A Study Comparing Different Treatment Approaches for the Initiation of Puberty in Girls With Turner Syndrome Using a TRIFECTA-DARED Approach for Rare Diseases

Summary

Turner syndrome is a condition in which a girl's body does not make enough estrogen on its own, so doctors give estrogen to help start breast and uterine (womb) development. Hence, the goal of this clinical trial is to learn whether two different ways of giving estrogen help girls and young women with Turner syndrome go through puberty normally, and to compare how well each method works and how safe they are.

The main questions the trial aims to answer are:

1. Does taking an oral estrogen tablet (Progynova) or applying an estrogen gel (Oestrogel) lead to better breast development?
2. Does one method lead to a larger uterine size as seen on ultrasound?
3. Do participants start menstrual-like (withdrawal) bleeding, and does one method cause it sooner?
4. What side effects (for example, headaches, nausea, changes in blood tests) happen with each method?

Who can take part?

* Girls and young women aged 11-30 years with a confirmed diagnosis of Turner syndrome and no previous estrogen treatment.
* They have not yet begun puberty (no breast growth, and a small uterus on ultrasound).
* They agree to adhere to the study schedule and keep a diary of any bleeding or side effects

What will happen to the participants during the clinical trial?

* Get assigned at random to one of two groups (1:1 ratio):

1. Gel group: Apply Oestrogel (17β-estradiol) to the skin, starting twice a week, then daily with increasing doses over 19 months.
2. Tablet group: Swallow Progynova (estradiol valerate) tablets, starting twice a week, then daily with increasing doses over 19 months.
* Visit the clinic at the start of study (baseline), month 1, 7, 13, and 19 for:

1. A physical exam (including breast staging).
2. An ultrasound to measure uterine length and thickness.
3. A blood test for safety checks (triglycerides and other markers).
4. Keep a diary noting any spotting or bleeding (called withdrawal bleeding) and any side effects.

Why does this matter?

Girls and young women with Turner syndrome often need estrogen to begin puberty safely. This trial will show which method-gel or tablets-best mimics natural puberty (breast and uterine growth), how quickly menstrual-like bleeding begins, and which has fewer unwanted effects. The findings will help doctors choose the most effective and safe treatment for people with Turner syndrome.

Conditions

• Turner Syndrome

Interventions

DRUG

Oral estradiol valerate

Progynova is an oral hormone replacement therapy containing the active ingredient estradiol valerate, a synthetic ester of 17β-estradiol that, upon ingestion, is rapidly converted to bioidentical estradiol. Each film-coated tablet delivers either 1 mg or 2 mg of estradiol valerate, with inactive excipients including lactose monohydrate, maize starch, povidone, magnesium stearate, and hypromellose. In terms of pharmacokinetics, oral estradiol valerate undergoes first-pass metabolism in the liver, yielding a peak serum estradiol concentration within 4-8 hours of dosing and a biological half-life of approximately 20 hours. Progynova tablets are supplied in blister packs of 28 tablets, with recommended storage at room temperature (15-30 °C), protected from moisture and direct sunlight.

DRUG

Transdermal 17β estradiol

Oestrogel® is a transdermal hormone replacement therapy containing 17β-estradiol in a hydroalcoholic gel formulation designed for topical application. Each pump actuation delivers 0.75 mg of estradiol in a 1.25 g dose of gel, which is formulated with excipients including ethanol, propylene glycol, carbomer, sodium hydroxide, and purified water to ensure consistent hormone release and skin penetration. Upon application to intact skin-typically the forearm or thigh-the gel allows for direct systemic absorption of estradiol, bypassing first-pass hepatic metabolism. Peak serum estradiol levels are generally reached within 6-12 hours post-application, with a half-life of approximately 10-20 hours, resulting in more physiological, steady- steady-state estradiol exposure compared to oral formulations. The gel is supplied in multi-dose pump bottles (150 g), each providing up to 120 actuations.

Sponsors & Collaborators

• Universiti Kebangsaan Malaysia Medical Centre

  lead OTHER

Principal Investigators

• MUHAMMAD IRFAN ABDUL JALAL, MBChB BAO, PhD · Universiti Kebangsaan Malaysia Medical Molecular Biology Institute (UMBI)

• ANI AMELIA ZAINUDDIN, MBBS, PhD · FACULTY OF MEDICINE, UNIVERSITI KEBANGSAAN MALAYSIA

• NUR AZURAH ABDUL GHANI, MBBS, MMed (Obs and Gynae) · National University of Malaysia

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

11 Years

Max Age

30 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-02-15

Primary Completion

2029-04-30

Completion

2029-10-31

Countries

• Malaysia