Strength Training Induces Muscle Hypertrophy and Functional Gains in Black Prostate Cancer Patients Despite Androgen Deprivation Therapy

Abstract

Background.

Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with weakness, fatigue, sarcopenia, and reduced quality of life (QoL). Black men have a higher incidence and mortality from PCa than Caucasians. We hypothesized that despite ADT, strength training (ST) would increase muscle power and size, thereby improving body composition, physical function, fatigue levels, and QoL in older black men with PCa.

Methods.

Muscle mass, power, strength, endurance, physical function, fatigue perception, and QoL were measured in 17 black men with PCa on ADT before and after 12 weeks of ST. Within-group differences were determined using t tests and regression models.

Results.

ST significantly increased total body muscle mass (2.7%), thigh muscle volume (6.4%), power (17%), and strength (28%). There were significant increases in functional performance (20%), muscle endurance (110%), and QoL scores (7%) and decreases in fatigue perception (38%). Improved muscle function was associated with higher functional performance (R ² = 0.54) and lower fatigue perception (R ² = 0.37), and both were associated with improved QoL (R ² = 0.45), whereas fatigue perception tended to be associated with muscle endurance (R ² = 0.37).

Conclusions.

ST elicits muscle hypertrophy even in the absence of testosterone and is effective in counteracting the adverse functional consequences of ADT in older black men with PCa. These improvements are associated with reduced fatigue perception, enhanced physical performance, and improved QoL. Thus, ST may be a safe and well-tolerated therapy to prevent the loss of muscle mass, strength, and power commonly observed during ADT.

Prostate cancer (PCa) is the most common hormone-dependent, nondermatological malignancy in older black men and the second leading cause of cancer mortality in the United States (1). Black men have significantly higher incidence rates, more advanced PCa at diagnosis, and greater mortality from PCa than Caucasians (1,2).

Androgen deprivation therapy (ADT) slows the growth of this hormone-dependent tumor; however, the suppression of endogenous testosterone reduces muscle mass and strength (3–5) and increases fat mass (4,6) and generalized fatigue (6). Collectively, this can lead to a deterioration in physical function (3,7–10) and quality of life (QoL [5,11]). The muscle atrophy, functional declines, and weakness associated with ADT mimic effects seen with declines in testosterone with aging (12) but occur at faster rates and may accelerate the onset of sarcopenia and its related health consequences (13,14). Strength training (ST) is an effective therapeutic approach for the musculoskeletal declines associated with sarcopenia (15), specifically by increasing muscle strength, power, and mass and physical performance (16–19). The health-related benefits of ST in PCa patients on ADT could prevent their functional declines and subsequent risk for frailty, dependence, and long-term care. Although initial studies in these patients show promising results, several important therapeutic issues warrant further investigation, such as whether ST increases muscle mass and power during ADT.

Early studies of the effects of ST in Caucasian PCa patients on ADT demonstrated significant improvements in muscle strength, endurance, physical function, and QoL, with no change in muscle or fat mass (20,21). More recent studies examining the effects of ST on muscle hypertrophy in ADT-treated PCa patients report equivocal findings, with one study showing no differences compared with non-ADT groups (22), whereas others report attenuated gains (23,24). There are also no studies in black PCa patients, who are more likely to be on ADT (2) and may respond differently to ADT than Caucasians (25,26). Consequently, it is unclear whether suppression of testosterone with ADT will limit ST-induced improvements in muscle mass and power, crucial determinants of physical function (27). Studying black PCa patients on ADT provides a unique model to assess the role of testosterone deficiency in mediating the effects of ST on changes in muscle mass and function in a group of understudied older men with weakness, fatigue, anemia, and mobility limitations. This preliminary study was designed to test the hypothesis that despite ADT, ST would increase muscle power and mass, thereby improving body composition, physical function, fatigue levels, and QoL in an understudied subset of black PCa patients on ADT.

Methods

Recruitment

PCa patients were recruited from the Veteran Affairs Medical Centers in Washington, DC and Baltimore, Maryland and through advertisements sent to local urologists and to the surrounding communities. Exclusionary criteria were metastatic PCa, symptomatic cardiovascular disease, any conditions that caused severe pain with exertion, type 1 diabetes, history of bone fractures, inability to engage safely in moderate exercise, lack of medical clearance from their physician, or not on ADT throughout the study.

Participants

All men underwent a detailed medical questionnaire and received clearance from their physician. Patients maintained all medications, stable body weight (within 5% of their initial weight, monitored weekly), and regular physical activity levels and dietary habits throughout the study. After all methods and procedures were explained, patients signed the written informed consent approved by the University of Maryland College Park and Baltimore Institutional Review Boards.

Forty-four PCa patients responded initially and 22 met all inclusion criteria. After orientation, 3 declined to participate. Patients were sedentary, defined as not exercising regularly (with the exception of walking) and no ST in the last 6 months. Of the 19 patients who completed baseline testing, 17 completed all follow-up testing. One participant dropped out due to recurring hypotension following ST and the other due to an unrelated illness.

Strength Testing

One repetition maximum (1RM) strength testing for the unilateral knee extension, chest press, and leg press were performed using Keiser air-powered machines (Keiser Corporation Inc., Fresno, CA) via standardized protocols (16,17). Two sessions were performed prior to baseline testing to familiarize the participants with the equipment. Localized muscle endurance was assessed by performing as many consecutive chest and leg press repetitions as possible at 70% of baseline 1RM. The same absolute load was replicated after the ST protocol.

Power Testing

Unilateral power, velocity, and torque of the knee extensors were measured on a Keiser A-430 air-powered machine designed specifically for assessing muscle power, as described previously (17). After familiarization, patients completed trials at 50%, 60%, and 70% of their relative knee extension 1RM. The peak power, velocity, and torque values were selected for each relative load and at least one absolute load replicated from baseline testing. If no such load could be found, additional trials were performed during the after training test, using a replicated load from baseline.

Body Composition

Muscle mass and %fat, were measured by dual-energy x-ray absorptiometry using fan-beam technology (model QDR 4500A, Hologic, Waltham, MA [17]). The ischial crest of the pelvis was the boney landmark used to differentiate between upper and lower body segments. Appendicular body composition was the sum of the lower body combined with the sum of the arms, using the medial aspect of the humeral head as the cutpoint to differentiate the arms from the trunk.

Computed tomography (GE Lightspeed Qxi, General Electric, Milwaukee, WI) images of the thighs were manually traced to quantify leg muscle volume (MV) and subcutaneous and intermuscular fat cross-sectional area, as described previously (18) with slight modifications to include total thigh musculature for MV. Final MV was calculated using the truncated cone formula (28).

Functional Performance Testing

Physical function was assessed using 6-m walk, timed up and go, chair stands, stair climb, and 400-m walk, as described previously (16,21), except for the chair stands. The chair stands test was the number of successful repetitions completed in 30 seconds. All tests were preceded by a practice trial and were performed in duplicate (except the chair stands and 400-m walk). The fastest time was recorded.

Fatigue Perception and QoL

The Brief Fatigue Inventory (University of Texas MD Anderson Cancer Center, Houston, TX) and the Functional Assessment of Cancer Therapy-Prostate (FACT-P; FACIT.org, Elmhert, IL) questionnaires were administered as indicators of generalized fatigue perception and QoL, respectively.

Training Protocol

The program consisted of 12 weeks of whole-body ST, 3 days per week for approximately 1 hour using Keiser air-powered equipment as used previously (phase 2 of ST program [16]). Exercises included unilateral knee extension, chest press, seated row, seated hamstring curl, abdominal crunch, and leg press. A single training set of 15 repetitions was performed at the 5 RM. Participants completed the first 4–5 repetitions and once they could no longer complete the movement, the weight was lowered so that they could complete 1–2 additional repetitions. This process was repeated until all 15 repetitions were completed, and the weight used was progressed throughout the program to reflect strength gains. This high-intensity protocol combined heavy resistance with high volume while eliciting near-maximal effort on all repetitions and has produced significant gains in muscle and physical function in healthy older adults (16). Training sessions were conducted in small groups under direct supervision and compliance was 94.6±1.6%.

Blood Biomarkers

Venous blood was sampled following an overnight fast to measure hemoglobin (HemoCue Hb201+ Analyzer, Lake Forrest, CA) and prostate-specific antigen (R&D Systems Quantikine Human Kallikrein 3/PSA ELISA, Minneapolis, MN). Total testosterone was measured using liquid chromatography–tandem mass spectroscopy and luteinizing hormone and sex hormone–binding globulin by two site-directed immunofluorometric assays, as described previously (29). Free testosterone was calculated using the law of mass action equation (30). The interassay coefficient of variation for the testosterone assay was 7.7%, 4.4%, and 3.3% at 241, 532, and 1016ng/dL of testosterone, respectively (31). The interassay coefficient of variation for sex hormone–binding globulin was 8.3%, 7.9%, and 10.9% and intra-assay coefficient of variation was 7.3%, 7.1% and 8.7%, respectively, in the low, medium, and high pools. Interassay coefficient of variation for luteinizing hormone in the low, medium, and high pools was 8.0%, 6.0%, and 4.0%, respectively.

Statistical Analyses

Changes with ST were determined by paired t tests (one tailed), and multiple regression analyses determined associations among changes in physical function, fatigue, and QoL with muscle mass, function, and body composition. The dependent variables in the regression models were the change scores that were significantly different from baseline for physical function, fatigue, and QoL, and the independent variables were the absolute change scores that were significantly different from baseline for muscle power, strength, and mass. Data were analyzed using SPSS statistical software (SPSS Inc., Chicago, IL) and expressed as means ± SEM. Statistical significance was at p < .05.

Results

There were no differences at baseline or in the response to ST between the right and left legs for knee extensor 1RM, muscle power, MV, and subcutaneous and intermuscular fat; hence, only right leg data are reported.

Patient Characteristics and Effects of ST on Body Composition

The PCa patients were hypogonadal, borderline anemic, obese, and received ADT on average for 3.7 years (Table 1). Laboratory values remained constant during ST except sex hormone–binding globulin, which increased slightly (6.9±2.8%, p = .025). ST elicited significant increases in body mass (1.5±0.5%, p = .023); total body muscle mass (2.7±0.4%, p < .001); and muscle mass in the upper body (2.2±0.5%, p = .003), lower body (3.8±1.0%, p = .001), and appendicular (3.6±0.9%, p = .001) regions. ST increased thigh MV by 6.4% (p < .001; Figure 1A) and decreased % body fat by 2.2% (p = .012) but did not change subcutaneous (baseline: 118±22 vs after ST: 118±22cm²) or intermuscular fat (7.9±0.9 vs 7.6±1.0cm²).

Table 1.

Baseline and After ST Physical Characteristics of PCa Patients

	Baseline	After ST	p Value
Age (y)	67±2	—	—
Height (cm)	172.8±1.7	—	—
Mass (kg)	96.5±4.7	97.9±4.9	.012
Body mass index (kg/m2)	32.3±1.2	32.7±1.3	.028
% fat	31.4±1.4	30.7±1.5	.006
Fat mass (kg)	31.2±3.0	31.1±3.2	.359
Lean Mass (kg)	62.4±1.8	64.1±1.8	<.001
Total testosterone (ng/dL)	19.3±11.2	44.1±28.2	.176
Free testosterone (pg/mL)	3±2	7±5	.178
Luteinizing hormone (U/L)	0.6±0.4	0.9±0.5	.191
Sex hormone-binding globulin (nmol/L)	51.1±4.9	54.5±4.7	.025
Prostate-specific antigen (ng/mL)	0.58±0.15	0.32±0.15	.716
Hemoglobin (g/dL)	12.9±0.3	12.7±0.3	.717
Hematocrit (%)	38.3±0.8	37.8±0.9	.610
Days since PCa diagnosis	2738±492	—	—
Length of ADT (d)	1303±328	—	—
Radiation therapy	41.2%	—	—
Prostatectomy	29.4%	—	—
Types of ADT
LHRHa	93.8%	—	—
Bicalutamide	31.3%	—	—

Note. ADT = androgen deprivation therapy; LHRHa = luteinizing hormone-releasing hormone agonist; PCa = prostate cancer; ST = strength training.

Figure 1.

(A) Thigh muscle volume (MV) is increased with strength training (ST) in prostate cancer (PCa) patients on androgen deprivation therapy (ADT). (B) One repetition maximum (1RM) strength levels increased with ST. The left y-axis is scaled for the knee extension and chest press, whereas the right y axis is scaled for the leg press. (C) ST increased muscle endurance at 70% of baseline 1RM in PCa patients. ***Significantly different from baseline (p < .001).

Muscle Strength and Endurance

ST substantially increased unilateral 1RM strength for the knee extensors (27.8±3.4%), chest press (18.4±3.3%), and leg press (22.5±3.3%, p’s < .001; Figure 1B), as well as chest and leg press muscle endurance (64±7% and 110±40%, respectively, p’s < .001; Figure 1C).

Muscle Power, Torque, and Velocity

ST increased power at both absolute (15.1±3.5%, p < .001) and relative loads (range: 10.3%–17.1%, p’s < .01; Figure 2A) and also increased peak torque at all loads (all p < .05; Figure 2B) and absolute peak velocity (p < .001, Figure 2C).

Figure 2.

Strength training (ST) increased absolute and relative knee extensor: (A) peak power, (B) peak torque, and (C) peak velocity. Abs = absolute PP; PP = peak power at 50%, 60%, and 70% of knee extension one repetition maximum (1RM). Significantly different from baseline: *p < .05 and ***p < .001.

Physical Function, Fatigue Perception, and QoL

ST produced the greatest increase in chair stands (20.3±4.3%, p < .001; Figure 3A) and 6-m walk test (12.0±2.1%, p < .001), with 6.7%–8.0% improvements in the timed up and go, stair climb, and 400-m walk (p’s < .05). ST decreased fatigue perception by 38% (p = 0.011) and increased overall Functional Assessment of Cancer Therapy-Prostate scores by 6.6% (p = .042) and the Physical Well-Being subsection by 13.1% (p = .003; Figure 3B). There was a trend for improvement in the Functional Well-Being subsections (7.6%; p = .067).

Figure 3.

(A) Strength training (ST) increased all measures of physical function. The left y-axis is scaled in seconds for the all walking tests, whereas the right y-axis is scaled for the number of successful chair stands in 30 s. (B) Fatigue perception and quality of life (QoL) are improved with ST. The left y-axis is scaled for the Brief Fatigue Inventory score and each subsection of the Functional Assessment of Cancer Therapy-Prostate (FACT-P), whereas the right y-axis is scaled for the composite FACT-P score. Significantly different from baseline: *p < .05, **p < .01, ***p < .001.

Relationships Between Physical Performance, Fatigue, QoL, and Musculoskeletal Function

After controlling for ADT duration, improvements in functional performance were related to increased muscle strength and power. There was a significant relationship between the improvements in 400-m walk time and knee extensor 1RM (R ² = 0.54, p = .020) and the increase in 6-m rapid walk with the increase in power (R ² = .40, p = .045). QoL was influenced by both fatigue perception and physical function (R ² = .45, p = .022). There was a trend for a relationship between the reduction in fatigue perception with improved muscle endurance (R ² = 0.37, p = .079).

Discussion

This preliminary study shows that despite the absence of testosterone, a high-intensity short-term ST program improves muscle mass, power, strength, endurance, physical function, and QoL and reduces fatigue perception in older black men with PCa. This confirms the benefits of ST observed previously in PCa patients on ADT (20,21,24,32,33) and demonstrates the independent effects of high-intensity ST to elicit increases in muscle power, strength, and mass that are associated with meaningful improvements in physical function, fatigue, and QoL in an understudied population of black men with PCa.

This study is the first to report increases in both total body muscle mass and direct measurements of local muscle hypertrophy in ADT-treated PCa patients. The high correlation between both measures indicates that the training-induced increases in muscle mass are due to hypertrophy, which occurred despite the absence of testosterone. This refutes previous work that used less progressive, low-intensity, and nonspecific resistance exercise protocols (24) and imprecise skinfold measures to assess body composition (20) to conclude that ST cannot increase muscle mass in men on ADT and provides promise for the successful rehabilitation of these patients. More recent studies using more direct assessments of body composition report either significant increases in quadriceps thickness (21) or no change in quadriceps MV (24) but none show increases in total body muscle mass. To further confound the matter, mixed aerobic and ST protocols in men on ADT showed significant increases in total body and appendicular muscle mass measured using dual-energy x-ray absorptiometry (32,34); however, the gains are smaller than the increases observed in this study and do not show the specific, independent effects of ST. Indeed, the increases in muscle mass observed in our study are similar to the 1.9% and 1.5% increases previously reported in healthy older adults (16,19). The positive response to ST in women (18), albeit lower than men, and the lack of differences in the response to ST with and without ST-induced elevations in testosterone (35) further supports the nonessential role of testosterone in load-mediated muscle hypertrophy.

The gains in muscle power in this study are comparable to responses observed in healthy older adults studied in our laboratory (16,17). Increases in muscle power, both at the same absolute and relative workloads, have important functional and health implications for older cancer survivors (27), as power declines faster than strength with aging. In these PCa patients, the associations between improvements in power and strength with functional performance are quite similar, although muscle power had stronger correlations with physical function at baseline (data not shown), supporting previous work (36,37). The finding that ST improves both peak torque and peak velocity at a given absolute power, but torque production increases only when velocity remains constant at each relative load provides insights into potential mechanisms for training-induced increases in muscle power in androgen-deficient PCa patients. The greater gains in torque production across all relative loads suggests that strength is the major factor driving the increase in power output, as increasing strength reduced the relative effort required to move an absolute load. This would shift the force–velocity relationship to faster movement velocities. A real-world application of this outcome would be improved ambulation, which translates into lifestyle gains in functionality in these chronically ill PCa patients on ADT with modest mobility limitations, anemia, and fatigue.

The physical function levels of our patients are similar to other PCa patients on ADT (7,8,21,24,34) and are substantially lower than healthy older adults (3,16,19) and other non-ADT PCa patients (24). The improvements in functional capacity with ST are greater (34), similar (24), or less (21) than in other studies but compare favorably with observations in healthy older adults (16). Furthermore, the improvements exceeded the minimal meaningful and detectable changes for the ambulatory tests (38). The decrease in fatigue perception corresponds with and exceeds changes reported by others in cancer survivors (20,33,34), whereas QoL improvements are nearly identical to previous reports (20,24,33). Interestingly, there may be an association between ST intensity and improved QoL, as studies using moderate-intensity training (60%–70% of 1RM) report smaller changes (20,33) than the current and another study (34), which used higher intensities (70%–85% of 1RM).

The improvements in physical function and fatigue perception are related to gains in muscle function, most notably strength and power. The association between improved muscle endurance and fatigue perception suggests that the latter is likely influenced by both physiological and psychological factors, as muscle endurance explains only a portion of the variability. Other studies in PCa patients show improved function, fatigue, and QoL but do not identify the specific factors associated with these improvements (20,21,32,33). Moreover, the changes in physical function and fatigue perception associated with improved Functional Assessment of Cancer Therapy-Prostate scores support that physiological improvements, among other factors, with ST are linked to improvements in fatigue resistance and function that ultimately may translate to better QoL in black men with PCa.

Despite the unique aspects of this study, there are several limitations. This preliminary study was hampered by recruitment difficulties, which obviated randomization into exercise versus nonexercise groups; thereby preventing proper controls for methodological, biological, and seasonal variation. Nevertheless, the improvements in muscle mass, physical function, and fatigue were quite robust and not likely influenced by these factors. When we compared the results in this study to those of 20 healthy black men of similar age from our lab undergoing a similar but even more rigorous ST program (17,18), there were no differences in the improvements of muscle mass, power, and strength with ST (data not shown). Additionally, given the length of time our PCa patients were on ADT, we could only examine ST in men on chronic ADT treatment (>1 year). Since the effects of ADT tend to be most prominent in the first 6–12 months, it is possible that the greatest benefits of ST might be accrued during this time period, although one recent study suggests otherwise (32).

In conclusion, high-intensity ST is effective in counteracting the adverse musculoskeletal side effects of ADT in black PCa patients. Contrary to the commonly accepted role of testosterone in ST-induced muscle hypertrophy and within the limitations of this study, we present preliminary evidence that near optimal muscle adaptations can occur in older hypogonadal men. The observed gains in muscle mass, strength, and power are associated with improved functional independence and QoL in these men. A better understanding of the optimal timing of ST in relation to ADT and the mechanisms responsible for the increases in muscle hypertrophy, strength, and physical function in the absence of testosterone could help prevent the mobility limitations, weakness, fatigue, and poor QoL common in men with PCa receiving ADT.

Funding

This work was supported by the National Institutes of Health (CA127784, AG000268), the Claude D. Pepper Older Americans Independence Center (P30 AG 028747), and the Department of Veterans Affairs.