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.
Females aged 11-30 years old with karyotype-verified (45, X or other similar karyotypes) and clinically confirmed Turner's syndrome prior at the time of pubertal induction
Confirmed estrogen deficiency with primary ovarian failure (high level of follicular stimulating hormone (FSH > 25 IU/L))
Patients who have not undergone pubertal development ( no breast development and underdeveloped uterus size).
Hormone Replacement Therapy (HRT)-naive TS patients
Patients with signs of spontaneous puberty
Contraindications to trial products (e.g hypersensitivity to any components of the HRT) based on the most recent version of the British National Formulary (BNF 85)
Previous history of exposure to estrogen treatment.
Concomitant use of other drugs that affect the bone mineral density (BMD) of the participants (e.g. Bisphosphonates or prolonged use of systemic corticosteroids). Vitamin D supplementation and short corticosteroid usage are allowed.
Parallel
Oral estradiol valerate
DrugProgynova 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.
Transdermal 17β estradiol
DrugOestrogel® 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.
Proportions of Turner Syndrome with Satisfactory Breast Development (defined as Turner Breast Stage 3 (B3) and above)
Tanner Staging System for Breast Development as assessed by a trained pediatric and adolescent gynaecologist specialist at Hospital Canselor Tuanku Muhriz (HCTM)'s Pediatric and Adolescent Gynaecology (PAG) Unit. Tanner Staging System has a range between Tanner Breast Stage 1 (B1) (minimum value) and Tanner Breast Stage 5 (B5) (maximum value). Each stage is classified as follows: B1: Prepubertal - no glandular tissue. Only the nipple is raised. B2: Breast bud stage - small mound forms. Areola begins to enlarge. B3: Further enlargement of the breast and areola with no separation of their contours. B4: Areola and nipple form a secondary mound above the level of the breast. B5: Mature adult breast - breast contour is smooth. The areola recedes to the general contour of the breast (although in some women, the areola may remain raised). Higher Tanner breast stage means better breast development (i.e. better outcome)
Median time to achieving Tanner Breast Stage 4 (B4) and above (in days)
Tanner Staging System for the assessment of Breast Development as assessed by the paediatric and adolescent gynaecology specialist at Hospital Canselor Tuanku Muhriz (HCTM)'s Pediatric and Adolescent Gynaecologist. Tanner Staging System has a range between Tanner Breast Stage 1 (B1) (minimum value) and Tanner Breast Stage 5 (B5) (maximum value). Each stage is classified as follows: B1: Prepubertal - no glandular tissue. Only the nipple is raised. B2: Breast bud stage - small mound forms. Areola begins to enlarge. B3: Further enlargement of the breast and areola with no separation of their contours. B4: Areola and nipple form a secondary mound above the level of the breast. B5: Mature adult breast - breast contour is smooth. Areola recedes to the general contour of the breast (although in some women areola may remain raised). Higher Tanner breast stage means better breast development (i.e. better outcome)
Uterine length (in cm)
Ultrasonographic scan conducted at the Paediatric and Adolescent Gynaecology (PAG) unit performed by a trained PAG Specialist (trial outcome assessor)
Anteroposterior uterine fundal diameter (in cm)
Ultrasonographic scan conducted at the Paediatric and Adolescent Gynaecology (PAG) unit, performed by a trained PAG Specialist (trial outcome assessor)
Proportions of TS subjects achieving self-reported withdrawal bleeding (defined as spotting or bleeding episodes that occur at least for one day) during the treatment with Progynova or Oestrogel regimen
Self-reported by patients through documentation in a personal diary
Median time to withdrawal bleeding (in days)
The exact number of days of the time from the commencement of intervention until the occurrence of the first withdrawal bleeding. The occurrence of the first withdrawal bleeding is self-reported by patients through documentation in a personal diary. Withdrawal bleeding is defined as the occurrence of at least spotting (defined as bloody discharge that requires not more than a panty liner) based on Zhang and colleagues' criteria (reference 36)
Serum Triglyceride levels (in mmol/L)
Serum triglyceride level of the participant as reported by the laboratory based on the blood samples taken during the follow-ups at the PAG unit of HCTM.
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