, Divigel permits a maximum daily dose of 10 mg and a total maximum dose of 140 mg over 14 days. The gel is produced by **Orion Corporation** and is likewise not a pediatric formulation. Participant compliance with the application of the gel is monitored to maintain consistency in the treatment protocol.

Both treatments are evaluated in the context of their effects on various **estradiol**-dependent surrogate markers, with the primary objective of determining the equipotency of the oral versus transdermal administration routes. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is conducted under strict adherence to the dosing schedules, and participant compliance is closely monitored to ensure the integrity of the study results.

Efficacy in this clinical trial will be assessed by determining the equipotency of two different **estradiol** regimens, specifically oral versus transdermal administration, in participants with Turner syndrome. The primary endpoint for evaluating efficacy involves measuring the levels of luteinizing hormone and follicle-stimulating hormone at different doses of **estradiol**. These hormone levels serve as estradiol-dependent surrogate markers to assess the hormonal response and effectiveness of the treatment regimens. The trial aims to establish whether the two administration routes provide equivalent hormonal effects, thereby determining their equipotency. The measurements will be conducted using validated laboratory tests to ensure accuracy and reliability of the data collected. The trial is designed to provide insights into the endocrine, cardiovascular, pharmacological, and physiological aspects of sex hormone therapy in Turner syndrome, contributing to the optimization of treatment strategies for this condition.