The relation between serum testosterone levels and cardiovascular risk factors in patients with kidney transplantation

Hulya Colak; Ismail Sert; Yusuf Kurtulmus; Cezmi Karaca; Huseyin Toz; Seyhun Kursat

doi:10.4103/1319-2442.139862

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ORIGINAL ARTICLE

Year : 2014 | Volume : 25 | Issue : 5 | Page : 951-959

The relation between serum testosterone levels and cardiovascular risk factors in patients with kidney transplantation

Hulya Colak¹, Ismail Sert², Yusuf Kurtulmus³, Cezmi Karaca⁴, Huseyin Toz⁵, Seyhun Kursat⁶
¹ Tepecik Training and Research Hospital, Nephrology Clinic, Izmir, Turkey
² Department of General Surgery, Van Training and Research Hospital, Van, Turkey
³ Department of Clinical Biochemistry, Izmir Tepecik Training and Research Hospital, Izmir, Turkey
⁴ General Surgery Clinic, Izmir Tepecik Training and Research Hospital, Izmir, Turkey
⁵ Nephrology Department, Ege University Medical Faculty, Izmir, Turkey
⁶ Nephrology Department, Celal Bayar University Medical Faculty, Manisa, Turkey

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Date of Web Publication

2-Sep-2014

Abstract

The objective of the study is to evaluate the relationship between serum testosterone levels and cardiovascular risk factors (CVRF) in patients after kidney transplantation and with chronic kidney disease (CKD). Seventy-five male patients, aged between 18 and 68 years, who had kidney transplantation at least six months earlier, were enrolled into the study. Only renal transplant recipients and CKD patients with a creatinine level of <2.5 mg/dL were included in this study. Patients were divided into three groups as patients receiving calcineurine inhibitors (CNIs) and Mammalian target of rapamycin inhibitors (m-TORi) and CKD. Serum ceatinine, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), triglyceride (TG) as well as left ventricle mass (LVM), left ventricle mass index (LVMI), left atrium (LA), inferior vena cava (IVC) inspiratory and expiratory diameters and collapse index (CI) and blood pressure (BP) were evaluated. Serum testosterone levels were significantly higher in the m-TORi and CNIs groups when compared with the CKD cases (P <0.05). When kidney recipients (both groups) were compared with CKD patients, we observed positive outcomes in serum testosterone levels and CVRF at significant levels. There was no significant difference in terms of age, serum creatinine, serum testosterone, FSH, LH, prolactin, hs-CRP, LVMI, TC and TG and between the CNIs and mTORi groups (P >0.05). Serum testosterone levels were independent risk factors affecting IVC collapse index, systolic BP and LA. m-TORi and CNIs drugs might have no negative effect on serum testosterone levels, and improvement of the serum testosterone levels after transplantation might have a positive contribution on cardiac risk factors.

How to cite this article:
Colak H, Sert I, Kurtulmus Y, Karaca C, Toz H, Kursat S. The relation between serum testosterone levels and cardiovascular risk factors in patients with kidney transplantation. Saudi J Kidney Dis Transpl 2014;25:951-9

How to cite this URL:
Colak H, Sert I, Kurtulmus Y, Karaca C, Toz H, Kursat S. The relation between serum testosterone levels and cardiovascular risk factors in patients with kidney transplantation. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Jan 23];25:951-9. Available from: https://www.sjkdt.org/text.asp?2014/25/5/951/139862

Introduction

Low serum testosterone levels are associated with certain components of the metabolic syndrome including hypertension, abdominal obesity, insulin resistance, high levels of inflammation markers and increased cardiovascular disease (CVD) in non-uremic patients. ^[1],[2] Low testosterone levels have been reported to increase mortality risk due to CVD as well as other causes. ^{[3],[4],[5],[6],[7],[8],[9],[10],[11],[12]} Previously, improvements in certain cardiovascular risk factors (CVRF) (such as visceral obesity, insulin resistance, lipid markers and inflammation markers) were demonstrated in cases with testosterone replacement. ^[13] Hypothalamic-pituitary-gonadal dysfunction has been frequently encountered in chronic kidney disease (CKD). ^[14] In cases with renal failure, serum testosterone levels have been considerably low because of altered sex-hormone metabolism. ^[15],[16] The relation of low serum testosterone levels to endothelial dysfunction and atherosclerosis was reported in a previous study conducted on non-diabetic male patients with end-stage renal failure. ^[17] Serum testosterone levels have been known to decrease during end-stage renal failure. ^[17],[18] Sex hormones were reported to be normalized in most cases after six months of renal transplantation. ^[18] Some studies emphasize that different immunosuppressive drugs have different effects on the serum testosterone level, ^{[19],[20],[21],[22]} and debates in this subject are still continuing. We aimed to evaluate the relationship between serum testosterone levels and CVRF in patients with kidney transplantation and CKD. In addition, kidney transplant recipients were divided into two groups [receiving Mammalian target of rapamycin inhibitors (m-TORi) or calcineurine inhibitors (CNIs)] to evaluate the relationship between serum testosterone levels and CVRF.

Materials and Methods

Study design and patients

Seventy-five male patients, aged between 18 and 68 years old, who had kidney transplantation at least six months ago, were enrolled into the study. Only patients with stable renal function after renal transplantation (RT) and with creatinine level of <2.5 mg/dL were included in this trial. Thirty male patients, who were in the same age range with CKD, were included in the control group.

All patients had their first RTs. Patients were divided into three groups as patients with kidney transplantation receiving m-TORi or CNIs and CKD. In all cases, donor kidney functions were similar. Donor data being a deceased/live donor was been recorded. Co-morbid diseases, duration of chronic renal failure (CRF), cause of CRF, time of transplantation and all medications were evaluated.

Serum creatinine, total cholesterol and triglyceride level were determined by an auto-analyzer (Integra 600) using Roche Diagnostics (Mannheim, Germany) kits.

This study was designed retrospectively and the study protocol was approved by the Tepecik Research Hospital Ethic Committee and informed consent was obtained from all the participants. No extramural funding was used to support this work. Investigation was conducted in accordance with the guidelines proposed in the Declaration of Helsinki.

Immunosuppressive therapy

Drug levels in renal transplant patients were consistent with the time of transplant. All patients received the stated base immunosuppressant as a de novo regimen and used myco-phenolic acid and steroids in addition to the above-mentioned treatment.

Standard maintenance immunosuppressive therapy generally consisted of prednisolone, Calcineurine inhibitors (microemulsion formulation of cyclosporine (CsA) or tacrolimus) or m-TORi (everolimus or sirolimus), combined with mycophenolate-mofetil (MMF).

Exclusion criteria

Patients with gynecomastia, galactorrhea, testicular atrophy, acute graft rejection, graft loose, post-transplant diabetes mellitus, congestive heart failure and using drugs affecting sex hormones (H2 receptor blockers, spironolactone, ketaconazole, benzodiazepines, tricyclic antidepressants and opiates) were excluded from the study.

All patients were examined in terms of testicular atrophy by a urologist. The profile of the androgenic hormones [follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, total testosterone] was obtained. ^[1],[2],[3] Physical examination and ultrasonographic evaluation was performed and patients with a diagnosis of testicular atrophy were excluded from the study.

For diagnosis of gynecomastia, all patients were examined by a general surgeon and, if need be, ultrasonographic screening and hormone levels (estrogen and progesterone) were obtained. Patients with gynecomastia were excluded from the study.

Hormonal evaluation

FSH (normal level = 0.7-11.1 mlU/mL), LH (normal level = 0.8-7.6 mlU/mL) and prolactin (normal level = 2.5-17 ng/mL) levels were examined by solid-phase, two-site chemiluminescent immunometric assay methods.

Total testosterone (normal levels for 18-49 years of age = 9.1-55.2 nmol/L; for 50-79 years of age = 6.3-26.3 nmol/L) levels were examined by a solid-phase, competitive chemiluminescent enzyme immunoassay method. ^{[23],[24],[25]}

Determination of cytokine serum levels

High-sensitivity C-reactive protein (hs-CRP) was determined using an automated-immunoturbidimetric assay with a Roche Diagnostics (Mannheim, Germany) kit. All investigations were carried out at the laboratory of biochemistry in the Tepecik Training and Research Hospital.

Echocardiographic evaluation

Two-dimensional guided M-mode echocardiography was performed using standard methods by an echocardiography system (General Electric Vingmed Vivid 3 Pro, Wauwatosa, WI, USA, with a 2.25 MHz transducer). Then, an echocardiographic assessment [including left atrium (LA) diameter, inferior vena cava (IVC) inspiratory and expiratory diameters and collapse index (CI) (=maximal diameter on expiration - minimal diameter on deep inspiration)/maximal diameter on expiration'), ^[26] left ventricular mass (LVM) and left ventricular mass index (LVMI) was carried out with the same echocardiographic device by the same operator. LVM was calculated using the thick-wall prolate-ellipsoidal model ^[27] LVM was standardized for body surface area (BSA) as LVMI. BSA was calculated by using the formula: 0.007184 × [weight (kg)] 0.425 × [height (cm)] 0.725. ^[28],[29] The upper gender-specific limit of the normal value for LVMI was 131 g/m ² for men.

Evaluation of blood pressure

Blood pressure was measured three times by a well-trained physician with the use of a standard mercury sphygmomanometer after the subject rested 5 min, and the average of the three measurements was used for the level of blood pressure during their outpatient department visits. Systolic blood pressure (SBP) was determined by the first Korotkoff sound and diastolic blood pressure (DBP) was determined by the fifth Korotkoff sound. ^[30]

Statistical Analysis

All statistical analyses were performed using SPSS 15.0 (Statistical Package for Social Sciences, Chicago, IL, USA) software. The data were expressed as mean ± standard deviation. The Kruskal-Wallis, Mann-Whitney U and multiple linear regression tests were used as the statistical analysis methods. A P-value of <0.05 was accepted as being significant.

Results

There was no significant difference in terms of mean age, creatinine levels and duration of renal failure among all the cases. Causes of renal failure in renal transplant patients (n = 75) were as follows: Unknown (n = 40), diabetes mellitus (n = 6), hypertension (n = 13), polycystic renal disease (n = 4), glomerulo-nephritis (n = 11) and nephrolithiasis (n = 1). The numbers of deceased and living donors were 30 and 45, respectively. The patients with hypertension (n = 34) were receiving angiotensin-converting enzyme inhibitors (n = 20), calcium channel blockers (n = 9) and beta blockers (n = 5) as anti-hypertensive treatment. Sixty patients with hyperlipidemia were receiving treatment with an anti-hyperlipidemic agent. Causes of renal failure in CKD patients (n = 30) were as follows: Unknown (n = 4), diabetes mellitus (n = 10), hypertension (n = 8), polycystic renal disease (n = 5), glomerulo-nephritis (n = 2) and nephrolithiasis (n = 1). These patients were receiving angiotensin-converting enzyme inhibitors (n = 19), calcium channel blockers (n = 7) and beta blockers (n = 4). Twenty-six CKD patients were receiving an anti-hyperlipidemic agent due to hyperlipidemia.

When comparing the patients with CKD, transplant recipients have shown improvement in testosterone levels and a decrease in cardiovascular risk factors. However, the relation between lipids and testosterone could not reach a statistically significant level [Table 1]. The groups were similar in terms of race/ethnicity, body mass index, smoking status/history, serum albumin, anemia, delayed graft function and acute rejection (P >0.05). There was no statistically significant difference in terms of age, creatinine, testosterone, FSH, LH, prolactin, LA, LVM, LVMI, IVC inspiratory and expiratory diameters, IVC collapse index, hs-CRP, TC, TG,SBP-DBP between the CNI and m-TOR groups (P >0.05) with the Mann-Whitney U test.

Table 1: Comparison of demographic data, sex hormones and CVRF between patients with kidney transplantation and CKD.

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In terms of other factors affecting the kidney function (acute rejection, viral infection, hypertension, hyperlipidemia, recurrent or de novo glomerulonephritis), there was no difference among the two groups.

Pre-transplant time on dialysis (39.1 ± 34.6 months and 38 ± 35 months) and time of transplantation (56.4 ± 41 months and 53.1 ± 47.2 months) between CNI and m-TOR groups were comparable (P >0.05) (Mann-Whitney U test).

Multiple linear regression analyses were performed to detect the independent risk factors among cardiac risk factors (IVC inspiratory and expiratory diameters, IVC collapse index LVM, LVMI, LA, hs-CRP, TC, TG, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and SBP-DBP) related to the serum testosterone levels. Testosterone levels were independent risk factors affecting IVC collapse index, systolic BP and LA [Table 2]. All the other remaining parameters lost their statistical significance in the multiple linear regression analyses.

Table 2: Multivariate-adjusted linear regression analysis of the testosterone levels and cardiac risk factors.

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Discussion

CVD is the leading cause of morbidity and mortality after kidney transplantation; it is also the most common cause of death with functioning graft. Transplant recipients have a lower risk of fatal and non-fatal cardiovascular events compared with wait-listed patients on dialysis, ^{[31],[32],[33],[34]} but much higher risk compared with the general population. ^[35] CVRF in these patients are as follows: Conventional risk factors (older age, diabetes mellitus, male gender, smoking, hypertension, high level of serum cholesterol) and unconventional risk factors (malnutrition, hyperhomosisteinemia, immune-suppressive drugs or decrease in physical activity, high level of lipoprotein, high CRP and IL-6 levels and proteinuria). ^{[36],[37],[38],[39],[40]} Immuno-suppressive agents (CNIs, m-TORi and steroids) contribute to the formation of atherosclerosis by causing hyperlipidemia, hypertension, diabetes mellitus and hyperhomosisteinemia. In addition to these factors, a negative correlation between serum testosterone levels and CVRF has been revealed in this study.

This study shows that CKD patients had more CVRF than transplant patients and also that their concomitant testosterone levels were low. There was no significant difference in terms of CVRF and testosterone levels between the transplant patients using CNIs or m-TORi.

Cardiac risk factors are associated with CVD in CKD, and hypertension, dyslipidemia, pro-inflammatory cytokines (hs-CRP, TNF-alfa), left ventricular hypertrophy (LVH), larger LVM, larger LVMI, IVC collapse index and low serum testosterone levels are known to contribute to the atherosclerotic processes. ^{[15],[40],[41],[42],[43],[44]}

Patients with end-stage renal disease (ESRD), particularly those requiring dialysis and transplantation, have an increased risk of premature CVD. ^[45] LVH is a common feature of patients with ESRD, a component of uremic cardio-myopathy, and an independent risk factor for sudden cardiac death, heart failure and cardiac arrhythmias in the general population and dialysis patients. ^{[45],[46],[47]} Furthermore, successful RT is associated with lower cardiovascular morbidity and mortality compared with patients who remain on the transplant waiting list, ^[48] and has been reported to be associated with significant echocardiographic regression of LVH. ^[49],[50]

However, accurate echocardiographic estimation of LVM in ESRD patients is difficult because of large variation in intravascular (and hence intraventricular) volume during the inter-dialytic period and during dialysis therapy. ^[51] Patients with a successful transplant have reduced cardiac risk compared with patients who remain on dialysis. ^[48] A number of studies have suggested that transplantation may be associated with regression of LVH. ^[52]

Abnormalities in lipid metabolism occur in patients with all stages of CKD. ^{[53],[54],[55],[56],[57],[58],[59]} The most common dyslipidemia in patients with CKD and dialysis is hypertriglyceridemia, whereas the total cholesterol concentration is normal or low, probably due to malnutrition. ^[60]

Lipid abnormalities are also common complications of kidney transplantation; a causal association of dyslipidemia with cardiovascular risk has not been proven in this patient population. ^[61] Despite advances in short-term allograft survival due to improvements in immunosuppressive regimens, dyslipidemia remains a significant problem in the transplant population. Corticosteroids, cyclosporine, rapamycin and, to a lesser extent, tacrolimus increase serum triglyceride and cholesterol levels. Hyperlipidemia is a frequent finding among renal transplant recipients, although renal function is often normal or near-normal. Increases in total cholesterol levels are most common, with elevated hypertriglyceride levels also usually noted. ^[61] Total cholesterol and triglyceride levels were higher in renal transplant and renal failure cases, but there was no relation with testosterone levels in this study. However, Gungor et al reported that there was a negative correlation between total cholesterol-triglyceride and testosterone levels in the cases on the chronic hemodialysis schedule. ^[62] It is likely that we could not find a relation between testosterone levels and lipids due to the small control group and high number of patients using anti-hyperlipidemic agents in the transplant group.

In this study, the relationship between testosterone levels and cardiac risk factors was investigated. The highest testosterone levels were observed in the RT patients. Increase of cardiac risk factors were related to decrease of testosterone levels. According to multiple regression analysis, testosterone levels were independent risk factors affecting IVC collapse index, systolic BP and LA.

Testosterone deficiency is related to an increased rate of CVDs in male patients with CRF. ^[63] Moreover, cardiovascular diseases are the most frequently encountered mortality reason after RT. ^[16] Gonadal functions in male CRF and dialysis patients are characterized with hypotestosteronism and hypospermatogenesis. ^[19] Additionally, hypothalamic-pituitary dysfunction may aggravate the hypogonadism. ^[65] Including vasculogenic, neurologic, endocrine, psychological, biochemical and pharmacological factors, the etiology of sexual dysfunction is considered to be multi-factorial among uremic patients. ^[64] However, gonadal dysfunction has a definite central role. ^[64] Uremic hypogonadism improves with increased testosterone levels following transplantation. ^[18],[19] However, this correlation is not evident in all patients. ^[19] Some conditions may continue to suppress the gonadal functions. The effect of immunosuppressive agents on hypothalamic-pituitary- gonadal functions was reported in a number of studies in the literature. ^[19],[20] In our study, the immunosuppressive agents (CNIs and m-TORi) did not have any negative effect on the hypothalamic-pituitary-gonadal functions.

CNIs were documented to have a positive effect on sexual hormone levels (FSH, LH, prolactin, testosterone) in male renal transplant patients. ^[20] Some studies reported a decrease in testosterone levels for the patients receiving sirolimus treatment after RT. ^[19],[21] In another study, the increase in testosterone levels was reported to affect renal functions positively and to protect against rejection in patients receiving low-dose cyclosporine and evero-limus treatment. ^[22] In our study, no negative contributions have been observed on testosterone levels in cases receiving m-TORi or CNIs.

Conclusion

m-TORi and CNIs drugs might have no negative effect on the testosterone levels, and improvement of the testosterone levels after transplantation might have positive contributions on cardiac risk factors. Multi-institutional, comprehensive studies are required to verify our findings.

Limitations

Although the relation between testosterone levels and CVRF has been evaluated in detail, this study has some limitations.

Microalbuminuria and albuminuria, two important CVRF, and also m-TORi are known to cause proteinuria; unfortunately, these relations could not be evaluated in this study.

Data about the marital and fertility status and sexual dysfunction are not available in this study.

The marital, and fertility status were not mentioned, which is important particularly in the m-TORi group as it causes secondary infertility.

In this study, some potential CVR factors (like NT-pro, BNP, troponin levels, parathormone and FGF-23 and phosphorous levels) could not be evaluated. 24-h Holter monitoring could not be used for blood pressure measurement. The other limitation is the lack of the data about the pre-transplant testosterone levels of the kidney recipients. This deficiency was attempted to be resolved by comparing the kidney recipients with the CKD patients.

Although testosterone levels were higher in kidney recipients and lower in CKD patients, this indirectly shows the possibility of positive effects of kidney transplantation on testosterone level. The use of the same patient group's pre-post transplant testosterone levels might be more powerful and clear to understand the relation of testosterone level and kidney transplantation.

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