A Phase 2 interventional study of Oral estradiol valerate and Transdermal 17β estradiol in Turner Syndrome, sponsored by Universiti Kebangsaan Malaysia Medical Centre. Not yet recruiting at 1 site in Malaysia. Open to female participants aged 11 Years to 30 Years. Per ClinicalTrials.gov, last updated 2026-02-02.
Sponsored by Universiti Kebangsaan Malaysia Medical Centre · Phase 2, Interventional, and Treatment
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:
Who can take part?
What will happen to the participants during the clinical trial?
Get assigned at random to one of two groups (1:1 ratio):
Visit the clinic at the start of study (baseline), month 1, 7, 13, and 19 for:
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.
Turner syndrome (TS) is a chromosomal condition in which the loss of one X chromosome leads to ovarian failure, absent or delayed natural puberty, reduced bone density, and elevated cardiovascular and metabolic risk. This interventional, Bayesian Phase II pragmatic trial is being undertaken within the TRIFECTA-DARED framework to address a critical gap in the management of pubertal induction for adolescent and young adult females with TS. While estrogen replacement therapies are standard, there remains uncertainty about which regimen best approximates natural pubertal development, optimizes uterine growth, and minimizes adverse metabolic or thromboembolic risks. Our trial arises from the need for robust, locally generated evidence in Malaysia to inform clinical practice in this rare-disease context.
This single-centre study, conducted at Hospital Canselor Tuanku Muhriz (HCTM) and Hospital Pakar Kanak-Kanak at the Cheras Campus of Universiti Kebangsaan Malaysia, received ethics approval from the Universiti Kebangsaan Malaysia Research Ethics Committee (UKMREC). The trial design uses an open-label, randomized,1:1 ratio design, augmented by matched historical control data. After providing informed consent, participants are allocated by a central, computer-generated sequence (stratified by age category and body mass index) to receive either oral estradiol valerate (Progynova) or transdermal 17β-estradiol gel (Oestrogel). Treating clinicians and participants remain unblinded, while the trial statistician is masked until the database lock.
Both regimens begin with twice-weekly dosing for the first four weeks, followed by once-daily administration for the remaining 18 months. Incremental dose doubling at month 7 and again at month 13 is designed to mimic the gradual rise in endogenous estradiol characteristic of normal puberty. Doses are dispensed and tracked through an electronic case report form (eCRF) with real-time logging of medication issuance and returns, and participants maintain a daily diary to record dosing adherence, any spotting or bleeding episodes, and all adverse experiences.
Scheduled study visits occur at baseline and at months 7, 13, and 19, with quarterly safety check-ins during the first year. At each visit, a pediatric or adolescent gynecologist performs a comprehensive physical examination-including growth measurements, vital signs, and breast development staging-and obtains a transabdominal ultrasound to document uterine dimensions. Blood samples are drawn for routine safety laboratories (liver function, lipid profile, complete blood count) and hormone assays.
Safety oversight is provided by an independent Data Monitoring Committee (DMC), which reviews periodic safety reports prepared by an external statistician. Adverse events are graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Any life-threatening or disabling event associated with the study drug triggers immediate notification to the ethics committee and regulatory authorities within 24 hours; other Grade 3 or higher events are reported within five business days. Prespecified halting criteria include unexplained severe laboratory abnormalities, life-threatening reactions deemed drug-related, or anaphylactic-type responses within 24 hours of dosing.
All data are captured in a secure REDCap eCRF with built-in validation and audit trails. Concomitant medications are coded using the World Health Organization Anatomical Therapeutic Chemical (WHO-ATC ) classification system, and adverse events use MedDRA terminology. The database is backed up daily across multiple secure servers and locked after each monitoring visit. Quality assurance involves internal audits every six months by the sponsor, all in accordance with Good Clinical Practice (GCP) standards.
Data analysis follows an intention-to-treat framework with multiple imputation for missing values and sensitivity checks in a per-protocol subset. Although specific outcome measures are recorded elsewhere, continuous and categorical data will be analyzed using appropriate statistical models. In addition, Bayesian hierarchical modelling will be carried out to incorporate informative priors derived from matched historical TS cohorts, yielding posterior estimates of treatment effects and enabling predictive checks, thus providing robust inference despite the small sample inherent to this rare-disease study.
The trial is registered on ClinicalTrials.gov and the Malaysian National Medical Research Registry. Aggregate results will be posted within six months of study completion and disseminated through peer-reviewed publications and conference presentations following International Committee of Medical Journal Editors (ICMJE) authorship guidelines.
125 studies on the registry are indexed under Turner Syndrome; 33 are open to participants now.
This study's planned enrollment of 24 is below the median of 67 across 52 interventional studies indexed under Turner Syndrome.
Browse Turner Syndrome studies →Universiti Kebangsaan Malaysia Medical Centre is the lead sponsor of 58 studies on the registry; 8 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Severely obese patients based on the following criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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. 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. In this trial, Progynova will be administered starting at 1 mg twice weekly and titrated up to 4 mg daily over an 18-month period, in accordance with local clinical guidelines for pubertal induction in Turner Syndrome.
Drug: Oral estradiol valerate
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. The gel is supplied in multi-dose pump bottles (150 g), each providing up to 120 actuations. In this trial, Oestrogel® will be administered starting at one pump actuation (0.75 mg) twice weekly, with dose escalation every 3 months according to predefined protocol milestones, up to a maximum of four actuations daily (3 mg estradiol) over an 18-month induction period. Participants will be instructed on correct application technique-applying gel to clean, dry skin and allowing at least 5 minutes for drying before dressing-to ensure optimal absorption and minimize residue transfer
Drug: Transdermal 17β estradiol
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.
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.
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)
Time frame: From enrollment (baseline) to 19 months after the commencement of intervention (end of follow-up)
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)
Time frame: From enrollment to 19 months after the commencement of interventions (end of follow-up)
Uterine length (in cm)
Ultrasonographic scan conducted at the Paediatric and Adolescent Gynaecology (PAG) unit performed by a trained PAG Specialist (trial outcome assessor)
Time frame: From enrollment to 19 months after the commencement of interventions (end of follow-up)
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)
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow-up)
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
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow-up)
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)
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow up)
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.
Time frame: From enrollment to 19 months after the commencement of intervention (end of follow-up)
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — The final and cleaned-up version of the trial dataset containing individual clinical-trial participant data (IPD) for all study variables will be deposited in a public repository such as the Harvard Dataverse data repository (available from: https://dataverse.harvard.edu/) to ensure the transparency of trial reporting and compliance with the clinicaltrials.gov data sharing policies. The preliminary trial results will first be uploaded into the clinicaltrials.gov registry within 6 months after the completion of the last patient visit for early dissemination of trial results. The final trial findings (including trial objectives, the design of the trial (including revisions), the statistical analysis plan (including amendments) and the originally planned measurements of efficacy and safety parameters) will then be published as presentations at scientific conferences and in a complete published manuscript, even if the trial has to be prematurely halted.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
Time frame: 01/11/2029 until 31/10/2039 (10 years)
Access criteria: The general public and all researchers will have access to the IPD. The supporting information (full trial protocol and statistical analysis plan, informed consent form and case report form (CRF; English version) is available for download as separate study documents uploaded on this website.
This study is not yet recruiting, as verified in Jan 2026. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Estradiol
Universiti Kebangsaan Malaysia Medical Centre