The potential effects of anabolic-androgenic steroids and growth hormone as commonly used sport supplements on the kidney: a systematic review

In 2009, Daher et al. reported the case of a 21-year-old male athlete, admitted to the emergency department with complaints of nausea, progressive abdominal pain, dizziness, vomiting, headache, weakness, fever, and profuse sweating in the last month. Nausea and vomiting were in association with oliguria and arterial hypertension (160/120 mmHg). The results of laboratory tests upon admission indicated an increase in the serum levels of calcium (13.2 mEq/L), creatinine (3.9 mg/dL), and urea (79 mg/dL). The urinary analysis indicated leukocyturia (+++), hematuria (+), and proteinuria (traces). The amount of protein in the 24-h urine was 259 mg. The kidney size and renal arteries were normal. The renal biopsy showed moderate interstitial inflammatory infiltrates with eosinophils, calcium deposits, tubular necrosis, and interstitial edema. History-taking revealed that the patient was receiving anabolic steroids and veterinary supplements containing vitamin A, vitamin D, and vitamin E, respectively (20,000,000, 35,000,000, and 6000 IU, respectively). All causative agents were discontinued, and hypertension and hypercalcemia were controlled via pharmacotherapy. The patient was discharged with almost normal renal function after 20 days. In this study, the case of a 30-year-old man, experiencing nausea, vomiting, diarrhea, and fever in the past month before admission, was also reported. He was referred to the emergency department with the main complaint of persistent vomiting. The physical examination revealed the patient’s good general condition, except for abdominal pain upon palpation. According to the laboratory tests upon admission, the serum levels of urea (52 mg/dl), creatinine (1.9 mg/dl), and calcium (11 mEq/l) increased. The urinalysis showed blood (+) and protein (++). Also, the urinary level of calcium was 390 mg/24 h. The kidney size was normal. The patient confirmed the use of anabolic steroids and veterinary supplements containing vitamin A, vitamin D, and vitamin E (20,000,000, 35,000,000, and 6000 IU, respectively) in the past two years before admission. In addition, the patient was receiving 12 mg of dexamethasone every two weeks. Despite intravenous hydration and administration of furosemide and prednisolone (1 mg/kg per day), renal function did not improve. The renal biopsy revealed mild interstitial lymphmononuclear inflammatory infiltrates with eosinophils, without any remarkable tubular abnormalities. After discontinuing the use of these agents, the patient’s renal function gradually recovered after one month of hospitalization [20]. The authors also briefly described 14 other cases of AKI and relevant complications (e.g., cholestasis and rhabdomyolysis) associated with anabolic steroids (e.g., metandienone, stanozolol) and vitamin supplements (e.g., vitamins D and A) in males and females aged between 21 and 63 years published in the literature between 1988 and 2009. They demonstrated that apart from potential adverse effects of anabolic steroids on the kidney, interstitial nephritis, hypercalcemia, and nephrocalcinosis secondary to vitamin D intoxication were also capable of inducing renal dysfunction in these cases. Rhabdomyolysis has been reported in the setting of AKI due to anabolic-androgenic steroids and it can independently induce or aggravate AKI caused by these agents [20]. Nephrocalcinosis secondary to exogenous vitamin D intoxication in a bodybuilder athlete has been described in another case report [21].

Almukhtar et al. in 2015 also reported 4 bodybuilders referred to the nephrology department of a university hospital with the chief complaint of weakness and lethargy. All patients had taken more than 400 mg/week testosterone proprionate and/or nandrolone decanoate intramuscularly. They also had consumed supplementary proteins (containing 78–104 g of whey powder added to regular dietary protein including 2–3 L of milk to reach 278–354 g daily) and creatine (15 g per day). Their serum creatinine and estimated glomerular filtration rate (eGFR) were 229.84–335.92 μmol/L and 0.37–0.57 mL/s, respectively. Renal biopsy revealed acute tubular necrosis. By discontinuing all the above agents, serum creatinine became normal within four weeks. The authors attributed AKI in the bodybuilders to the combination effects of excess creatine and protein with steroid injections along with hypervitaminosis D and phosphate nephropathy [22].

Bile acid nephropathy, also known as cholemic nephrosis, can be typically associated with AKI. At least 3 case reports published between 2014 and 2016 described bile acid nephropathy secondary to cholestatic jaundice caused by anabolic steroids in bodybuilders with no underlying liver or kidney diseases. The abused anabolic steroids in the above case reports were oral or injectable stanazolol, injectable nandrolone, injectable testosterone, and oral methandrostenolone consumed for 5 to 6 weeks or oxandrolone, boldenone undecyclenate, stanazolol, and trenabol for an unidentified duration. Hyperbilirubinemia, increased serum creatinine, oliguria and tubular bile acid casts in urine specimen were observed in the cases. All AKI episodes were resolved by either only discontinuing the offending medication or along with supportive care and renal replacement therapy [19, 23, 24].

Regarding the effects of endogenous sex hormones on the urinary markers of nephrotoxicity, an experimental study in rats demonstrated that there was a significant association between testosterone and urinary excretion of leucine aminopeptidase, alkaline phosphatase, γ-glutamyl transpeptidase, cystatin C and β2-microglobulin, as biomarkers of kidney’s proximal tubule [25]. The authors stated that these data should be considered in the accurate interpretation of studies about markers of nephrotoxicity in animals.

Endocrine dysfunctions, such as testosterone deficiency and hypogonadism may occur in male patients with CKD [26]. These dysfunctions are associated with a higher risk of morbidity and mortality, possibly due to anemia, mineral as well as bone disorders (osteoporosis & osteodystrophy), and cardiovascular diseases in CKD individuals [27]. Conversely, exogenous testosterone administration can also cause renal dysfunction, renal injury progression, and proteinuria [28]. Anabolic-androgenic steroids can cause or exacerbate CKD and also kidney fibrosis or sclerosis with different mechanisms:

A number of investigations have shown a relation between the male gender and multiple kidney disorders, such as IgA nephropathy, polycystic kidney disease, and membranous nephropathy. Therefore, androgens can be involved in the progression of CKD [49‐51]. Accordingly, in diabetic nephropathy, male gender is a risk factor for proteinuria progression [52]. In contrast, some evidence suggested that an imbalance in sex hormones’ ratio (rather than androgen excess alone) may cause or aggravate kidney dysfunction. For example, Maric et al. demonstrated that lower levels of endogenous testosterone and higher levels of blood estradiol were associated with the development of diabetic nephropathy in men [53]. Administration of exogenous testosterone and aromatase inhibitors can restore dihydrotestosterone and estradiol levels to their physiological range. Consequently, they can even act as renal protective agents in the progression of diabetic nephropathy via reducing inflammatory process and fibrosis [54, 55].

Xu et al. demonstrated a dose-dependent relation between administration of exogenous dihydrotestosterone and albuminuria, glomerulosclerosis, and tubule-interstitial fibrosis progression in castrated male diabetic rats. Administration of 0.75 mg/day dihydrotestosterone (low dose) had nephroprotective effects; whereas, administration of 2.0 mg/day dihydrotestosterone (high dose) accelerated renal injury process. Additionally, estradiol could affect the dose-dependent action of dihydrotestosterone on the kidneys [56].

Herlitz et al. in 2010 described variable degrees of renal insufficiency, proteinuria, and nephrotic syndrome in 10 bodybuilders with the mean age of 37 years abusing anabolic steroids. At least one anabolic-androgenic steroid, usually combined with dietary supplements (e.g., monohydrate, creatine, and a high-protein diet). They manifested along with proteinuria and renal insufficiency (mean creatinine level, 3.0 mg/dl). Nephrotic syndrome was detected in three out of 10 (30%) patients. According to the renal biopsy, FSGS and ≥ 40% tubular atrophy and interstitial fibrosis were found in nine and three patients, respectively. Among all seven patients with long-term follow-ups, discontinuation of anabolic steroids, along with the use of RAAS blockers and/or corticosteroids, has led to the improvement or stabilization of serum creatinine, weight loss, and proteinuria reduction. The authors hypothesized that secondary FSGS in anabolic-androgenic steroid abusers may be related to different pathways: 1) an increase in lean body mass which may result in glomerular hyperfiltration; 2) overexpression of a potent profibrotic and proapoptotic cytokine (TGF-β1); 3) induction of oxidative stress; and 4) upregulation of RAAS components. The last three mechanisms can be attributed to the potential toxic effects of anabolic-androgenic steroids on glomeruli. Besides these mechanisms, other factors including high-protein diet (by increasing the renal blood flow and GFR) and elevated blood pressure (via hypertensive arterionephrosclerosis) may have additive/synergistic adverse effects on glomeruli [57].

One year later, Harrington et al. reported another case of secondary FSGS caused by anabolic steroid abuse in a 38-year-old man. History taking revealed regular use of anabolic steroids, both orally and intramuscularly since the age of 18. Para clinical evaluation demonstrated high serum creatinine (1797 μmol/l), increased serum urea concentration (55.2 mmol/l), low hemoglobin level (6.0 g/l), intrinsic renal parenchymal damage, and FSGS. The patient required renal replacement therapy due to his end-stage renal disease (ESRD). Hemodialysis and after that, continuous ambulatory peritoneal dialysis were initiated for him [58]. It is noteworthy that these two reports are just case descriptions and obviously, not epidemiological studies. A summary of published experimental and clinical studies regarding renal safety of anabolic-androgenic steroids is shown in Table 1 in the order of study type (first experimental and after that clinical) and publication year.

In brief, regular, long-term use of anabolic-androgenic steroids can induce various renal disorders directly or indirectly through different mechanisms [19]. Some mild renal abnormalities, such as increase in serum creatinine, blood urine nitrogen, or uric acid, without sclerotic/fibrotic morphological alteration or decrease in cystatin C clearance, can be recovered after discontinuing anabolic-androgenic steroids [59]. However, their consumption by some individuals may be associated with poor kidney prognosis, resulting in ESRD. As a result, well-designed clinical studies are warranted to examine the exact pathological effects and roles of different doses of endogenous or exogenous androgens on the progression of kidney dysfunction in patients with CKD.

GH is a polypeptide hormone [63]. GH genes are expressed in pituitary somatotropic cells, placenta, and to a lesser extent in lymphocytes [64]. GH expression in lymphocytes is merely adequate for local paracrine/autocrine regulations, and all physiological actions of this hormone are mediated by pituitary and placental GH [65]. The most important sites of GH metabolic clearance are the kidneys and liver [65].

GH plays a crucial role in some biological activities, including nitrogen retention, amino acid transportation into muscle, promotion of somatic growth, growth plate elongation, generation of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP), lipolysis, sodium or phosphorus retention, producing insulin antagonistic effects, cell hyperplasia, and lactogenesis [65]. GH can also convert T4 to T3 and active cortisone to its inactive form [66].

Due to the beneficial effects of GH on lean body mass, and performance, as well as not being detected within the body, GH abuse is very common among athletes [67, 68]. Although a systematic review in 2008 claimed that GH can elevate lean body mass [69], at least one randomized, placebo-controlled, blinded study demonstrated that this increase in lean body mass is primarily the result of the extracellular water volume expansion [70]. However, some evidence suggested that an increase in GH level may enhance physical performance, increase tolerance for hard training, and shorten recovery time after exercise [71].

Regarding safety, GH can cause a number of adverse reactions, such as muscle pain, joint stiffness and pain, paresthesia, carpal tunnel syndrome, and headache. These adverse effects may be caused through fluid retention and are generally preventable by decreasing the dose [66]. Since GH can affect calcium absorption in the intestine and increase its excretion, calcium balance may be disturbed [72]. Although some evidence have shown that GH treatment can elevate plasma insulin concentration leading to increased risk of diabetes type II [73], no evidence of high fasting glucose level and diabetes type II was observed 6 years after discontinuing GH treatment in children born small for gestational age [74]. According to these data, long-term administration of GH does not increase the risk of diabetes type 2 and metabolic syndrome [74]. Otitis media, scoliosis, slipped femoral capital epiphyses, increased risk of malignancies, and sudden death are other rare and also even unproven complications of GH treatment [75].

The functions of GH are induced directly or indirectly via synthesis of IGF-I. Since GH receptors, IGF-I, IGF-I receptors, and IGF binding proteins are expressed in the kidney tissue, GH and IGF-I can affect different aspects of this organ, such as its morphology and size, GFR, and minerals’ hemostasis [76].

GH can change the level of serum creatinine by its anabolic effects on muscles [77‐79]. Although GH administration can increase GFR by about 10–15% [80], GH at the dose of 50 ng/kg/min for 2 h did not affect the GFR in healthy men [81]. Similarly, a double-blind, placebo-controlled study implicated that GH administration at the dose of 0.125 IU/kg per week subcutaneously for the first 4 weeks and 0.25 IU/kg per week for a subsequent 5 months did not increase GFR [82]. On the other hand, various studies have demonstrated elevation of GFR and renal plasma flow in patients with acromegaly [83‐85].

Studies have demonstrated that GH administration in female rats [86] and dogs [87], as well as non-viral GH transmission in mice [88] resulted in the enlargement of kidneys. In line with these findings, renal parenchyma was modified in transgenic mice models by over-expressing genes coding for GH and IGF-I [89]. Wanke et al. observed that not only the mean glomerular volume, but also the number of endothelial and mesangial cells per glomerule increased in the GH transgenic mouse model of progressive renal disease compared to the control group [90]. Over-expression of IGF-I in transgenic mice caused the expansion of extracellular matrix and glomerulosclerosis [91]. In contrast to animal studies, glomerulosclerosis and renal failure are rare among patients with acromegaly [83, 92].

GH hypersecretion can increase kidney size by about 6–54% [76]. Although 7 days of GH treatment [93] or 3 days of IGF-I injection [78] did not affect human kidney size, GH administration for 6 months in individuals with GH deficiency led to an increase in its size [82, 94]. In accordance to the mentioned statement, a case report described that kidney shrinkage by about 10–20 and 20% occurred 1 and 5 months after hypophysectomy, respectively [95]. Noting that some studies have demonstrated that the kidney weight/body weight ratio is constant and this increase in the size of kidney is associated with body weight gain [86, 96].

Regarding glomerulopathy, GH hypersecretion [77] or subcutaneous injections of GH (with the dose of 2 IU in the morning and 4 IU in the evening for one week) [93] and rhIGF-I (with the dose of 60 μg/kg, at 800, 1400 and 2000 h) [78] did not significantly alter albuminuria (as an index for glomerular permeability) and β₂-microglobin (as an index for proximal tubular involvement). However, microalbuminuria was significantly increased (but not in a pathological pattern) in acromegalic patients [79, 85], especially in those with hypertension or diabetes mellitus [97].

Extracellular volume overload, hypertension, electrolyte disorders (such as hyperphosphatemia, hypophosphaturia, hypercalciuria), and urine acidification with reduced kaliuria are other consequences of GH hypersecretion [76]. Inversely, GH treatment caused extracellular volume reduction in patients with GH deficiency [95, 98]. In addition to extracellular volume overload, GH can increase sodium and water reabsorption from renal tubules [85, 99]. It can also activate RAAS [99, 100] which may lead to hypertension.

Considering the fact that growth retardation is a common complication of CKD in children, GH has been used to treat short stature in this population, including children under conservative treatment or hemodialysis and the ones who are kidney transplant recipients [101]. A meta-analysis of 16 relevant studies (including 809 children) published from 1980 to 2011 demonstrated that apart from clinical efficacy, GH therapy did not alter kidney function (e.g., GFR) nor did it increase episodes of acute rejection, compared to placebo in children with CKD (pre-dialysis, dialysis) or transplanted kidney, respectively [102].

Overall, although GH may adversely affect different aspects of kidney such as size, GFR, and tubule functions either directly or indirectly, it has not been clarified yet whether GH at doses used by athletes and body builders can truly cause kidney dysfunction. In addition, there is no definite and conclusive clinical evidence about the detrimental effects of GH on the kidney in these populations. Details of published experimental and clinical studies about the renal safety of GH in the order of study type (first experimental and after that clinical) and publication year are summarized in the Table 2.