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Testosterone replacement therapy is associated with an increased risk of urolithiasis

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Abstract

Purpose

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

Methods

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.

Results

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).

Conclusion

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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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

  1. Division of Urology, Brigham and Women’s Hospital, Harvard Medical School, 45 Francis St, ASB II-3, Boston, MA, 02115, USA

    Tyler R. McClintock, Alexander P. Cole, Martin N. Kathrins, George E. Haleblian & Quoc-Dien Trinh

  2. Geisel School of Medicine at Dartmouth, Hanover, NH, USA

    Marie-Therese I. Valovska

  3. Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Nicollette K. Kwon, Alexander P. Cole, Wei Jiang, Adil H. Haider & Quoc-Dien Trinh

  4. Department of Urology, University of Montreal, Montreal, QC, Canada

    Naeem Bhojani

  5. Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Tracey Koehlmoos

  6. Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Adil H. Haider

  7. Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Shehzad Basaria

Authors
  1. Tyler R. McClintock
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  11. Shehzad Basaria
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Contributions

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.

Ethics declarations

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.

Human and animal rights

This article does not contain any studies with human participants or animals performed by any of the authors.

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For this type of study, formal consent is not required.

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Appendices

Appendix 1: Study cohort selection and matching

figure a

Appendix 2: Codes for diagnoses and procedures

Diagnosis

ICD-9 diagnosis

Testicular dysfunction

257.1–257.9

Procedure

ICD-9 procedure

HCPCS/CPT

Testosterone pellet; 75 mg

 

S0189/11980

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

 

J0900

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

 

J1060

Injection, testosterone cypionate, up to 100 mg

 

J1070

Injection, testosterone cypionate, 1 cc, 200 mg

 

J1080

Injection, nandrolone decanoate, up to 50 mg

 

J2320

Injection, testosterone enanthate, up to 100 mg

 

J3120

Injection, testosterone enanthate, up to 200 mg

 

J3130

Injection, testosterone suspension, up to 50 mg

 

J3140

Injection, testosterone propionate, up to 100 mg

 

J3150

Unclassified drug (Testopel)

 

J3490

Topical formulations (by name)

 

 AndroGel

 

 Axiron

 

 Fortesta

 

 Testim

 

 Vogelxo

 

Oral formulations (by name)

 

 Android

 

 Methitest

 

 Oxandrin

 

 Oxandrolone

 

 Testred

 

Indicators of urolithiasis

ICD-9

CPT

ESWL

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)

Lithotripsy

 

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

26,093

1035

3.97

Polycythemia diagnosis

493

26

5.27

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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). https://doi.org/10.1007/s00345-019-02726-6

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