Effects of Testosterone Plus Dutasteride or Placebo on Muscle Strength, Body Composition and Metabolism in Transmen

Study Overview
=================
Brief Summary
-----------------
To compare the effects on body composition and muscle strengthof 54-weeks treatment with of testosterone undecanoate combined with placebo or with the 5a-reductase inhibitor dutasteride

Detailed Description
-----------------
Transmen who have undergone gender-affirming surgery require long-lasting treatments with androgens to maintain male phenotypic characteristics and to preserve their health. In this population the effects on muscle and the relative role of testosterone and its metabolite dihydrotestosterone (DHT) on the skeletal muscle are still largely unknown. In this pilot study, we evaluated the effects of testosterone and DHT on muscle strength, body composition, metabolism. Also cutaneous androgenic effects such as acne and androgenetic alopecia were evaluated. DESIGN For this purpose, in this randomized, double-blind placebo-controlled pilot trial we treated variectomized transmen for 54 weeks with: Testosterone Undecanoate (TU) 1000 mg i.m. at weeks zero, six, 18, 30, 42 + a daily oral placebo pill (TU+PL) TU 1000 mg i.m. at weeks zero, six, 18, 30, 42 + dutasteride 5 mg/day (TU+DUT). Prospective, phase III, randomized study design was used. Subjects were seen every 12 weeks for safety monitoring that included evaluation of hematocrit, transaminases, alkaline phosphatases and bilirubin, creatinine, urea and serum electrolyte as potassium and sodium. Baseline and week-54 evaluations included the following measurements: blood drawings for measurements of: hormonal profile (serum testosterone, estradiol, luteinizing hormone and follicle-stimulating hormone, prolactin, sex hormone binding globulin, and thyroid stimulating hormone), haematocrit (Ht) and haemoglobin (Hb), glucidic and lipidic profile (fasting glucose, fasting insulin, total cholesterol, high- and low-density lipoproteins, and triglycerides), hepatic function (aspartate and alanine aminotransferases) and bone related markers (osteocalcin, parathyroid hormone, bone alkaline phosphatase and 25-hydroxyvitamin, 24h urinary excretion of calcium, potassium, magnesium and creatinine). anthropometry: weight, measures DEXA for bone mass determination and body composition Isokinetic knee extension and flexion peak torque (PT-IKE and PT-IKF) Handgrip strength evalutation of the psychological profile with the brief Profile of Mood State (POMS) sexual life satisfaction evalutation with a Visual Analogue General Satisfaction Scale (VAS) physical examination: inspection of external genitalia (clitorides) and a visit to detect appearance of acne and gynecomastia During the treatment phase all injections will be administered by the investigator or co-investigators for the entire study. Fasting (10 hours) blood samples will be taken (immediately before giving the injections) every time subjects come for injections (week 0, 6, 18, 30 and 42) and at the end of the treatment phase. In the sexual and behavior questionnaire the subjects will judge their sexual activity and behavior in the period between visits. The subjects have the possibility to making additional comments about important events and disturbances.

Official Title
-----------------
A Randomized Double-blind Placebo-controlled Pilot Trial on the Effects of Testosterone Undecanoate Plus Dutasteride or Placebo on Muscle Strength, Body Composition and Metabolic Profile in Transmen

Conditions
-----------------
Transgenderism, Hypogonadism

Intervention / Treatment
-----------------
* Drug: dutasteride 5 mg/day
* Drug: Testosterone Undecanoate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy transmen Previous bilateral gonadectomy during sex reassigning surgery Body Mass Index (BMI) between 20 and 29 kg/m²; (body weight in kilograms divided by body height in meters squared) Clinical examination without pathological findings relevant to the study No concomitant use of drugs known to affect the hypothalamic-pituitary-ovarian axis Written Consent Form High probability of a good compliance and termination of the study Exclusion Criteria: Participation in another clinical trial within the 30 days preceding the first administration Simultaneous participation in another clinical trial Subjects institutionalized or imprisoned by order of the court Subject who compete in sports Subjects reporting desire to perform regular physical exercises for the duration of the study Serious organic or psychic disease suspected from history and/or clinical examination Diseases (especially tumors) that might represent an actual contraindication for testosterone Past or present history of thrombotic or embolic diseases Arterial hypertension Diabetes mellitus Acute or chronic hepatic diseases Manifest renal diseases with renal dysfunction Severe internal diseases Biochemical and/or hematological laboratory values beyond normal ranges unless the Investigator confirms that the deviations are of no clinical relevance Any indication of chronic use of drugs, alcohol, opiates or recreational drugs Use of any drug known to affect biotransformation of testosterone and/or progestin, e.g. chlorcycline, phenobarbital, phenylbutazone, aminophenazone within the 30 days preceding the first administration of the test medication and during the study Use of oral anticoagulatory drugs within the 30 days preceding the first administration of the test medication and during the study Any oral or transdermal hormone medication within the 12 weeks preceding the first administration and during the study Probability of poor compliance and termination of the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Testosterone Undecanoate plus dutasteride<br>Testosterone Undecanoate (TU) 1000 mg i.m. at weeks zero, six, 18, 30, 42 + dutasteride 5 mg/day | Drug: dutasteride 5 mg/day<br>* Administration of a placebo pill or dutasteride 5 mg pill daily in addition to intramuscolar testosterone undecanoate<br>Drug: Testosterone Undecanoate<br>* Administration of a placebo pill or dutasteride 5 mg pill daily in addition to intramuscolar testosterone undecanoate<br>|
| Placebo Comparator: Testosterone Undecanoate plus placebo<br>Testosterone Undecanoate (TU) 1000 mg i.m. at weeks zero, six, 18, 30, 42 + a daily oral placebo pill | Drug: Testosterone Undecanoate<br>* Administration of a placebo pill or dutasteride 5 mg pill daily in addition to intramuscolar testosterone undecanoate<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in isokinetic knee extension and flexion peak torque (PT-IKE and PT-IKF) | Isokinetic peak torques were determined using isokinetic dynamometry (Biodex System 4 Pro, Medical Systems, Shirley, NY) at all four time points. | At baseline and after 54 weeks of treatment | 
| Change in handgrip strength | Three trials of three sets of maximal isometric handgrip on a mechanical dynamometer (model Grip-A, Takei Physical Fitness Test TKK 5001, Japan), alternately with the dominant and non-dominant hand, with a three minute rest between each trial | At baseline and after 54 weeks of treatment | 
| Change in body composition | Dual-energy X-ray absorptiometry was performed using the Hologic 49159 densitometer and standard QDR body composition software (Model QDR4500W, Software Level 11.2, Hologic Spine; Hologic, Bedford, MA) for the measurement of body fat and lean mass | At baseline and after 54 weeks of treatment | 
| Change in bone mineral density | Dual-energy X-ray absorptiometry was performed using the Hologic 49159 densitometer and standard QDR body composition software (Model QDR4500W, Software Level 11.2, Hologic Spine; Hologic, Bedford, MA) for the evaluation of bone mineral density at lumbar and femoral site | At baseline and after 54 weeks of treatment | 
| Change in anthropometric assessment: BMI | weight, stature will be combined to report the BMI (kg/m^2) | At baseline and after 54 weeks of treatment | 
| Change in anthropometric assessment: waist-to-hip ratio | Waist and hip circumferences will be combined to report the waist-to-hip ratio (WHR) | At baseline and after 54 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in psychological profile with the brief Profile of Mood State (POMS) | The POMS is a self-reporting questionnaire consisting of 30 items in six categories: tension-anxiety, depression, anger-hostility, vigor, fatigue and confusion, which are scored from 1-4 according to severity | At baseline and after 54 weeks of treatment | 
| Change in the satisfaction with their sexual life | using a Visual Analogue General Satisfaction Scale (VAS). A VAS for satisfaction is a horizontal line of 10-cm long. At the start and finish there are two descriptors representing extremes of satisfaction (i.e. no satisfaction and extreme satisfaction). Subjects respond to the question 'Are you satisfied with your sexual life now?' and rate their satisfaction by making a vertical mark on the 100-mm line. The measurement in millimeters is converted to the same number of points ranging from zero to 10 points. | At baseline and after 54 weeks of treatment | 
| Change in in the bone metabolism: osteocalcin | Evaluation of serum osteocalcin (OC) change | At baseline and after 54 weeks of treatment | 
| Change in in the bone metabolism: parathyroid hormone | Evaluation of serum parathyroid hormone (PTH) changes | At baseline and after 54 weeks of treatment | 
| Change in in the bone metabolism: bone alkaline phosphatase | Evaluation of serum bone alkaline phosphatase (BAP) changes | At baseline and after 54 weeks of treatment | 
| Change in in the bone metabolism: urinary excretion of electrolites | Changes in the 24h urinary excretion of electrolites | At baseline and after 54 weeks of treatment | 
| Change in in the insulin resistance | Change in the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) | At baseline and after 54 weeks of treatment | 
| Change in the lipid profile | Changes in cholesterol (Tot Chol and high- and low-density lipoproteins) levels | At baseline and after 54 weeks of treatment | 
| Change in the lipid profile | Changes in triglycerides levels | At baseline and after 54 weeks of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Muscle strenght, Testosterone, Dutasteride, dihydrotestosterone, 5a-reductase inhibitor