OBJECTIVE
- 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.