Introduction
Approximately 0.7-2% of patients admitted to the hospital have hypercalcemia noted in their laboratory evaluation [ 1 - 3 ]. In the setting of hypercalcemia, patients most commonly present with neuropsychiatric or gastrointestinal complaints, which can include weakness, lethargy, coma, nausea, vomiting, constipation, or weight loss [ 1 ]. The severity of these symptoms often correlates with the acuity of the onset and the level of measured serum calcium [ 1 ].
Trenbolone is a synthetic anabolic-androgenic steroid (AAS) often used for its performance-enhancing abilities or cosmetic effects [ 4 ]. Approximately three to four million Americans have used AAS in their lifetime, with the highest prevalence in young adult males [ 5 ]. The mechanism by which trenbolone and other AAS cause hypercalcemia is not completely known, but there are multiple proposed mechanisms [ 6 , 7 ].
Recognition of the association between AAS use, hypercalcemia, and acute kidney injury (AKI) is critical for timely diagnosis and treatment. This case report aims to highlight the clinical presentation, diagnostic considerations, and pathophysiological mechanisms underlying these complications in the context of AAS misuse, contributing to the growing body of evidence on the renal and metabolic risks associated with performance-enhancing drug use [ 8 - 10 ].
Case presentation
A 41-year-old man presented to the emergency department (ED) after referral from an urgent care clinic for abnormal laboratory results from the previous day. He was informed that his calcium level and kidney function were abnormal and was advised to seek further evaluation. He reported one week of progressive fatigue and dizziness with positional changes. He described mid-epigastric pain radiating to the sternum associated with nausea without vomiting, as well as darker-than-normal urine. He reported working outdoors but noted difficulty maintaining adequate hydration. The patient denied any medication use at home, including no analgesics. Additionally, he disclosed the use of trenbolone but declined other supplements or steroid use.
Vital signs demonstrated tachycardia with a heart rate of 108; otherwise, vital signs were normal. Physical examination was normal, without focal findings or abdominal tenderness. Laboratory evaluation showed significant hypercalcemia of 15 mg/dL (reference range: 8.7-10.4 mg/dL) with a serum albumin of 2.7 g/dL (reference range: 3.4-5 g/dL). Calcium corrected for albumin was 16.5 mg/dL. Additionally, the patient had elevated bicarbonate >40 mmol/L (reference range: 20-31 mmol/L), blood urea nitrogen of 33 mg/dL (reference range: 9-23 mg/dL), creatinine of 6.02 mg/dL (reference range: 0.70-1.3 mg/dL), creatine kinase of 376 U/L (reference range: 46-171 U/L), aspartate aminotransferase of 92 U/L (reference range: <34 U/L), and alanine aminotransferase of 37 U/L (reference range: 7-49 U/L). Urinalysis showed trace blood with no RBCs, no bilirubin, and no ketones. Parathyroid hormone (PTH) was ordered to evaluate for primary hyperparathyroidism as the cause of hypercalcemia. The PTH level was low at 7.4 pg/mL (reference range: 18.4-90.1 pg/mL), suggesting non-PTH-mediated hypercalcemia. PTH-related peptide was slightly elevated at 3.7 pmol/L (reference range: 0-2.3 pmol/L). An electrocardiogram, noted in Figure 1 , was remarkable for sinus rhythm at 86, a QT of 296, and no significant ST changes. A computed tomography scan of the chest, abdomen, and pelvis was performed to evaluate for malignancy and was unremarkable.
The patient was started on intravenous fluids for treatment of AKI and hypercalcemia and was admitted to the hospital. Nephrology recommended pamidronate, which was started within hours after admission. During hospitalization, the patient had normal 25-hydroxyvitamin D levels with low 1,25-dihydroxyvitamin D, supporting a non-vitamin D-toxicity etiology. Over the next few days, with continued intravenous fluids and pamidronate, the patient’s hypercalcemia and kidney function improved, allowing for discharge from the hospital as noted in Figure 2 . After exclusion of malignancy, hyperparathyroidism, and vitamin D toxicity, trenbolone use was the most likely cause of hypercalcemia.
Discussion
Hypercalcemia is defined as serum calcium above the upper limit of normal, greater than 10.5 mg/dL [ 2 ]. This condition can arise from various underlying causes, such as primary hyperparathyroidism and malignancy, which account for approximately 90% of cases. Less commonly, hypercalcemia can be secondary to vitamin D toxicity, drug-related issues, or other endocrine-related disorders [ 2 ]. While moderate hypercalcemia (12.0-13.9 mg/dL) may present with constitutional symptoms such as fatigue and constipation, severe hypercalcemia or hypercalcemic crisis (≥14 mg/dL) can often produce acute issues such as altered mental status and cardiovascular membrane instability [ 2 ].
Calcium levels in the body are regulated by PTH and vitamin D. About half of the calcium in the body is ionized and biologically active, while the other half binds to albumin and immunoglobulins [ 11 ]. PTH is released when ionized calcium levels are low to stimulate calcium release through osteoclast-mediated bone resorption and to increase distal nephron and loop of Henle reabsorption of calcium [ 11 , 12 ]. In the proximal nephron, PTH increases 1α-hydroxylase transcription, which stimulates conversion of 25-hydroxyvitamin D (calcidiol) to 1,25-dihydroxyvitamin D (calcitriol) [ 12 , 13 ]. This results in calcitriol-mediated upregulation of calcium channels and exchangers in the small intestine, increasing absorption [ 13 ].
The leading cause of hypercalcemia is malignancy [ 2 , 3 ]. Up to 44% of hypercalcemia is secondary to malignancy, with lung cancer followed by multiple myeloma and renal cell carcinoma [ 2 ]. Hyperparathyroidism is the second most common cause of hypercalcemia [ 1 - 3 ].
Less commonly, hypercalcemia may arise from multi-substance use, including vitamin D intoxication, or as a paraneoplastic-like effect of anabolic-androgenic steroids (AAS). AAS use has been implicated in cases of multi-organ dysfunction, including AKI, among bodybuilders [ 8 , 9 ]. The literature describes three cases of hypercalcemia associated with AAS and other supplement use, leading to AKI and systemic complications [ 8 - 10 ]. AAS misuse is increasingly recognized as a cause of diverse renal pathologies, including acute tubular necrosis, focal segmental glomerulosclerosis, and bile nephropathy, often manifesting as AKI [ 14 ]. The pathophysiology of AAS-induced renal injury is multifactorial, involving direct nephrotoxicity, hemodynamic changes, and secondary effects from associated practices such as high protein diets, dehydration, and concomitant use of other nephrotoxic agents [ 14 ]. Furthermore, AAS-induced hepatotoxicity can lead to cholestatic jaundice and secondary bile nephropathy, further contributing to AKI [ 14 ].
Our patient presented with hypercalcemia with no evidence of elevated PTH, malignancy, significant dehydration, or vitamin D toxicity as the primary cause. The suspected source of the patient’s hypercalcemia was secondary to trenbolone use.
As a synthetic AAS, trenbolone has potent anabolic effects and limited androgenic activity [ 4 ]. Despite well-recognized performance-enhancing and cosmetic effects, AAS are associated with incompletely characterized multisystem toxicities, with approximately one-third of users experiencing adverse effects, including acne, gynecomastia, hirsutism, hypertension, and cardiac dysrhythmias [ 4 ].
The mechanism by which trenbolone causes hypercalcemia is not completely known. Vincieto et al. suggest that AAS may influence calcium levels through two pathways: a non-genomic (rapid) pathway and a genomic (slow) pathway [ 6 ]. In the non-genomic pathway, androgens bind to a membrane receptor, activating a signaling cascade that stimulates voltage-dependent calcium channels to release calcium into the cytosol from the endoplasmic and sarcoplasmic reticulum via inositol 1,4,5-trisphosphate receptors [ 6 ]. Membrane-bound proteins modulate the efflux of calcium from the cell into the plasma [ 6 ]. Androgen receptors in the cytosol bind androgens to activate the genomic pathway, altering the expression or regulation of calcium transporters, pumps, or channels and leading to increased efflux of calcium into the plasma [ 6 ].
In addition to these proposed mechanisms, trenbolone may cause hypercalcemia through its anabolic and androgenic effects on bone metabolism. Trenbolone stimulates androgen receptors in bone, leading to increased bone turnover and potential release of calcium into the circulation [ 7 ].
Trenbolone may have a direct nephrotoxic effect or may have resulted in AKI secondary to severe hypercalcemia, as calcium is excreted primarily by the kidneys. While dehydration could have been a contributing factor, it was less likely to be the primary cause of significant kidney injury. Laboratory evaluation showed no ketonuria, which is often observed in the setting of dehydration, and the patient’s blood urea nitrogen to creatinine ratio was 5.5, well below the typical threshold of >20 seen with dehydration-induced azotemia.
Our case adds to the limited body of literature describing serious adverse effects associated with AAS use. To date, only three published case reports have described anabolic steroid-induced hypercalcemia. These cases reported multi-organ dysfunction linked to AAS use, specifically testosterone, often in combination with other supplements or substances. Trenbolone, a synthetic analogue of testosterone from the nandrolone group of AAS, possesses approximately three times the affinity for androgen receptors compared with testosterone, producing potent anabolic effects on skeletal muscle and bone [ 7 ]. This enhanced activity could also have contributed to the multi-organ failure observed in these patients [ 8 - 10 ].
Our patient reported isolated anabolic steroid use, suggesting that anabolic steroids alone may precipitate clinically significant hypercalcemia. Workup in the ED and upon admission revealed no other obvious cause of hypercalcemia, and AKI improved with supportive care and intravenous fluids during hospitalization. While a small number of cases have been reported in the literature, in addition to our case, this does not establish causality.
A limitation of this case is that the duration, dose, and route of trenbolone use were not available. Additionally, while AAS are implicated in metabolic disturbances, other causes of hypercalcemia, such as vitamin A toxicity, cannot be fully excluded, as a vitamin A level was not obtained. Furthermore, unreported concomitant use of other steroids, supplements, or vitamins may have contributed to the patient’s metabolic and renal abnormalities. These limitations highlight the challenges in evaluating substance-related metabolic derangements.
Our case emphasizes the importance of obtaining a thorough history, including the use of supplements, performance-enhancing agents, and nonprescribed substances, as these may contribute to unexpected metabolic or systemic complications such as hypercalcemia.
Conclusions
This case highlights a patient with hypercalcemia likely secondary to AAS (trenbolone) use. It underscores the importance of considering a thorough history, including the use of supplements, performance-enhancing agents, and nonprescribed substances, as these can be contributing factors to a patient’s presentation in the ED. As there is limited literature on trenbolone and AAS use, this case report contributes to the literature and increases awareness of complications that may arise from their use.
Disclosures
Human subjects: Informed consent for treatment and open access publication was obtained or waived by all participants in this study.
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:
Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.
Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.
Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
Author Contributions
Concept and design: Kaitlyn C. Lizardo, Sarah Merchant
Acquisition, analysis, or interpretation of data: Kaitlyn C. Lizardo, Emily Drone
Drafting of the manuscript: Kaitlyn C. Lizardo, Emily Drone, Sarah Merchant
Critical review of the manuscript for important intellectual content: Kaitlyn C. Lizardo, Emily Drone, Sarah Merchant
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