Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement

Abstract

Patients with hypogonadism not only present with poor libido, loss of energy, muscle atrophy and depression but also with chronic metabolic disorders such as dyslipidemia, obesity, hypertension and type 2 diabetes mellitus (T2DM) [1][2][3] and increased mortality [4]. The dysmetabolic features of hypogonadism are present even in the very young age, in patients with congenital hypogonadotrophic hypogonadism (CHH) [5].Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement (TRT) is not clear. We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects. A total of 60 patients with CHH (mean age 21.82±2.22 years) and 70 healthy control subjects (mean age 21.32±1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT. The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls. After 5.56 ± 2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant. The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT. Key words: Endothelial dysfunction, Insulin resistance, Inflammation, HypogonadismHowever, whether the testosterone replacement treatment (TRT) improves the metabolic and cardiovascular risks of patients with hypogonadism is not clear. Several reports mention favorable metabolic effects of TRT [6-9] while others do not confirm these data [10][11][12][13]. The meta-analyses show no significant metabolic benefit but a tendency towards increased cardiovascular events due to TRT [14][15][16]. Meanwhile, a prospective cohort of elderly hypogonadal men was recently terminated due to the increased cardiovascular mortality in the testosterone replacement arm [13]. There may be several reasons for the inconsistencies of the previous reports. Most of these studies were per-

Wpływ testosteronowej terapii zastępczej na stężenia witaminy D i FGF-23 w hipogonadyzmie wrodzonym

“…However, plasma ADMA levels did not improve but worsened after TRT in our homogenous study population. This is in accordance with our previous report of a similar follow-up study in a CHH population [20]. The mechanism of this increase in ADMA levels after TRT is not clear.…”

“…Most of these studies showing adverse effects of TRT were by and large performed on frail elderly populations with several confounders. However, we also reported endothelial dysfunction, inflammation and insulin resistance after TRT in unconfounded, young hypogonadal patients [18][19][20]. To our knowledge, the present study is the first to search for the effect of TRT on 25(OH)D3 and FGF-23 levels .…”

“…In our CHH group, the secondary sexual characteristics significantly improved, but the BMI and WC were increased after the TRT. A general response that we observed in this study population is a significant improvement in the secondary sexual characteristics along with a significant increase in BMI and WC [17][18][19][20]. It is likely that TRT ignites pubertal growth in these young patients, which is not seen in elderly hypogonadal patients of other aetiologies This may partly explain the rapid increase in BMI and waist circumference of these patients.…”

“…Some of these hypogonadal patients, generally the ones living in the rural regions, have never been treated before. Information about the enrolment criteria and the testosterone replacement procedures of our hypogonadal cohort were given in detail in previous articles [18][19][20]. Briefly, young patients diagnosed as CHH, who were not treated with testosterone replacement and who did not have any other chronic diseases, were enrolled.…”

Rola krążącego sTWEAK w patogenezie choroby Hashimoto — badanie pilotażowe

“…Because TWEAK is a subgroup of TNFSF that is synthesized by Th1 lymphocytes, we consider that TWEAK may play role in increased autoimmune response. Indeed, a number of previous studies showed that TWEAK was associated with etiopathogenesis of several autoimmune diseases (systemic lupus erythematosus (SLE), multiple sclerosis, type 1 diabetes mellitus etc) [6,7]. However, it is not known whether TWEAK has a role in the etiopathogenesis of HT, which is an autoimmune disease.…”