Short summary

Bariatric surgery is an effective method in the treatment of severe obesity and type 2 diabetes mellitus achieving high remission rates. However, weight loss also causes loss of skeletal muscle and bone mass which at least partly could be prevented by exercise and dietary intervention although the counselling of obese and sedentary individuals in order to increase their physical activity presents a challenge. As up to 78.8% of men undergoing bariatric surgery have low levels of testosterone, testosterone therapy could be considered an attractive alternative or supplement to prevent the immense loss of muscle mass during weight loss.

Rationale

Obesity, poor physical fitness and low muscular strength are associated with all-cause mortality. Loss of bodyweight is commonly achieved by diet with or without exercise intervention. However, both diet and diet+exercise programs are often followed by weight regain and it is generally difficult to achieve long-term weight loss.

There are many challenges associated with the counselling of obese and sedentary individuals in order to increase their physical activity (PA), and there may be a need for a tight schematic counselling to achieve positive results. Additionally, promoting PA among patients that have undergone bariatric surgery has also shown to be challenging even though PA may be of a great importance regarding several postoperative outcomes. Lifestyle changes following bariatric surgery may be important for the overall effect of the BS in the long term. Therefore, it is vital to find an appropriate and well-suited setting to improve PA among these patients. When structuring PA counselling, the five A´s (Assess, Advise, Agree, Assist, Arrange) might be a helpful tool and it is considered important to engage the patients in PA counselling both before and after the surgery.

Loss of bodyweight reduces morbidity and mortality. Bariatric surgery is the most effective method to treat severe obesity and type 2 diabetes mellitus achieving high remission rates. However, weight loss also decreases skeletal muscle mass which might counterbalance the positive effects of a bariatric surgery since low lean body mass is linked to increased mortality under various circumstances (i.e., heart disease, cancer, burn injuries). Furthermore, a substantial loss of bone mass is seen after bariatric surgery despite weight stability in the second-year post-operative, which could have important clinical implications for long-term skeletal health with increased fracture risk. On the other hand, the loss of muscle and bone mass could merely be a natural adaptation to a lower weight after bariatric surgery. Studies trying to establish whether the loss of muscle mass is disproportionately in patients following bariatric surgery compared to BMI-matched controls are conflicting, showing lower muscle mass in both sexes after surgery compared with their respective matched controls assessed by magnetic resonance imaging in one study whereas another study has shown comparable fat-free mass 24 months post-operative assessed by bioelectric impedance. Currently, there are no effective approaches to prevent the immense loss of muscle and bone mass following bariatric surgery although several approaches can be considered, e.g. exercise and dietary intervention. Low testosterone levels have been associated with sarcopenia, insulin resistance, increased body fat, reduced quality of life and loss of libido and sexual function. Testosterone therapy increases lean body mass (i.e. muscle mass), improves bone density and decreases fat mass. As up to 78.8% of patients undergoing bariatric surgery suffer from low testosterone levels, testosterone therapy prior to and after bariatric surgery may prevent or reduce the considerable loss of muscle mass during the weight loss period. So far, no studies have evaluated the effect of testosterone therapy combined with exercise and diet counselling on body composition and quality of life in men undergoing bariatric surgery.

Testosterone therapy and cardiovascular risk

Studies on cardiovascular risk during testosterone therapy are conflicting. A study in old men with limitations in mobility showed significantly more cardiovascular events during testosterone therapy compared to placebo and the study was ended prematurely. Low HDL levels are linked to an increased morbidity and mortality of cardiovascular disease. A significant small decrease in HDL cholesterol levels in men treated with testosterone was reported in a meta-analysis and a systematic review. However, a large observational study on pooled data in obese, hypogonadal diabetic men during six years of testosterone therapy reported a favorable change in lipid profile along with reduced pulse pressure and reduced arterial stiffness, which are independent risk factors for cardiovascular disease. Another approach in clarifying the effect of testosterone therapy on cardiovascular disease risk is the evaluation of biomarkers for cardiovascular disease during therapy, i.e. soluble Klotho, a protein, which may function as a hormone. Higher levels of soluble Klotho are independently associated with a lower likelihood of having cardiovascular disease. To date, no reports on Klotho have been published in obese patients undergoing bariatric surgery during testosterone therapy.

Few studies have addressed the influence of testosterone therapy on the haemostatic system. Thrombin generation (TG) measures are risk markers of cardiovascular disease and address the composite of multiple factors that influence blood coagulation. One intervention study showed that i.m. testosterone treatment for one year in elderly men with low testosterone levels had no impact on thrombin generation measured at one year. A significant number of patients sustaining venous thrombotic events after initiation of testosterone therapy often had inherited cardiovascular risk factors such as Factor V Leiden, and thrombotic events were primarily observed within the first months of testosterone treatment, suggesting that testosterone therapy triggers cardiovascular events in thrombosis prone individuals. Thus, studies on both the short term and the long term impact of testosterone treatment on the haemostatic system are warranted.

Pseudo-Cushing's syndrome

Central obesity results in a cluster of metabolic abnormalities contributing to premature death, so-called Pseudo-Cushing's syndrome. Glucocorticoids regulate adipose-tissue differentiation, function and distribution, and in excess, cause central obesity. To our knowledge, no studies have reported results on levels of cortisol and testosterone before and after bariatric surgery.

Description of the cohort

A randomized, double-blind, placebo-controlled intervention study in men eligible for bariatric surgery and low testosterone levels (total testosterone < 12.0 nmol/l). Patients will be recruited among bariatric patients at Hospital of Southwest Jutland and at Odense University Hospital.

Data and biological material

Primary outcome:

• Maximal isometric muscle strength (N) in shoulder muscles (shoulder elevation.

Secondary outcomes:

• Regional body composition (DXA scan, BMI, Waist/hip-ratio)
• Physical strength: maximal isometric muscle strength in lower extremities (hip extension, hip abduction), muscle strength in upper-extremities (shoulder abduction, shoulder adduction)
• Physical function: performance-based measures of physical function (stair climb test) and maximal oxygen uptake (VO2max).
• Glucose metabolism (HOMA-R, HbA1c, Fasting-P-Blood glucose)
• Coagulation/fibrinolysis status (thrombin generation measures)
• Adipokines and inflammation markers (leptin, adiponectin, hsCRP, IL-6, suPAR, lipid profile (HDL, LDL, triglycerides))

Hormones and binding proteins (testosterone, SHBG, LH, FSH, prolactin, CBG, growth hormone-axis (IGF-I and IGF-II, IGFBPs, bioactive IGF-I), cortisol, aldosterone, Cortisol and cortisol metabolites)

• Vascular markers (soluble Klotho, fibulin-1)
• Bone markers and calcitropic hormones (osteocalcin, PINP, 1CTP, CTX, PTH, 25OH-vitaminD, 1.25(OH)2-Vitamin-D)
• Quality of life and sexual function (International Index of Erectile Function (IIEF-5), Major Depression Inventory (MDI), World Health Organization Well Being Index (WHO-5), Physical function component of Vitality scale of Short Form 36 (SF36)

Collaborating researchers and departments

The Endocrinology units, Hospital of Southwest Jutland (SVS) and Odense University Hospital (OUH)

• Line Velling Magnussen, MD, PhD

The Endocrinology unit and bariatric team, Hospital of Southwest Jutland

• Alin Andries, MD, PhD, 
• Claus Juhl, MD, PhD, 

Institute of Regional Health Research/Centre of Southwest Jutland

• Cand.scient. Bibi Gram, PhD

Department of Endocrinology, Odense University Hospital

• Jeppe Gram, MD, PhD
• Professor Marianne Andersen, MD, DMSc
• Dorte Glintborg, MD, DMSc
• ProfessorRené Støving, MD, PhD 

Collaborators:

KBA at SVS (biochemistry)

The GCP-section at Odense University Hospital (monitoring)

OPEN (randomization and eCRF)

Pharmacy at SVS (handling of study medicine)