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Testosterone replacement therapy is associated with an increased risk of urolithiasis

World Journal of Urology Aims and scope Submit manuscript



To determine whether TRT in men with hypogonadism is associated with an increased risk of urolithiasis.


We conducted a population-based matched cohort study utilizing data sourced from the Military Health System Data Repository (a large military-based database that includes beneficiaries of the TRICARE program). This included men aged 40–64 years with no prior history of urolithiasis who received continuous TRT for a diagnosis of hypogonadism between 2006 and 2014. Eligible individuals were matched using both demographics and comorbidities to TRICARE enrollees who did not receive TRT. The primary outcome was 2-year absolute risk of a stone-related event, comparing men on TRT to non-TRT controls.


There were 26,586 pairs in our cohort. Four hundred and eighty-two stone-related events were observed at 2 years in the non-TRT group versus 659 in the TRT group. Log-rank comparisons showed this to be a statistically significant difference in events between the two groups (p < 0.0001). This difference was observed for topical (p < 0.0001) and injection (p = 0.004) therapy-type subgroups, though not for pellet (p = 0.27). There was no significant difference in stone episodes based on secondary polycythemia diagnosis, which was used as an indirect indicator of higher on-treatment testosterone levels (p = 0.14).


We observed an increase in 2-year absolute risk of stone events among those on TRT compared to those who did not undergo this hormonal therapy. These findings merit further investigation into the pathophysiologic basis of our observation and consideration by clinicians when determining the risks and benefits of placing patients on TRT.

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The Center for Surgery and Public Health and the Uniformed Services University of Health Sciences are jointly supported by the Henry M. Jackson Foundation for the Advancement of Military Medicine to provide protected research efforts involving the analysis and study of military TRICARE data (Grant # HU0001-11-1- 0023). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, assertions, opinions, or policies of the Uniformed Services University of the Health Sciences (USUHS), the United States Department of Defense (DoD), or any other agency.


Dr. Haider reports receiving grants from the Henry M. Jackson Foundation of the Department of Defense, the Orthopaedic Research and Education Foundation, and the National Institutes of Health, and non-financial research supports from the Centers for Medicare and Medicaid Services Office of Minority Health. Dr. Trinh reports receiving research support from the Brigham Research Institute Fund to Sustain Research Excellence, the Bruce A. Beal and Robert L. Beal Surgical Fellowship, the Genentech Bio-Oncology Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology (Grant # 10202), a Health Services Research pilot test grant from the Defense Health Agency, the Clay Hamlin Young Investigator Award from the Prostate Cancer Foundation (Grant # 16YOUN20), and an unrestricted educational grant from the Vattikuti Urology Institute.

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Authors and Affiliations



TRM, M-TI, TK, SB, and Q-DT developed the protocol/project, were involved in data collection or management, analyzed and interpreted the data, and wrote/edited the manuscript. NKK developed the protocol/project, was involved in data collection or management, analyzed the data, and wrote/edited the manuscript. APC, MNK, NB, GEH, and AHH analyzed and interpreted the data and wrote/edited the manuscript. WJ analyzed the data and wrote/edited the manuscript.

Corresponding author

Correspondence to Quoc-Dien Trinh.

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Conflict of interest

Dr. Basaria reports receiving consulting fees from Eli Lilly and Takeda Pharmaceuticals. Dr. Trinh reports receiving consulting fees from Bayer, Astellas, and Janssen. All other authors have nothing to disclose.

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Appendix 1: Study cohort selection and matching

figure a

Appendix 2: Codes for diagnoses and procedures


ICD-9 diagnosis

Testicular dysfunction



ICD-9 procedure


Testosterone pellet; 75 mg



Injection, testosterone enanthate and estradiol valerate, up to 1 cc



Injection, testosterone cypionate and estradiol cypionate, up to 1 ml



Injection, testosterone cypionate, up to 100 mg



Injection, testosterone cypionate, 1 cc, 200 mg



Injection, nandrolone decanoate, up to 50 mg



Injection, testosterone enanthate, up to 100 mg



Injection, testosterone enanthate, up to 200 mg



Injection, testosterone suspension, up to 50 mg



Injection, testosterone propionate, up to 100 mg



Unclassified drug (Testopel)



Topical formulations (by name)












Oral formulations (by name)












Indicators of urolithiasis




98.5 Extracorporeal shock wave lithotripsy

50590 Lithotripsy, extracorporeal shock wave


98.51 Extracorporeal shock wave lithotripsy of the kidney, ureter and/or bladder

S0400 Global fee for extracorporeal shock wave lithotripsy treatment of kidney stone(s)



52352 Cystourethroscopy, with ureteroscopy and/or pyeloscopy; with removal or manipulation of calculus


52353 Cystourethroscopy, with ureteroscopy and/or pyeloscopy; with lithotripsy

Nephrolithotomy (percutaneous and open)

55.03 Nephrostomy

50060 Nephrolithotomy; removal of calculus


50065 Nephrolithotomy; secondary surgical operation for calculus


50070 Nephrolithotomy; complicated by congenital kidney abnormality


50075 Nephrolithotomy; removal of large staghorn calculus filling renal pelvis and calices


50080 Percutaneous nephrostolithotomy or pyelostolithotomy, up to 2 cm


50081 Percutaneous nephrostolithotomy or pyelostolithotomy, over 2 cm

Urinary calculi

274.11 Uric acid nephrolithiasis


592 Calculus of kidney and ureter


592.1 Calculus of ureter


592.0 Calculus of kidney—nephrolithiasis not otherwise specified


592.9 Urinary calculus, unspecified


Appendix 3: Occurrence of stone events among those diagnosed with secondary polycythemia within the testosterone replacement therapy cohort of hypogonadal men in TRICARE, 2006–2014


Number of individuals

Individuals with stone event

Percent with stone event

No polycythemia diagnosis




Polycythemia diagnosis




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McClintock, T.R., Valovska, MT.I., Kwon, N.K. et al. Testosterone replacement therapy is associated with an increased risk of urolithiasis. World J Urol 37, 2737–2746 (2019).

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