Preoperative testosterone replacement therapy: a potential risk-factor for complications and reoperation after rotator cuff repair

Abstract

Background

Prior studies have shown that testosterone replacement therapy (TRT) may be a risk-factor for complications after rotator cuff repair (RCR). This study evaluated complication rates among male RCR patients with and without a history of TRT preoperatively.

Methods

A retrospective review of 33,032 male patients undergoing RCR in the PearlDiver database was performed. Patients receiving TRT within 1-year of surgery were propensity score matched 1:3 to those not receiving TRT, 8,258 TRT, and 24,774 no-TRT patients were included. Univariate and multivariate analyses were performed to compare outcomes between groups.

Results

After controlling for decreased libido, benign prostatic hypertrophy, tobacco use, alcohol disorders, liver disease, rheumatologic disease, and preoperative steroid injections, TRT patients were more likely to be readmitted within 90 days (odds ratio [OR]: 1.26, P = .013). Within 2 years postoperatively, TRT patients were more likely to undergo (OR: 1.70, P < .001) or revision RCR (OR: 1.53, P < .001) and to have prolonged opioid use (OR: 1.32, P < .001), frozen shoulder (OR: 1.37, P < .001), and stroke/myocardial infarction (OR: 1.20, P < .001). Patients whose last TRT fill was within 6 months prior to surgery had higher rates of 90-day readmission (2.1% vs. 1.3%; P = .048), prolonged opioid use at 2 years (66.6% vs. 62.1%; P = .002), revision RCR at 2 years (13.1% vs. 8.7%; P < .001), and increased 2-year cost ($18,740 vs. $16,006; P < .001) compared to those whose last fill was 6-12 months preoperatively.

Conclusion

TRT within 1 year of RCR appears to be a risk factor for multiple postoperative complications and subsequent shoulder surgery. Cessation of TRT prior to RCR should be considered on a patient-specific basis.

Rotator cuff repairs (RCRs) are the most common shoulder surgery in the United States with an estimated 250,000 operations per year.¹⁸ About 58% of patients undergoing rotator cuff surgery are male with an average age of 58 years; between 2007 and 2016, RCR rates in patients aged 50 – 64 years increased 2% every year, the highest rate of any age group.³⁵ As our population lives longer with the desire to maintain an active lifestyle, it can be expected for this trend to continue. RCR is a safe and effective surgical procedure that can optimize function, range of motion, and pain relief for patients.^12,19,27 As with any surgical procedure, there are complications that can occur after RCR, leading to poorer patient outcomes and potentially necessitating additional intervention.^11,14,27 These can include persistent stiffness, possibly requiring operative intervention, and retear, which may require repeat RCR or total shoulder arthroplasty (TSA).^6,13,16,27 Identifying patient factors that may contribute to increased complications and poorer patient outcomes is necessary to improve the success of the RCR surgery.

Testosterone replacement therapy (TRT) has surged amongst men in the United States since the early 2000s, with over 1.6 million patients receiving a prescription in 2022.²⁶ TRT usage has increased exponentially in the last 20 years, although growth plateaued for a time following the Food and Drug Administration's warning on cardiovascular risks in 2014 but has increased again recently.^3,25,26 TRT is Food and Drug Administration–approved in primary or secondary hypogonadism but is often used off-label for a variety of complaints including erectile dysfunction, fatigue, and depression.³⁶ Exogenous testosterone can increase the risk of tendon injuries requiring surgical repair such as tears of the Achilles, quadriceps, and biceps, and a recent study found that TRT users are 3 to 5 times as likely to have rotator cuff tear.^1,21,23,30 Despite a known increase in TRT users needing RCR, limited data exist on postoperative outcomes in this population, although a recent study found that patients who received at least 90 days of TRT prior to RCR had increased rates of revision surgery.³⁰ In patients undergoing total joint arthroplasty who were prescribed TRT within 6 months of surgery, increased rates of revision surgery and periprosthetic infection were observed,⁷ highlighting the need for examination of TRTs effect on outcomes of RCR.

The purpose of this study is to analyze how preoperative TRT influences outcomes up to two years after RCR surgery, and whether this risk is modified by timing of the last TRT dose. We hypothesized that preoperative TRT use would be associated with increased risk of postoperative complications and the proximity of TRT use to surgery would be associated with worse outcomes.

Materials and Methods

This study was deemed exempt by the institutional review board as retrospective review of a deidentified database.

Data source

The PearlDiver (PearlDiver Inc., Colorado Springs, CO, USA; www.pearldiverinc.com) Mariner 170 dataset was retrospectively analyzed.²² The database contains claims records from over 170 million patients across all-payers including commercial, Medicare, Medicaid, and self-pay. Data are searchable by Predefined Cohorts, International Classification of Diseases, Ninth Revision, International Classification of Diseases, 10th Revision, and Current Procedural Terminology codes.

Study population

All patients included in this study were male and had undergone RCR. Patients were active in the database for at least 1 year prior to RCR and 2 years postoperatively. Patients with a history of any of the following diagnoses were excluded from this study: Marfan syndrome, Ehlers-Danlos syndrome, prostate cancer, breast cancer, testicular cancer, lupus, Sjogren syndrome, dermatomyositis, polymyositis, or mitochondrial disease. Patients were grouped by whether they had been prescribed TRT within the year prior to RCR. The code definitions of inclusion/exclusion criteria, independent variables, and outcomes are presented in the Appendix.

Independent variables

Demographics and comorbidities (based on International Classification of Diseases, Ninth/Tenth Revision codes) of interest were age, obesity, hypogonadism, erectile dysfunction, decreased libido, depression, benign prostatic hypertrophy (BPH), tobacco use, alcohol disorders, diabetes, liver disease, anemia, rheumatologic disease and preoperative steroid injection within the 6 months prior to RCR.

Outcome measures

Infection and readmission were assessed at 90 days postoperatively. Total shoulder arthroplasty, revision RCR, frozen shoulder, cardiovascular complications (including stroke, cardiac arrest, dysrhythmia/arrhythmia, deep vein thrombosis, and pulmonary embolism), and total cost were assessed at 2 years postoperatively. Opioid use was defined as prolonged use continuing at 2 years postoperatively.

Statistical analysis

Patients who were not prescribed TRT were propensity score matched 3:1 on obesity, hypogonadism, erectile dysfunction, decreased libido, depression, BPH, tobacco use, alcohol disorders, diabetes, liver disease, anemia, rheumatologic disease, and preoperative steroid injections to patients who were prescribed TRT. These factors were selected for inclusion in the match as they represent potential indications for TRT use and known risk factors for complications after RCR. The propensity score matching was performed using the nearest neighbor without replacement methodology. After propensity score matching, univariate analyses (chi-square and independent samples t-tests) were performed to compare demographics, comorbidities, and outcomes between groups. Multivariate linear and logistic regressions were used to assess the association between TRT use and outcomes controlling for comorbidities that were significantly different after propensity score matching. Patients prescribed TRT were further grouped by the time of their last TRT use: within 6 months prior to RCR and between 6 and 12 months prior to RCR. Univariate analyses were performed to compare outcomes between patients whose last TRT use was within 6 months prior to surgery and those whose last TRT use was between 6 and 12 months prior to surgery. All statistical analysis was performed within the PearlDiver platform using R (R Studio, Posit, Boston, MA, USA). Statistical significance was assessed at P < .05.

Results

After propensity score matching, there were 8,258 patients who had been prescribed TRT within the year prior to RCR and 24,774 patients who were not. There were no differences in age, rates of obesity, hypogonadism, erectile dysfunction, depression, diabetes or anemia between those who used testosterone and those who did not. Those who used TRT had higher rates of decreased libido (15.6% vs. 14.4%; P = .001), BPH (21.9% vs. 20.3%; P = .002), tobacco use (45.8% vs. 44.4%; P = .031), alcohol disorder (9.3% vs. 8.0%; P < .001), rheumatologic disease (3.3% vs. 2.6%; P < .001), and preoperative steroid injections (9.6% vs. 8.7%; P = .012) compared to those who did not use TRT preoperatively. However, patients who used TRT were less likely to have liver disease (14.3% vs. 21.2%; P = .002) (Table I).

Table I.

Demographics and comorbidities postpropensity score matching.

Demographics and comorbidities	No testosterone use (n = 24,774)	Testosterone use (n = 8,258)	P value
Age, yr	58.4 ± 9.3	58.6 ± 9.3	.076
Obesity	13,121 (53.0)	4,408 (53.4)	.520
Hypogonadism	17,067 (68.9)	5,689 (68.9)	1.000
Erectile dysfunction	10,215 (41.2)	3,403 (41.2)	.979
Decreased libido	3,579 (14.4)	1,312 (15.6)	.001
Depression	9,498 (38.3)	3,261 (39.5)	.065
Benign prostatic hypertrophy	5,030 (20.3)	1,806 (21.9)	.002
Tobacco use	11,009 (44.4)	3,783 (45.8)	.031
Alcohol disorders	1,979 (8.0)	768 (9.3)	<.001
Diabetes	11,224 (45.3)	3,765 (45.6)	.660
Liver disease	5,247 (21.2)	1,185 (14.3)	.002
Anemia	7,482 (30.2)	2,583 (31.3)	.067
Rheumatologic disease	634 (2.6)	275 (3.3)	<.001
Preoperative steroid injection	2,152 (8.7)	793 (9.6)	.012

SD, standard deviation.

P value <.05 in bold; all data presented as n (%) or mean ± SD.

On univariate analysis, there were no differences in 90-day readmission or infection between those who used TRT and those who did not. At 2 years postoperatively, patients with TRT use had increased rates of prolonged opioid use (62.8% vs. 61.2%; P = .010), increased rate of TSA (1.7% vs. 1.1%; P < .001), revision RCR (9.4% vs. 6.8%; P < .001), frozen shoulder (3.4% vs. 2.4%; P < .001), and cardiovascular complications (19.3% vs. 17.4%; P < .001). In addition, patients with TRT use had increased cost at 2 years ($20,260 ± 31,668 vs. $18,257 ± 26,442; P < .001) compared to those who did not use TRT preoperatively (Table II).

Table II.

90-d and 2-year outcomes.

Outcome	No testosterone use (n = 24,774)	Testosterone use (n = 8,258)	P value
90-d
Infection	188 (0.8)	62 (0.8)	1.000
Readmission	334 (1.3)	121 (1.5)	.462
2-y
Opioid use	15,167 (61.2)	5,187 (62.8)	.010
Total shoulder arthroplasty	270 (1.1)	139 (1.7)	<.001
Revision rotator cuff repair	1,677 (6.8)	776 (9.4)	<.001
Frozen shoulder	587 (2.4)	283 (3.4)	<.001
Cardiovascular complication	4,315 (17.4)	1,590 (19.3)	<.001
Cost, $ USD	$18,257 ± 26,442	$20,260 ± 31,668	<.001

USD, United States dollars; SD, standard deviation.

P value <.05 in bold; all data presented as n (%) or mean ± SD.

Within the 2-year postoperative period, after controlling for decreased libido, BPH, tobacco use, alcohol disorders, liver disease, rheumatologic disease, and preoperative steroid injections, those who used TRT were more likely to have undergone TSA (odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.23 to 1.86; P < .001), revision RCR (OR: 1.41, 95% CI: 1.29 to 1.54; P < .001), and experience frozen shoulder (OR: 1.45, 95% CI: 1.26 to 1.68; P < .001), or cardiovascular complications (OR: 1.10, 95% CI: 1.04 to 1.18; P = .003) compared to those who did not use TRT preoperatively (Table III and Fig. 1).

Table III.

Ninety-d and 2-year outcomes: Multivariate analysis.

Outcome	Testosterone use OR/β	95% CI	P value
90-d
Infection	0.97	0.72 to 1.28	.813
Readmission	1.04	0.84 to 1.28	.693
2-y
Opioid use	1.04	0.15 to 4.52	.962
Total shoulder arthroplasty	1.52	1.23 to 1.86	<.001
Revision rotator cuff repair	1.41	1.29 to 1.54	<.001
Frozen shoulder	1.45	1.26 to 1.68	<.001
Cardiovascular complication	1.10	1.04 to 1.18	.003
Cost (β)	0.0003	−0.0002 to 0.0008	.222

CI, confidence interval.

P value <.05 in bold; controlling for decreased libido, benign prostatic hypertrophy, tobacco use, alcohol disorders, liver disease, rheumatologic disease, and preoperative steroid injections.

Figure 1.

Multivariate analysis of 2-year complication and reoperation rates: TRT vs. no TRT. Odds ratios >1 indicate higher odds with TRT use. Patients taking TRT within 1 year of surgery had significantly higher odds of cardiovascular complication, frozen shoulder, revision rotator cuff repair, total shoulder arthroplasty, and prolonged opioid use at 2 years postoperatively. TRT, testosterone replacement therapy.

Postoperatively, those whose last TRT use was within 6 months prior to surgery had higher rates of readmission at 90 days (2.1% vs. 1.3%; P = .048), higher rates of prolonged opioid use at 2 years (66.6% vs. 62.1%; P = .002), higher rates of revision RCR at 2 years (13.1% vs. 8.7%; P < .001), and increased 2-year postoperative cost ($18,740 ± 22,324 vs. $16,006 ± 27,149; P < .001) compared to those whose last TRT use was between 6 and 12 months prior to surgery (Table IV and Fig. 2).

Table IV.

Subgroup: 90-d and 2-year outcomes by last testosterone use.

Outcome	Last testosterone use 6 mo (n = 1,335)	Last testosterone use 6 to 12 mo (n = 6,923)	P value
90-d
Infection	12 (0.9)	50 (0.7)	.609
Readmission	28 (2.1)	93 (1.3)	.048
2-y
Opioid use	889 (66.6)	4,298 (62.1)	.002
Total shoulder arthroplasty	26 (1.9)	113 (1.6)	.482
Revision rotator cuff repair	175 (13.1)	601 (8.7)	<.001
Frozen shoulder	43 (3.2)	240 (3.5)	.712
Cardiovascular complication	234 (17.5)	1,356 (19.6)	.088
Cost, $ USD	$18,740 ± 22,324	$16,006 ± 27,149	<.001

USD, United States dollars; SD, standard deviation.

P value <.05 in bold; all data presented as n (%) or mean ± SD.

Figure 2.

Univariate subgroup analysis of 2-year complication and reoperation rates by last testosterone use. Statistically significant differences between groups indicated by ∗. Patients with a last testosterone use within 6 months of surgery experienced higher rates of revision rotator cuff repair and prolonged opioid use at 2 years postoperatively than those ceasing use 6-12 months preoperatively.

Discussion

In this study, TRT use within 12 months prior to RCR was associated with adverse outcomes including increased prolonged opioid use, TSA, revision RCR, frozen shoulder, and cardiovascular complications. After propensity matching, men prescribed TRT within 1 year prior to RCR showed higher rates of revision RCR, conversion to TSA, frozen shoulder, prolonged opioid utilization, cardiovascular events, and overall costs of care compared to nonusers. Patients who were prescribed TRT within 6 months of RCR had increased 90-day readmissions, prolonged opioid use, revision RCR, and increased cost when compared with patients who were prescribed TRT 6 to 12 months prior to RCR.

Patients in the TRT group had higher odds of undergoing revision RCR or TSA within two years postoperatively. These findings are consistent with that of Testa et al, who found that patients on TRT had a substantially increased risk of subsequent RCR within 1 year following the initial surgery.³⁰ The increase in revision RCR or TSA may be attributed to testosterone's negative effect on wound healing; testosterone has been shown to increase total wound healing time, promote proinflammatory cytokines and inhibit collagen synthesis.^2,34 In addition, it is well established that testosterone exerts anabolic effects on skeletal muscles by increasing muscle protein synthesis leading to hypertrophy and activating satellite cells involved in muscle repair and decreasing muscle breakdown.^5,24 These changes in muscular architecture increase the cross-sectional area of muscle fibers which leads to greater contractile forces applied to tendons. The greater exertional forces on the tendon without proportionate tendon growth, may lead to rupture. Thus, in individuals already at higher risk of tendon injury given the prior RCR, TRT may exacerbate the risk of rerupture requiring revision. Our study also found that more recent TRT use was associated with higher revision rates. Discontinuing TRT in the months prior to RCR surgery may improve surgical outcomes. Patients in this study who stopped TRT use at least six months prior to RCR had a reduced risk of revision RCR when compared with patients using TRT within 6 months of surgery, although there was no difference in the rate of TSA. Additional studies are needed to determine the optimal timing of TRT cessation with precautions given to the underlying reasons for the prescription.

The increased rate of frozen shoulder in TRT users, despite propensity matching, represents an independent association between TRT therapy and frozen shoulder, beyond established risk factors. Frozen shoulder, or adhesive capsulitis, is caused by chronic inflammation of the glenohumeral joint capsule leading to fibrosis and contracture.^28,29 While it is considered an idiopathic condition, known risk factors for frozen shoulder are proinflammatory conditions such as rheumatoid arthritis and metabolic disorders such as diabetes and thyroid disease.⁸ Research has shown that testosterone may foster a molecular environment similar to these mentioned conditions with proinflammatory cytokines and fibroblast activation.¹⁵ Deghan et al found that testosterone supplementation led to decreased range of motion, stiffness, and altered the collagen content in the knee joints of rats.⁹ An in vitro study of cultured tenocyte cells found that there were higher rates of cell proliferation when exposed to dihydrotestosterone.¹⁰ Frozen shoulder can be a particularly debilitating and frustrating condition, often preventing patients from performing daily tasks of living. Our findings suggest that a more aggressive physical therapy regimen may be necessary in TRT users requiring RCR.

There was some increase in medical complications and cost in patients undergoing RCR while on TRT. Notably, there was an increase in cardiovascular events in patients who underwent surgery after being prescribed TRT within 1 year, and that association remained even after controlling for confounding variables. TRT has been linked to life-threatening cardiovascular events, arrhythmia, and stroke in men prescribed TRT for hypogonadism and other related issues.^17,31 While the relationship between TRT and cardiovascular events has shown mixed results across studies, potential mechanisms by which TRT may increase cardiovascular risk have been posited that warrant further investigation.^17,31 In healthy men, intramuscular testosterone has been linked with an increase in platelet thromboxane A2 receptor density and platelet aggregation, potentially increasing risk of coronary plaque formation and eventual rupture.³¹ Alternatively, laboratory studies have shown that testosterone metabolites increase smooth muscle proliferation and expression of vascular cell adhesion molecule 1, thus enhancing endothelial monocyte activation, and potentially promoting atherosclerosis.³¹ In the current study, there was no difference in the rate of cardiovascular events in patients who were taking TRT within six months of surgery and those that discontinued TRT 6-12 months prior to surgery. Men undergoing RCR while on TRT or having recently discontinued TRT may benefit from enhanced perioperative monitoring and discussions regarding the potential for increased cardiovascular complications. Patients in this study on TRT had a higher rate of prolonged opioid use, with the highest rate in men taking TRT within 6 months of surgery, although this difference disappeared in multivariate analysis. Testosterone deficiency has been identified in chronic opioid users and TRT may benefit patients who are dependent on opioid medications.^4,20 In addition, preoperative substance use disorders and mental health disorders are risk factors for prolonged opioid use following RCR.^32,33 Men undergoing RCR while on TRT may benefit from education regarding pain control options and alternative analgesia methods along with monitoring postoperative pain control and opioid use. The increased cost found in this study at two years in men undergoing RCR while on TRT may be related to the increased complication rates previously discussed. Patients that discontinued TRT at least 6 months prior to surgery did have significantly lower costs than patients who took TRT within 6 months of surgery, and those patients also had lower rates of some complications including subsequent TSA and frozen shoulder.

This study needs to be considered in light of its limitations. As an administrative database study, it relies on the accuracy of the coded data and limits variables to those that are included in the database itself. A notable example of this limitation is in our use of the TSA end point. Unfortunately, based on the use of Current Procedural Terminology codes to identify patients undergoing TSA we were unable to discern whether patients underwent anatomic or reverse TSA procedures, which share the same code. Furthermore, we were unable to identify whether TSA procedures were performed for osteoarthritis, cuff tear arthropathy, or another indication. Similarly, due to the database structure, we were unable to assess the specific reasons for readmission due to the low occurrence rate, as diagnosis codes are suppressed when the count is < 11 to protect patient privacy. In addition, we were unable to collect data on the type of rotator cuff tear or the quality of the repair, both of which are known to influence postoperative outcomes and complications. Importantly, this introduces potential confounding into our analysis, as differences in tear types or repair quality, rather than TRT use, may have led to the observed results. It is also possible that unmeasured confounding factors beyond clinical presentation and surgery, such as social determinants of health influenced the findings of this study. Patients were categorized as being on TRT or not based on prescription fills, and we were not able to assess whether patients actually took the medication as prescribed. We were also unable to determine dose and reason for TRT prescription, both factors which may influence the overall data. Therefore, while our results highlight a potential association between preoperative TRT use and inferior RCR outcomes, causation cannot be inferred. In addition, we were unable to assess important outcome measures such as functional recovery using patient-reported outcomes, range of motion, quality of life, and return to activity, all of which are necessary to fully assess patient recovery. Future studies are required to assess the influence of preoperative TRT use on these outcomes, as these are critical measures of surgical success. Despite these limitations, this study holds value as one of the first to examine the outcomes of RCR in patients prescribed TRT. Additional studies are required to assess the relationship between TRT use and RCR outcomes using more granular institutional data allowing for more robust risk adjustment and evaluation of patient-reported outcome measures. Ultimately, a prospective randomized controlled trial evaluating the impact of TRT on RCR outcomes may be warranted, although this may be ethically unfeasible if additional studies replicate the findings of the current study.

Conclusion

Preoperative TRT prior to RCR is associated with revision RCR, total shoulder arthroplasty, frozen shoulder, cardiovascular events, prolonged opioid use and increased costs within 2 years following surgery. In addition, patients on TRT within 6 months of RCR had worse outcomes including higher rates of 90-day readmission, prolonged opioid use, revision RCR, and increased costs at 2 years following surgery. This suggests that both TRT use overall and the timing of TRT use are risk factors that clinicians need to consider in male patients undergoing RCR. Further studies are needed to better understand the risks associated with TRT use, explore the underlying biological mechanisms connecting TRT use to tendon healing and shoulder pathology, and define the optimal window of discontinuation of TRT prior to RCR. These findings may help inform clinicians regarding perioperative TRT management in patients undergoing RCR.

Disclaimers:

Funding: No funding was disclosed by the authors.

Conflicts of interest: Cyrus Lashgari declares other professional activities with Smith and Nephew and is a board or committee member of the Association of Clinical Shoulder and Elbow Surgeons. All the other authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.