OBJECTIVES
Clarify endocrine, metabolic, cardiovascular and thromboembolic risk factors in
Turner syndrome (TS) after a wash out period
Compare the effects of oral versus transdermal (TD) estrogen replacement therapy
(ERT) in women with Turner syndrome
Examine long term effects of ERT via the two routes on endocrine, metabolic,
cardiovascular, physiologic and thromboembolic risk endpoints
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
Study group:
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.
An age-matched control group of healthy women is included by advertisement (n=50).
Inclusion criteria:
For participants with TS:
For healthy controls:
Female
Age 18-50 years
Previously healthy
Not receiving any medication
Not using any form of contraceptive pills
No mental or psychiatric disorders
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
Menopause (for the control group only)
Design:
A 14-month, phase IV, randomized controlled crossover study involving women with Turner
Syndrome (TS) (n=50) and healthy, age-matched controls (n=50). TS participants are
randomized to receive either oral or TD ERT for six months, followed by crossover to the
alternate treatment for another six months. Prior to randomization, any existing ERT will
be discontinued for a 1-month washout period. A second 1-month washout period will occur
between the two 6-month treatment phases. Healthy controls will not receive any
treatment. They will undergo a single set of assessments for comparison.
Laboratory analyses and clinical investigations will be conducted at the Department of
Endocrinology and the associated Medical Research Unit at Aarhus University Hospital.
These will include blood and urine sample collection, as well as specific clinical
investigations. At baseline, both TS patients and healthy controls will undergo these
assessments. Only TS patients will undergo follow-up assesments.
Clinical investigations:
Insulin sensitivity assessment
24-hour blood pressure monitoring
DEXA scan (Dual-Energy X-ray Absorptiometry)
Bioelectrical impedance analysis (Multiplate)
Comprehensive clinical examination
Quality of life assessments using questionnaires
SphygmoCor analysis
VO2 max test using a stationary bike
MRI of the thigh muscles to measure muscle cross-sectional area (CSA) and
intramuscular fat content
Isometric muscle strength testing and functional testing
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. If the investigators' hypotheses are
correct and if the side effects, including increased thromboembolic risk, are higher with
oral than TD ERT, this project could be crucial for optimizing treatment, improving
quality of life, and reducing morbidity and mortality in TS. The investigators aim for
this study to provide a basis for new and improved national and international
recommendations for ERT in TS patients and to contribute new knowledge about hormonal
treatment for the general population as well.