Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06245681 |
| Other study ID # |
1629/2017 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
October 20, 2017 |
| Est. completion date |
October 20, 2025 |
Study information
| Verified date |
January 2024 |
| Source |
Medical University of Vienna |
| Contact |
Carola Deischinger, MD PhD |
| Phone |
+43140400 |
| Email |
carola.deischinger[@]meduniwien.ac.at |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Background: Sex hormones are believed to play an important role in the development and
progression of cardiovascular disease. However, the gender gap in onset and mortality is not
yet completely understood. Transsexuals undergoing hormone therapy are a promising collective
for analyzing the effects of sex hormones on atherosclerosis and other cardiovascular
disease. Objectives of the study: To identify gender-specific cardiovascular changes
attributed to high-dose hormone therapy in male-to-female (MtF) and female-to-male(FtM)
transgender using sonography and magnet resonance spectroscopy. Study design: Longitudinal
cohort study. Transsexuals will undergo two 3 Tesla MRI scan sessions: 1. baseline (before
hormone treatment) and 2. after 6 months of treatment. An oral glucose tolerance test (OGTT)
will be performed at baseline and 6 months after treatment onset. We propose an overall study
duration of 12 months.
Materials and Methods: MRI measurements will be performed on a 3 Tesla scanner. Study
population: 10 FtM, 10 male-to-female MtF transsexuals (aged 18-50), free of
hormone-medication at baseline. Relevance and implications of the study: Changes in
atherosclerotic risk due to hormone therapy have been studied to no definite results and so
far, little is known about the effects of hormone therapy on hepatic and myocardial fatty
tissue. Hence this study will provide important new data on the broad clinical aspects of sex
hormones as hormone replacement therapy in particularly opposite-sex hormone therapy.
Description:
Background Atherosclerosis has been shown to differ in men and women regarding disease risk,
onset time and overall mortality. This gender gap is mostly attributed to sex hormones.
Pre-menopausal women have less atherosclerosis risk than men of the same age [1]; on the
other hand, however, overall mortality due to cardiovascular disease is higher in women.
Nonalcoholic fatty liver which is associated with liver cirrhosis and higher atherosclerotic
risk due to impaired liver function is more common in men and postmenopausal women as well
[2-3]. Therefore, a protective effect of estrogen has been proposed. Excessive androgens on
the contrary have been associated with atherogenic effects. Thus, men with high exogenous
testosterone supply show higher atherosclerosis risk as do women suffering from polycystic
ovary syndrome and hence hyperandrogenemia while men with an androgen deficit have an
increased risk of atherosclerosis as well [4-5]. Nonetheless, these findings could not be
backed up by clinical intervention studies yet and further research on this gender gap is
necessary [6-7]. Transsexuals are usually treated with high-dose opposite-sex hormone therapy
at least for one year before they undergo operations. Therefore, they are an auspicious
collective to study hormone-dependent changes in atherosclerosis risk and lipid profile. Even
though it has been shown that lipoproteins change during hormone therapy, leading to an
increase in triglycerides and cholesterol, significant effects on atherosclerotic risk have
not yet been detected. However, there is hardly any data yet available on the effect of
hormone therapy on cardiovascular risk factors and morbidities as nonalcoholic fatty liver,
increased fatty tissue in the myocardial cells [8-9]. Effects on heart function may exist as
well since elevated lipids can induce cardiac steatosis and hence diminish the diastolic
heart function.
Furthermore, hormone therapy has been associated with elevated blood pressure [10]. However,
while the increased cholesterol and triglycerides may boost the risk, estrogen is believed to
be a protective factor. Therefore, the effects of hormone therapy on cardiovascular disease
are hard to estimate and will be further analyzed in this study. Objectives of the study
- To examine the influence of high-dose, long-term opposite-sex steroid hormone treatment
on hepatic and cardiac fatty tissue and heart function in female to-male (FtM) and
male-to-female (MtF) transsexuals using 3 Tesla MRS.
- To examine the influence of high-dose, long-term opposite-sex steroid hormone treatment
on systolic and diastolic heart function in female to-male (FtM) and male-to-female
(MtF) transsexuals using 3 Tesla MRS.
- To examine the influence of high-dose, long-term opposite-sex steroid hormone treatment
on carotid-media-thickness in female to-male (FtM) and male-to-female (MtF) transsexuals
using sonography.
- To examine the influence of high-dose, long-term opposite-sex steroid hormone treatment
on diabetes risk and insulin sensitivity & secretion in female to-male (FtM) and
male-to-female (MtF) transsexuals via the oral glucose tolerance test (OGTT) and blood
sampling.
3.2.1 Study variables
Main study variables:
- changes in the hepatic and cardiac fat content due to long-term opposite-sex hormone
therapy measured by MRT
- the effect of hormone therapy on heart function (systolic and diastolic)
- the effect of hormone therapy on the carotid-media thickness
- changes in insulin sensitivity and secretion via OGTT
Other study variables:
-to examine the influence of high-dose, long-term opposite-sex steroid hormone treatment on
HbA1C, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, transaminases of
the liver, CRP and usCRP as well as cardiovascular risk markers as adiponectin and proBNP The
statistical tests that will be used for comparing parameters between groups at baseline and
after 6 months are described in the statistical section. Test that will be used for comparing
values of the same individual baseline versus 6 months are paired t-test or when non-
parametric distribution Wilcoxon test for paired samples. The methods are described more in
detail in the statistics section.
Hypotheses Due to the explorative character of the study we we did not perform an exact
calculation of the casenumbers. The numbers of participants were generated after an
interdisciplinary discussion of what is to be expected and realistic also due to the number
of patients that come to the clinic and could be possible participants.
Study Design This pilot study is designed as a longitudinal mono-center study. 20 transsexual
subjects (10 FtM, 10 MtF) will undergo two 3 -Tesla 1H magnet resonance spectroscopy as well
as 2 sonography measurements. The first scans (baseline) will be performed before treatment,
the second scans after 6 months of high-dose, long-term crosssex hormone treatment.
Subject Section Transsexuals urging sex reassignment in a clinical setting will be enrolled
in this study. 10 female-to-male (FtM) and 10 male-to-female (MtF) transsexuals will be
recruited. Transsexual subjects are aged between 18 and 99 years and free from
hormone-treatment at baseline. There will be no transsexual placebo group implemented in the
study because of ethical reasons. The hormone therapy they will receive is purely clinical
indicated and is prescribed by a doctor not included in the study. This study does not
influence either the choice nor the beginning or end of the crosssex hormone therapy
Inclusion criteria are:
• DSM-IV diagnosis of Gender Identity Disorder (DSM-IV: 302.85, 302.6; ICD-10: F64.9, F64.8)
by a structured clinical interview (SCID)
- general health based on history, physical examination, ECG, laboratory screening, SCID
- willingness and competence to sign the informed consent form
Exclusion criteria are:
- severe neurological or internal diseases
- steroid hormone treatment within 2 months prior to inclusion (including birth control
pill, phytohormones)
- treatment with psychotropic agents such as SSRIs
- any implant or stainless-steel graft
- abnormal values in routine laboratory screening or general physical examination
- current substance abuse (determined using drug screening at the screening visit)
- pregnancy (determined at screening visit and first MRI scan)
- failure to comply with the study protocol or to follow the instructions of the
investigating team.
4 METHODS AND MATERIALS Magnet Resonance Spectroscopy (MRS) MRS measurements of the
heart and the liver will be done at one session at the MR Center of Excellence, Medical
University of Vienna, Austria, on a 3.0-T Tim Trio System (Siemens Healthcare, Erlangen,
Germany) operated with a Syngo VB15 (Siemens Healthcare) user interface as described in
previous work of our group [11-12]. We expect an estimated average duration of 75
minutes for:
1. 1H-magnetic resonance spectroscopy (MRS) of the liver: Measurement will be
performed using a 3-T whole-body spectrometer. Localized 1H spectra will be used to
quantify the hepatocellular lipid content by the series stimulated echo acquisition
mode (STEAM) sequence within a volume of interest of 27 cm3.
2. 1H-magnetic resonance spectroscopy (MRS) of the heart: Retrospective ECG-gated cine
true fast imaging is used to portray heart function with steady state precession
(TrueFISP) sequences in two-chamber, four-chamber and short axes orientation. Left
ventricular global function (end-diastolic and end-systolic volume, stroke volume,
ejection fraction and myocardial mass) is computed using short axes cine series
(typically 11 slices, resolution 1.4×2.1×7.0 mm3, acquisition time per segment
48ms, 25 reconstructed cardiac phases) via Argus software (Siemens Healthcare). In
addition, fast low-angle shot-based retrospective ECG-gated cine phase velocity
encoding sequence (velocity encoding 80 cm/s, resolution 1.7×2.1×6.0 mm3,
acquisition time per segment 71ms, 20 reconstructed cardiac phases) is used to
determine the E/A ratio, which is a measure of left ventricular diastolic function
and is calculated as the peak velocity ratio between early (passive) filling of the
ventricle during diastole (E) and late (due to atrial contraction) mitral inflow
(A) [13-15]. Myocardial lipid measurements were performed using localized 1H-MRS
based on recently introduced methods [16-17]. Anatomical imaging is used to guide
water suppressed pointresolved spectroscopy sequence (echo time TE 30ms, number of
acquisitions (NA)=32). The volume of interest (7 cm3) is placed across the middle
inter-ventricular septum. The spectral signal is acquired following ECG and
navigator-based respiratory triggering using the multichannel cardiac- and
spine-reception coils, both of which are provided by the system manufacturer
(Siemens Healthcare). Repetition time of the sequence is given by the frequency of
individual breath movement. An additional spectrum without water suppression (NA=8)
is used as the internal concentration reference. The spectra are processed by the
spectroscopy processing tool provided by the system manufacturer (Siemens
Healthcare). The myocardial lipid content is calculated as a ratio of the sum of
intensities of (CH2) (1.25 ppm) and CH3 (0.8-0.9 ppm) group resonances to the
intensity of the water resonance from non-water suppressed spectra of the same
volume of interest. Intensities of lipid and water resonance lines are corrected
for spin-lattice (T1) and spin-spin (T2) relaxation using individual repetition
time and already published T1 and T2 relaxation times of skeletal muscle at 3T.
OGTT After fasting for 8 hours' patients will be offered 75 mg of glucose solution
which should be ingested within 2 minutes. Patients will receive intravenous
cannulation (venflon). First HbA1C, total cholesterol, LDL-cholesterol,
HDL-cholesterol, triglycerides, transaminases of the liver, CRP and usCRP as well
as cardiovascular risk markers as adiponectine, proBNP and cell adhesion molecules
(20ml) will be taken. Then blood samples will be collected 30, 60, 90, 120 and 180
minutes after glucose ingestion (20ml in total). Furthermore, a small blood sample
(4ml) will be frozen and used later on for analysis of insulin, proinsulin and
c-peptide if considered necessary. Finally, insulin sensitivity and secretion can
be calculated from glucose, insulin and c-peptide concentration. The OGTT will be
performed twice, after the initial screening and at the last screening, ergo 6
months after therapy start.
STATISTICAL AND DATA ANALYSIS Initially, the normal distribution of data will be
tested using descriptive statistics.
When comparing two means from the same individual before and after 6 months if data
is normally distributed a paired t-test will be conducted, if not the
non-parametric Wilcoxon signed-rank test for paired samples will be applied.
Comparisons of quantitative variables among groups will be performed using one-way
ANOVA for parametric and Mann-Whitney test for non-parametric samples as well as at
baseline as after 6 months. Correlation analysis between continuous variables will
be performed by Pearson's or by Spearman's analysis, if appropriate. Levels of
statistical significance will be set at p<0.05. Data will be given as mean ± SD All
tests will be performed using SPSS Version 17.0, SPSS Inc., Chicago, IL.
5 ETHICAL SECTION The study will be performed in accordance with the Declaration of
Helsinki (1964). There will be no placebo control in the study because a latency of more
than 3 months for the start of active treatment was considered as an ethical issue and
based on our experience with this subject group, will decrease compliance. All subjects
will be asked for written informed consent prior to inclusion in the study and will be
insured through the Department of Psychiatry in accordance with §32 of the Austrian
Medicines Act. At each time subjects can decide to withdraw from the study. The
investigator may remove the subjects from the trial if exclusion criteria have been met.
No significant side effects are expected from the MRI measurements, sonography and OGTT.
6 HUMAN RESOURCES, STUDY SITES, COOPERATIONS The proposed research will be conducted at
the Department for Endocrinology and Metabolism, Gender Medicine Unit (head Univ. Prof.
Alexandra
Kautzky-Willer) and the Centre of Excellence for High-Field Magnetic Resonance (head:
Univ.-Prof. Dr.med.univ. Siegfried Trattnig, Medical University of Vienna, Austria, and the
Department of Obstetrics and Gynecology, Division of Gynecologic Endocrinology and
Reproductive Medicine, Unit for Gender Identity Disorder (Dr. Ulrike Kaufmann, MD). All MRI
measurements will be performed on the 3T Siemens Scanner at the Centre of Excellence
7 RELEVANCE AND IMPLICATIONS OF THE STUDY To our knowledge no studies on the effects of
hormone therapy in transsexuals on heart function, fat content of heart and liver have been
performed yet. Studies investigating the overall cardiovascular risk changes in subjects
undergoing hormone therapy could not substantiate the protective effect of estrogen or an
increase of atherosclerotic events due to changes in the lipid profile [8].
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