This 5-week, phase IV randomized crossover trial aims to compare the effects of oral versus transdermal estrogen replacement therapy (ERT) in women with Turner syndrome (TS). The objective is to establish the equipotency between the two estradiol regimens by evaluating various estradiol-dependent surrogate markers. The study involves 50 women with TS, aged 18-50 years, who are randomized to receive either oral or transdermal ERT for 14 days, followed by a crossover to the alternate treatment for another 14 days, with a one-week washout period in between. Blood tests are conducted at baseline, after the first 14 days of treatment, after the washout period, and after the final 14 days of treatment. The investigators anticipate that this study will provide clinicians with a better understanding of ERT in treating women with TS.

OBJECTIVE

1. To determine the equipotency of two different estradiol regimens (oral versus transdermal administration) using various estradiol-dependent surrogate markers.

BACKGROUND Turner syndrome (TS) is a rare genetic condition affecting approximately 1 in 2,000 female births. A hallmark of TS is ovarian dysgenesis, leading to hypogonadism, premature ovarian failure, and infertility. Consequently, estrogen replacement therapy (ERT) is typically initiated around age 11-12 to induce puberty and continued until the average age of menopause (50-55 years), aiming for at least 42 years of adequate estrogen exposure.

Hypogonadism in TS is associated with various health complications. Importantly, estradiol (E2) replacement may mitigate these risks. Estrogen deficiency in TS affects cardiovascular health (hypertension, congenital cardiac disease, altered lipid profiles), metabolic function (diabetes, thyroid dysfunction, hepatic disorders, kidney disease, skeletal abnormalities), and is linked to neurocognitive and social challenges.

E2 can be administered orally or transdermally (TD), but it remains unclear whether either route offers specific advantages. There is ongoing debate regarding a potential increased thromboembolic risk in TS patients treated with oral E2. Epidemiological studies in postmenopausal women have reported an elevated thromboembolic risk associated with oral estrogen treatment, but to a lesser extent with TD administration. However, extrapolating data from postmenopausal women to TS patients is inappropriate, as women with TS receive estrogen as replacement therapy due to inadequate endogenous production. Furthermore, limited knowledge exists regarding the side effects of oral versus TD estrogen replacement therapy for TS patients.

MATERIALS AND METHODS

Women aged 18-50 years with TS recruited primarily from the Department of Endocrinology at Aarhus University Hospital (n=50); 300 patients with TS are currently followed in the outpatient clinic. The investigators also have the opportunity to recruit from the Turner Association in Denmark, and finally the investigators do have contact with other outpatient clinics with TS patients in Denmark from where the investigators have previously recruited TS patients.

Design:

A 5-week, phase IV randomized crossover trial involving 50 women with TS. Participants are randomized to receive E2 for 14 days, either as oral or TD treatment, followed by a crossover to the alternate treatment for another 14 days, with a one-week washout period in between.

Laboratory analyses:

Blood samples are collected at baseline, after the first 14 days of treatment, after the washout period, and after the final 14 days of treatment.

STATISTICS

Data will be summarized by treatment group and assessment time point. The investigators will use a mixed model with repeated measures analysis of variance (ANOVA) to compare the mean changes in each of the study variables between treatments over time. When appropriate, transformations or nonparametric methods will be used. All tests are two-tailed with a 5% level of significance. Data are presented as mean ± SE or median with CI for metrics not normally distributed.

PERSPECTIVES

Patients with TS undergo hormone replacement therapy from puberty to menopause, spanning more than 40 years of treatment. To date, only two experimental studies have compared oral and TD ERT in TS, focusing solely on metabolic parameters and finding no differences between the two regimens. The investigators aim for this study to provide clinicians with a better understanding of ERT in treating women with TS, and to contribute with new knowledge about hormonal treatment for the general population as well.

Inclusion Criteria:

• Diagnosis of TS regardless of karyotype
• Age 18-50 years
• Already receiving estrogen treatment

Exclusion Criteria:

• Active systemic chronic diseases
• Known or suspected breast cancer
• Known or suspected estradiol-dependent tumors (endometrial cancer or similar)
• Untreated endometrial hyperplasia
• Current or previous venous thromboembolism
• Acute or previous liver disease where liver enzymes are still elevated by a factor 3 or more
• Known hypersensitivity to the medications used
• Pregnancy

Only patients with Turner syndrome can participate

The patients with TS will be randomized to receive either oral (tablet) or transdermal (gel) estrogen replacement therapy. The study is not blinded, as both investigator and study participants know which medication, they are receiving.