Hypogonadism, Metabolic Syndrome X, Obesity
Conditions
Keywords
Metabolic syndrome X, Hypogonadism, Testosterone, Inflammation, Obesity
Brief summary
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
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.
Interventions
DRUGAnakinra
Anakinra 100mg s.c. bid
DRUGSodium Chloride 0.9%
Sodium Chloride 0.9% s.c. bid
Sponsors
University Hospital, Basel, Switzerland
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Informed consent as documented by signature, 2. Men at the age between 18 and 75 years, 3. BMI \>30 kg/m2 and at least 1 manifestation of the metabolic syndrome (i.e. prediabetes, diabetes, hypertension, dyslipidemia), 4. Total testosterone level \<12 nmol/l.
Exclusion criteria
1. Previous or current medication with testosterone, 2. 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, 3. Clinical signs of infection in the week before inclusion or history of a severe infection during the last 2 months, 4. 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), 5. Hematologic disease (leukocyte count \< 1.5 x 109/l, hemoglobin \< 11 g/dl, platelets \<100 x 103/µl), 6. Other clinically significant concomitant disease states (e.g., renal failure \[Creatinine-Clearance \< 30 ml/min\], hepatic dysfunction \[transaminases \>3x upper normal range\], active carcinoma, 7. History of tuberculosis, 8. Known or suspected non-compliance, drug or alcohol abuse, 9. Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to anakinra/Kineret®, 10. Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant, 11. Previous enrolment into the current study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Total morning testosterone (nmol/l) | 4 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Free testosterone (nmol/l) | 1 week, 4 weeks and 3 months | Assessed by equilibrium dialysis |
| Bioavailable testosterone (nmol/l) | 1 week, 4 weeks and 3 months | Assessed by equilibrium dialysis |
| 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 | — |
| Total morning testosterone (nmol/l) | 1 week 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 | — |
| IGF-1 (nmol/l) | 1 week, 4 weeks and 3 months | — |
Countries
Switzerland
Outcome results
None listed