Effects of Interleukin-1 Beta on Low Testosterone Levels in Men With Obesity and Metabolic Syndrome

Study Overview
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Brief Summary
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Obesity and the metabolic syndrome in men are associated with a high prevalence of hypogonadism of up to 50%. Increased fat mass leads to augmented release of adipocytokines and pro-inflammatory cytokines such as IL-1-beta, IL-6 and tumor necrosis factor-alpha which in turn suppress the hypothalamic-pituitary-gonadal (HPG) axis, leading to hypogonadism. This pathophysiological interplay is termed hypogonadal-obesity-adipocytokine hypothesis. TestIL is a prospective, multicenter, randomized, double-blinded, placebo-controlled trial to test the hypothesis that inhibition of IL-1-activity diminishes the inhibitory effects on HPG axis and increases testosterone levels in men with metabolic syndrome.

Detailed Description
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Obesity and the metabolic syndrome are considered as chronic low-grade inflammatory states. Elevated pro-inflammatory mediators in obesity and metabolic syndrome have an inhibitory effect on the hypothalamic-pituitary-gonadal axis (HPG axis) leading to hypogonadism. Decreased testosterone production in obese men in turn promotes additional fat deposition, contributing to a vicious cycle of fat accumulation. This complex pathophysiological interplay is termed hypogonadal-obesity-adipocytokine hypothesis, describing a bidirectional relationship between low levels of testosterone and the metabolic syndrome. TestIL is a prospective, multicenter, randomized, double-blinded, placebo-controlled trial to test the hypothesis that inhibition of IL-1-activity diminishes the inhibitory effects on HPG axis and increases testosterone levels in men with metabolic syndrome.

Official Title
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Effects of IL-1 Beta on the Hypothalamic-pituitary-gonadal (HPG) Axis in Men With Obesity and Metabolic Syndrome - The TestIL Trial

Conditions
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Hypogonadism, Metabolic Syndrome X, Obesity

Intervention / Treatment
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* Drug: Anakinra
* Drug: Sodium Chloride 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent as documented by signature, Men at the age between 18 and 75 years, BMI >30 kg/m2 and at least 1 manifestation of the metabolic syndrome (i.e. prediabetes, diabetes, hypertension, dyslipidemia), Total testosterone level <12 nmol/l. Exclusion Criteria: Previous or current medication with testosterone, Testosterone deficiency of other cause, i.e. primary hypogonadism caused e.g. by Klinefelters syndrome, cryptorchidism, condition following orchiectomy. Known secondary hypogonadism caused by pituitary adenoma. Patients on antiandrogen medication, Clinical signs of infection in the week before inclusion or history of a severe infection during the last 2 months, Severe immunosuppression (e.g. patients with previously known infection with human immunodeficiency virus and a cluster of differentiation 4 (CD4) count below 350 x 109/L, patients on immunosuppressive therapy after solid organ transplantation and neutropenic patients with neutrophil count < 500 x 109/L and patients under chemotherapy with neutrophils 500-1000 x 109/L with an expected decrease to values < 500 x 109/L), Hematologic disease (leukocyte count < 1.5 x 109/l, hemoglobin < 11 g/dl, platelets <100 x 103/µl), Other clinically significant concomitant disease states (e.g., renal failure [Creatinine-Clearance < 30 ml/min], hepatic dysfunction [transaminases >3x upper normal range], active carcinoma, History of tuberculosis, Known or suspected non-compliance, drug or alcohol abuse, Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to anakinra/Kineret®, Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, Previous enrolment into the current study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Anakinra<br>Anakinra//Kineret® 100mg s.c. bid | Drug: Anakinra<br>* Anakinra 100mg s.c. bid<br>* Other names: KINERET;|
| Placebo Comparator: Placebo<br>Sodium Chloride 0.9% s.c. bid | Drug: Sodium Chloride 0.9%<br>* Sodium Chloride 0.9% s.c. bid<br>* Other names: NaCl 0.9%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total morning testosterone (nmol/l) |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total morning testosterone (nmol/l) |  | 1 week and 3 months | 
| Free testosterone (nmol/l) | Assessed by equilibrium dialysis | 1 week, 4 weeks and 3 months | 
| Bioavailable testosterone (nmol/l) | Assessed by equilibrium dialysis | 1 week, 4 weeks and 3 months | 
| Erectile dysfunction as assessed by International Index of Erectile Function (IIEF) score |  | 1 week, 4 weeks and 3 months | 
| Clinical severity of hypogonadism as assessed by quantitative Androgen Deficiency in the Aging Male (qADAM) questionnaire |  | 1 week, 4 weeks and 3 months | 
| Proportion of muscle mass as assessed by bioelectrical impedance Analysis |  | 1 week, 4 weeks and 3 months | 
| Proportion of fat mass as assessed by bioelectrical impedance Analysis |  | 1 week, 4 weeks and 3 months | 
| HbA1c (%) |  | 1 week, 4 weeks and 3 months | 
| LH and FSH (IU/l) |  | 1 week, 4 weeks and 3 months | 
| Inhibin B, ACTH (pg/ml) |  | 1 week, 4 weeks and 3 months | 
| Prolactin, TSH, Insulin (mIU/l) |  | 1 week, 4 weeks and 3 months | 
| Interleukin-1, Interleukin-6 (pg/ml) |  | 1 week, 4 weeks and 3 months | 
| Cortisol basal (nmol/l) |  | 1 week, 4 weeks and 3 months | 
| C-reactive protein (mg/l) |  | 1 week, 4 weeks and 3 months | 
| free T4 (pmol/l) |  | 1 week, 4 weeks and 3 months | 
| T3 (nmol/l) |  | 1 week, 4 weeks and 3 months | 
| IGF-1 (nmol/l) |  | 1 week, 4 weeks and 3 months | 
| GH (mU/l) |  | 1 week, 4 weeks and 3 months | 
| Androstendione (μg/l) |  | 1 week, 4 weeks and 3 months | 
| DHEAS (μmol/l) |  | 1 week, 4 weeks and 3 months | 
| Oestradiol (pmol/l) |  | 1 week, 4 weeks and 3 months | 
| Oestron (ng/l) |  | 1 week, 4 weeks and 3 months | 
| 17-OH-progesterone (nmol/l) |  | 1 week, 4 weeks and 3 months | 
| Copeptin (pmol/l) |  | 1 week, 4 weeks and 3 months | 
| Sex hormone-binding globulin (SHBG) |  | 1 week, 4 weeks and 3 months | 
| Muscle strength as assessed by grip strength test |  | 1 week, 4 weeks and 3 months | 
| Waist-hip-ratio |  | 1 week, 4 weeks and 3 months | 
| BMI in kg/m2 |  | 1 week, 4 weeks and 3 months | 
| Insulin sensitivity as assessed by homeostasis model assessment insulin resistance (HOMA-IR) |  | 1 week, 4 weeks and 3 months | 
| Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides (mmol/l) |  | 1 week, 4 weeks and 3 months | 
| Leptin (μg/l) |  | 1 week, 4 weeks and 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic syndrome X, Hypogonadism, Testosterone, Inflammation, Obesity