Plant-based diet associated with better quality of life in prostate cancer survivors.

BACKGROUND: Plant-based diets have many health benefits, including a lower risk of fatal prostate cancer, and greater environmental sustainability. However, less is known regarding the impact of plant-based diets on quality of life among individuals diagnosed with prostate cancer. The authors' objective was to examine the relationship between plant-based diet indices postdiagnosis with quality of life. METHODS: This prospective cohort study included 3505 participants in the Health Professionals Follow-Up Study (1986-2016) with nonmetastatic prostate cancer. Food-frequency questionnaires were used to calculate overall and healthful plant-based diet indices. Quality-of-life scores were calculated using the Expanded Prostate Cancer Index Composite. Generalized estimating equations were used to examine associations over time between plant-based diet indices and quality-of-life domains (sexual functioning, urinary irritation/obstruction, urinary incontinence, bowel functioning, hormonal/vitality), adjusted for demographics, oncologic history, body mass index, caloric intake, health-related behaviors, and comorbidities. RESULTS: The median age at prostate cancer diagnosis was 68 years; 48% of patients underwent radical prostatectomy, and 35% received radiation as primary therapy. The median time from diagnosis/treatment to first the quality-of-life questionnaire was 7.0 years. A higher plant-based diet index was associated with better scores for sexual function, urinary irritation/obstruction, urinary incontinence, and hormonal/vitality. Consuming more healthful plant-based foods was also associated with better sexual and bowel function, as well as urinary incontinence and hormonal/vitality scores in the age-adjusted analysis, but not in the multivariable analysis. CONCLUSIONS: This prospective study provides supportive evidence that greater consumption of healthful plant-based foods is associated with modestly higher scores in quality-of-life domains among patients with prostate cancer.

Plant-based diet index and erectile dysfunction in the Health Professionals Follow-Up Study.

OBJECTIVE: To evaluate the longitudinal association between plant-based diet index (PDI) score and incident erectile dysfunction (ED). MATERIALS AND METHODS: We conducted a prospective analysis of 21 942 men aged 40 to 75 years who were enrolled in the Health Professionals Follow-Up Study. ED was assessed with questionnaires every 4 years starting in 2000. Dietary data were collected via validated food frequency questionnaires completed every 4 years and were used to calculate total PDI scores, as well as healthy (hPDI) and unhealthy (uPDI) subscores. Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) for incident ED. All models were stratified by age (<60, 60 to <70, ≥70 years). RESULTS: Among men aged 60 to <70 years, hPDI was inversely associated with incident ED. Those in the highest quintile of hPDI in that age group had an 18% lower risk of ED (HR 0.82, 95% confidence interval (CI) 0.73-0.91; P-trend <0.001) compared to those in the lowest quintile. Conversely, uPDI was positively associated with ED in men aged <60 years (HR 1.27, 95% CI 1.01-1.60; P-trend = 0.02). CONCLUSIONS: Encouraging a healthy plant-based diet may be an environmentally sustainable intervention for men interested in maintaining erectile function.

Lower urinary tract symptoms are associated with musculoskeletal pain among older men: Preliminary evidence for central sensitization as a mechanism?

AIMS: Features of central sensitization (CS) are present in almost all chronic pain conditions, including painful urinary conditions and back pain. Recently CS was proposed as a mechanism of nonpainful lower urinary tract symptoms (LUTS). Using musculoskeletal pain as an indicator of CS, we investigated whether the prevalence of musculoskeletal pain is greater among community-dwelling men with moderate or severe LUTS compared to those with mild LUTS. METHODS: We conducted a cross-sectional study of 5966 men ≥65 years who attended the Osteoporotic Fractures in Men Study baseline visit. LUTS were assessed with the American Urological Association Symptom Index (AUA-SI) and categorized as none/mild (0-7), moderate (8-19), or severe (≥20). Self-reported back, neck, hip, or knee pain within the 12 months before baseline was categorized as any pain and multilocation pain. We tested our hypothesis using odds ratios (OR) and 95% confidence intervals (CI) estimated from multivariable logistic regression models. RESULTS: The adjusted odds of any pain were higher among men with moderate (OR 1.49, 95% CI: 1.29-1.72) and severe LUTS (OR 1.76, 95% CI: 1.28-2.40) compared to those with no/mild LUTS. The adjusted odds of pain at ≥ 2 locations were 69% higher among men with moderate (OR 1.69, 95% CI: 1.45-196) and more than double among men with severe LUTS (OR 2.24, 95% CI: 1.62-3.10) compared to men with no/mild LUTS. CONCLUSIONS: Musculoskeletal pain, especially at multiple locations, is associated with greater LUTS severity among older men. CS may represent a novel shared mechanism of pain and LUTS.

Association of Lower Urinary Tract Symptom Severity with Kidney Function among Community Dwelling Older Men.

PURPOSE: Most international practice guidelines recommend screening for chronic kidney disease among older men with lower urinary tract symptoms. However, prior studies supporting these guidelines are insufficient due to incomplete assessments of kidney function and inadequate adjustment for confounding factors. MATERIALS AND METHODS: We conducted a cross-sectional study among 5,530 American men older than 65 years in the multicenter Osteoporotic Fractures in Men Study. Chronic kidney disease was defined per international guidelines as estimated glomerular filtration rate less than 60 ml/minute/1.73 m2 based on serum creatinine or cystatin C, or urinary albumin-to-creatinine ratio 30 mg/gm or greater. Lower urinary tract symptoms were assessed with the American Urological Association Symptom Index. Associations were estimated using multivariable linear and modified Poisson regression models. RESULTS: Chronic kidney disease prevalence was 16% among 5,530 men with serum creatinine, 24% among 1,504 men with serum cystatin C and 14% among 1,487 men with urinary albumin-to-creatinine measurements. Lower urinary tract symptoms were not associated with lower estimated glomerular filtration rate based on serum creatinine or cystatin C. Although symptom severity was modestly associated with a higher prevalence of chronic kidney disease in age/site adjusted analyses, confidence intervals were wide and associations using all 3 definitions were not statistically significant after adjustment for important confounders, including cardiovascular disease and analgesic use. CONCLUSIONS: Lower urinary tract symptoms are not independently associated with multiple measures of kidney dysfunction or prevalence of chronic kidney disease among older community dwelling men. Our results do not support recommendations for kidney function testing among older men with lower urinary tract symptoms.

Urinary Incontinence and Nocturia in Older Men: Associations with Body Mass, Composition and Strength in the Health ABC Study.

PURPOSE: In younger men lower body mass is associated with fewer urinary symptoms, including incontinence and nocturia. However, lower body mass may have different implications in older men due to age associated muscle atrophy and decreased strength. MATERIALS AND METHODS: We performed a prospective analysis of community dwelling men 70 to 79 years old in the multicenter Health ABC (Aging and Body Composition) study who underwent measurement of body mass on physical examination, composition using dual x-ray absorptiometry and strength according to grip and lower leg dynamometry. We evaluated associations with prevalent incontinence and nocturia on structured questionnaires as well as concurrent changes in urinary symptoms during 3 years using multivariate logistic regression. RESULTS: Of the 1,298 men analyzed 22% reported incontinence and 52% reported nocturia at baseline. Higher body mass index, fat mass and lower appendicular lean mass, and grip and quadriceps strength corrected for body mass index were associated with an increased prevalence of incontinence (each p <0.05). Higher body mass index and greater fat mass were also associated with an increased nocturia prevalence (each p <0.05). Concurrent 5% or greater decrease in body mass or fat mass was not associated with lower odds of new or worsening incontinence or nocturia, whereas a 5% or greater decrease in maximum grip strength was associated with higher odds of new or worsening incontinence. CONCLUSIONS: Older men with a higher body mass index and greater fat mass are more likely to report prevalent incontinence and nocturia. However, late life decreases in strength but not increases in body mass or fat mass were associated with a concurrent increase in urinary incontinence.

Mediterranean diet after prostate cancer diagnosis and urinary and sexual functioning: The health professionals follow-up study.

BACKGROUND: Men with prostate cancer often experience urinary and sexual dysfunction after treatment. Previous studies have demonstrated a relationship between dietary factors and these symptoms among men with diabetes or metabolic syndrome. However, there are limited data on whether diet after prostate cancer diagnosis, including a Mediterranean dietary pattern, affects urinary and sexual function among prostate cancer survivors. METHODS: Men diagnosed with non-metastatic prostate cancer in the Health Professionals Follow-up Study (n = 2960) from 1986 to 2012 were prospectively followed for a median of 8.3 years after treatment. Participants completed validated dietary questionnaires every 4 years and a health-related quality of life assessment in 2010 or 2012. We used generalized linear models to examine associations between post-diagnosis Mediterranean Diet Score (including individual score components and dietary fat subtypes) and quality of life domains (sexual functioning, urinary irritation/obstruction, urinary incontinence) assessed using the Expanded Prostate Cancer Index Composite Short Form (score 0-100; higher scores indicate better function). RESULTS: No statistically significant relationships were observed between the Mediterranean Diet Score after prostate cancer diagnosis and urinary or sexual function. However, the associations did vary depending on pre-diagnosis urinary and sexual dysfunction for urinary irritation/obstruction and sexual function scores, respectively (P-interactions < 0.0001). Men with higher post-diagnosis vegetable intake reported higher urinary incontinence scores (72 vs 76 comparing lowest to highest quintile; P-trend = 0.003). Similarly, higher vegetable intake and lower polyunsaturated fat intake were associated with higher urinary irritation/obstruction scores (vegetable: 80 vs 84 comparing lowest to highest quintile, P-trend = 0.01; polyunsaturated fat: 84 vs 78 comparing lowest to highest quintile, P-trend = 0.005), however these associations were observed only among men with urinary symptoms prior to their prostate cancer diagnosis. CONCLUSIONS: Among men with prostate cancer, diet intake after diagnosis was not significantly associated with urinary or sexual function, although some relationships appeared to differ among men with and without symptoms prior to their prostate cancer diagnosis. Higher vegetable intake and lower polyunsaturated fat intake after prostate cancer diagnosis may be associated with better urinary function. However, this analysis was exploratory, and further research is needed to better delineate these relationships and guide dietary recommendations for men with prostate cancer.

Predictors of higher-risk chronic opioid prescriptions in an academic primary care setting.

BACKGROUND: Patients with chronic noncancer pain treated with higher doses of opioids or concurrent substance use are at increased risk of adverse events. Although several national guidelines recommend maximum dosing thresholds and urine drug testing, adherence to these guidelines is inconsistent. METHODS: To identify predictors of higher-risk opioid prescriptions in 2 academic primary care clinics, the authors developed a retrospective cohort of 842 patients who were prescribed ≥5 opioid prescriptions for noncancer pain between March 2012 and March 2013. The authors evaluated odds of higher-dose opioid prescriptions and urine drug testing using multivariate logistic models. RESULTS: Among study subjects, 47% received prescriptions for the equivalent of ≥50 mg morphine per day. After adjustment for confounders, patients with a resident primary care provider were less likely to receive higher-dose prescriptions compared with faculty providers (odds ratio = 0.66, 95% confidence interval [CI]: 0.46-0.94), whereas patients with a nonlocal home address were more likely to be prescribed higher doses (odds ratio = 2.1, 95% CI: 1.5-2.9). Hispanic, Asian, and older patients were also less likely to be prescribed higher doses. Urine drug testing was not regularly completed (35% over 2 years), but odds of testing were higher for patients who self-identified as black, had resident primary care providers, lived locally, or were prescribed higher opioid doses. CONCLUSIONS: In this academic clinical setting, patients with a resident primary care provider are less likely to receive higher-risk opioid prescriptions, as are Hispanic, Asian, and older patients. Black patients complete urine drug tests more frequently independent of other patient and provider characteristics. Additional studies are needed to assess why patients who travel larger distances to their primary care clinic are prescribed higher doses of opioids for chronic noncancer pain.

Selenoprotein and antioxidant genes and the risk of high-grade prostate cancer and prostate cancer recurrence.

BACKGROUND: Observational studies suggest an inverse association between selenium and risk of prostate cancer. However, randomized controlled trials of selenium supplementation have reported conflicting results. Thus, we examined plasma selenium and selenium-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with non-metastatic disease. METHODS: We measured plasma selenium and genotyped 73 single nucleotide polymorphisms in TXNRD1, TXNRD2, GPX1, GPX3, GPX4, SEP15, SEPP1, SELENBP1, OGG1, and CAT among 568 men with non-metastatic prostate cancer who underwent radical prostatectomy. We examined associations between plasma selenium, genotypes, and risk of high-grade prostate cancer (Gleason grade ≥8 or 7 with primary score ≥4; n = 111) using logistic regression, and risk of prostate cancer recurrence (61 events; 3.8 y median follow-up) using Cox proportional hazards regression. RESULTS: Plasma selenium was not associated with risk of high-grade prostate cancer or prostate cancer recurrence. Less common alleles of rs11913319 in TXNRD2 and rs125701 in OGG1 were associated with an increased risk of high-grade prostate cancer. We observed associations between the risk of prostate cancer recurrence and multiple SNPs in TXNRD1, TXNRD2, GPX3, and SEP15. These associations were no longer statistically significant after adjustment for multiple comparisons. CONCLUSIONS: Among men with non-metastatic prostate cancer, there is suggestive evidence that genetic variation in selenoproteins and related antioxidant enzymes may be associated with risk of high-grade disease at diagnosis and prostate cancer recurrence.

Geographic Disparities in Access to Agencies Providing Income-Related Social Services.

Geographic location is an important factor in understanding disparities in access to health-care and social services. The objective of this cross-sectional study is to evaluate disparities in the geographic distribution of income-related social service agencies relative to populations in need within Boston. Agency locations were obtained from a comprehensive database of social services in Boston. Geographic information systems mapped the spatial relationship of the agencies to the population using point density estimation and was compared to census population data. A multivariate logistic regression was conducted to evaluate factors associated with categories of income-related agency density. Median agency density within census block groups ranged from 0 to 8 agencies per square mile per 100 population below the federal poverty level (FPL). Thirty percent (n = 31,810) of persons living below the FPL have no access to income-related social services within 0.5 miles, and 77 % of persons living below FPL (n = 83,022) have access to 2 or fewer agencies. 27.0 % of Blacks, 30.1 % of Hispanics, and 41.0 % of non-Hispanic Whites with incomes below FPL have zero access. In conclusion, some neighborhoods in Boston with a high concentration of low-income populations have limited access to income-related social service agencies.

Associations of Lower Extremity Muscle Strength, Area, and Specific Force With Lower Urinary Tract Symptoms in Older Men: The Baltimore Longitudinal Study of Aging.

BACKGROUND: Lower urinary tract symptoms (LUTS) in older men are associated with an increased risk of mobility limitations. Lower extremity muscle quality may represent a novel shared mechanism of both LUTS and mobility limitations. METHODS: We evaluated associations of thigh skeletal muscle measures (strength, area, and specific force) with total LUTS severity (American Urologic Association Symptom Index; AUASI) and voiding and storage subscores among 352 men aged ≥60 years enrolled in the Baltimore Longitudinal Study of Aging. Thigh muscle strength (Nm) was defined as maximum concentric 30°/s knee extensor torque, area (cm2), and specific force (Nm/cm2) defined as strength/area. Associations with AUASI score were estimated using multivariable linear regression and linear mixed models. RESULTS: Mean thigh muscle strength at baseline was 139.7Nm. In cross-sectional multivariable models, each 39Nm increment in thigh muscle strength and 0.28Nm/cm2 increment in specific force was associated with -1.17 point (95% CI: -1.93 to -.41) and -0.95 point (95% CI: -1.63 to -0.27) lower AUASI score, respectively. Similar associations were observed for voiding and storage subscores, although somewhat attenuated. In longitudinal analyses, baseline muscle measures were not associated with annual change in AUASI, and current changes in muscle measures and AUASI were unrelated. CONCLUSIONS: Cross-sectionally, higher thigh muscle strength and specific force were associated with decreased LUTS severity in older men. However, we did not observe concurrent worsening LUTS severity with declining thigh muscle strength, area, or specific force in longitudinal analyses.

Difference between kidney function by cystatin C versus creatinine and association with muscle mass and frailty.

BACKGROUND: A higher difference in estimated glomerular filtration rate by cystatin C versus creatinine (eGFRDiff = eGFRCys - eGFRCreat) is associated with decreased frailty risk. Since eGFRCreat is influenced by muscle more than eGFRCys, muscle mass may explain this association. Previous work could not account for this when considering regional muscle measures by imaging. Deuterated creatine (D3Cr) dilution measures whole body muscle mass (kilograms). We aimed to determine whether eGFRDiff is associated with D3Cr muscle mass and whether muscle mass explains the association between eGFRDiff and frailty. METHODS: Cross-sectional analysis within the multicenter MrOS Study at Year 14 (visit 4). 490 men of the original cohort of 5994 MrOS participants (aged ≥65 at enrollment) were included. Exposure was eGFRDiff (= eGFRCys - eGFRCreat), calculated using CKD-EPI equations 2012/2021. Primary outcome was D3Cr muscle mass. Secondary outcome was phenotypic pre-frailty (one or two criteria) and frailty (≥three criteria) including the following: weight loss, weakness, slow gait, physical activity, poor energy. The association of eGFRDiff with D3Cr muscle mass was examined by linear regression, that with prefrailty / frailty by multinomial logistic regression. RESULTS: Mean ± SD age was 84 ± 4 years, eGFRCreat 68 ± 16, eGFRCys 52 ± 16, eGFRDiff -15 ± 12 mL/min/1.73 m2 and D3Cr muscle mass 24 ± 4 kg. For each SD increment in eGFRDiff, D3Cr muscle mass was 1.4 kg higher on average, p < 0.0001 (fully adjusted). Higher eGFRDiff was associated with lower odds of frailty (OR = 0.63 95% CI [0.45;0.89]), but this was partially attenuated and insignificant after additionally adjusting for D3Cr muscle mass (OR = 0.85 95% CI [0.58; 1.24]). CONCLUSIONS: Higher eGFRDiff is associated with lower odds of frailty among late-life men. D3Cr muscle mass accounts for some of this association. This suggests that non-GFR determinants of creatinine and cystatin C, such as muscle mass, play a role in explaining the association of eGFRDiff with frailty. Future studies are needed to confirm.

Age-Dependent Effects of Voluntary Wheel Running Exercise on Voiding Behavior and Potential Age-Related Molecular Mechanisms in Mice.

BACKGROUND: Older men frequently develop lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). Risk factors for LUTS/BPH include sedentary lifestyle, anxiety/depression, obesity, and frailty, which all increase with age. Although physical exercise may reduce the progression and/or severity of LUTS/BPH, the age-related mechanisms responsible remain unknown. METHODS: Voiding symptoms, body mass, and frailty were assessed after 4-weeks of voluntary wheel running in 2-month (n = 10) and 24-month (n = 8) old C57Bl/6J male mice. In addition, various social and individual behaviors were examined in these cohorts. Finally, cellular and molecular markers of inflammation and mitochondrial protein expression were assessed in prostate tissue and systemically. RESULTS: Despite running less (aged vs young X¯ = 12.3 vs 30.6 km/week; p = .04), aged mice had reduced voiding symptoms (X¯ = 67.3 vs 23.7; p < .0001) after 1 week of exercise, which was sustained through week 4 (X¯ = 67.3 vs 21.5; p < .0001). Exercise did not affect voiding symptoms in young mice. Exercise also increased mobility and decreased anxiety in both young and aged mice (p < .05). Exercise decreased expression of a key mitochondrial protein (PINK1; p < .05) and inflammation within the prostate (CD68; p < .05 and plasminogen activator inhibitor-1; p < .05) and in the serum (p < .05). However, a frailty index (X¯ = 0.17 vs 0.15; p = .46) and grip strength (X¯ = 1.10 vs 1.19; p = .24) were unchanged after 4 weeks of exercise in aged mice. CONCLUSIONS: Voluntary aerobic exercise improves voiding behavior and mobility, and decreases prostatic mitochondrial protein expression and inflammation in aged mice. This promising model could be used to evaluate molecular mechanisms of aerobic exercise as a novel lifestyle intervention for older men with LUTS/BPH.

Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging.

BACKGROUND: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). 31Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATPmax) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOSCI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders. RESULTS: One-SD decrements of most respirometry measures (e.g., Max OXPHOSCI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATPmax with frailty were weaker than those between Max OXPHOSCI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components. CONCLUSIONS: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.

Antioxidant and vitamin E transport genes and risk of high-grade prostate cancer and prostate cancer recurrence.

BACKGROUND: Observational studies suggest an inverse association between vitamin E and risk of prostate cancer, particularly aggressive tumors. However, three large randomized controlled trials have reported conflicting results. Thus, we examined circulating vitamin E and vitamin E-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with clinically organ-confined disease. METHODS: We measured circulating α- and γ-tocopherol and genotyped 30 SNPs in SOD1, SOD2, SOD3, TTPA, and SEC14L2 among 573 men with organ-confined prostate cancer who underwent radical prostatectomy. We examined associations between circulating vitamin E, genotypes, and risk of high-grade prostate cancer (Gleason grade ≥ 8 or 7 with primary score ≥ 4; n = 117) using logistic regression, and risk of recurrence (56 events; 3.7 years median follow-up) using Cox proportional hazards regression. RESULTS: Circulating γ-tocopherol was associated with an increased risk of high-grade prostate cancer (Q4 v. Q1 odds ratio [OR] = 1.87; 95% confidence intervals [CI]: 0.97-3.58; P trend =0.02). The less common allele in SOD3 rs699473 was associated with an increased risk of high-grade disease (T > C: OR = 1.40, 95% CI: 1.04-1.89). Two independent SNPs in SOD1 were inversely associated with prostate cancer recurrence in additive models (rs17884057 hazard ratio [HR] = 0.49, 95%CI: 0.25-0.96; rs9967983 HR = 0.62, 95% CI: 0.40-0.95). CONCLUSIONS: Among men with clinically organ-confined prostate cancer, genetic variation in SOD may be associated with risk of high-grade disease at diagnosis and disease recurrence. Circulating γ-tocopherol levels may also be associated with an increased risk of high-grade disease at diagnosis.

Analgesic use in relation to sex hormone and prolactin concentrations in premenopausal women.

PURPOSE: Common analgesics (aspirin, non-aspirin NSAIDs, and acetaminophen) may be associated with hormone-related cancers, possibly via effects on sex hormone and prolactin concentrations. METHODS: Between 1996 and 1999, 29,611 participants in the Nurses' Health Study II (NHSII) provided blood samples; 18,521 provided samples timed in the early follicular and mid-luteal phases of the menstrual cycle, the remainder provided untimed samples. We assessed the cross-sectional relationship between analgesic use and plasma sex hormone and prolactin concentrations among 2,034 premenopausal women, 32-54 years old, who served as controls in nested case-control studies, or participated in a within-person hormone reproducibility study in the NHSII; this included 1,700 timed and 334 untimed samples. Estrogens and progesterone were measured in timed samples; androgens and prolactin were measured in timed and untimed samples. RESULTS: In multivariable models, non-aspirin NSAIDs were positively associated with follicular free estradiol [13.5 % higher, use ≥4 days/week vs. nonusers (p = 0.04; p trend = 0.11)]; results for follicular total estradiol were similar (13.2 % higher, p = 0.06; p trend = 0.11). Acetaminophen use was inversely associated with prolactin (11.8 % lower, use 2 days/week vs. nonusers, p = 0.01, p trend = 0.04). Acetaminophen was also inversely associated with free testosterone (7.1 % lower, use 2 days/week vs. nonusers, p = 0.04; p trend = 0.04). No other associations were observed with the other hormones, or with aspirin use. CONCLUSIONS: There were no clear patterns between analgesic use and sex hormones in premenopausal women. Acetaminophen use may be modestly associated with prolactin and free testosterone. Our results do not support that analgesic use influences cancer risk through alterations in premenopausal circulating sex hormones or prolactin.

Lower urinary tract symptom severity, urinary bother, and incident life-space mobility restriction among older men.

BACKGROUND: Life-space mobility represents the distance, frequency, and independence of mobility, ranging from one's bedroom to beyond their town. Older men with lower urinary tract symptoms (LUTS) may limit their life-space to stay close to a bathroom. However, it's unknown whether LUTS severity or urinary bother are associated with risk of life-space mobility restriction. METHODS: We analyzed data from 3025 community-dwelling men age ≥71 years without life-space mobility restriction at analytic baseline (Year 7) of the Osteoporotic Fractures in Men (MrOS) study. The American Urologic Association Symptom Index (AUASI) was assessed at baseline and includes one question assessing urinary bother ("If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?"; score 0-1,2,3,4-6) and seven items to classify LUTS severity as none/mild (score 0-7), moderate (8-19), or severe (20-35). The University of Alabama Life-space Assessment was used to define life-space mobility restriction (≤60) at baseline and follow-up (Year 9). We used log-binomial regression with robust variance estimators to model adjusted risk ratios (ARR) for LUTS severity and urinary bother with incident life-space mobility restriction, controlling for age, site, health-related factors, and comorbidities. We then mutually adjusted for urinary bother and LUTS severity. RESULTS: Overall, the 2-year risk of life-space mobility restrictions was 9.9%. Compared to men without urinary bother (scores 0-1), the risk of life-space mobility restriction was significantly higher among men with bother scores of 4-6 (ARR = 2.20, 95% CI: 1.52, 3.19), independent of LUTS severity and confounders. Conversely, LUTS severity was not independently associated with the risk of life-space mobility restriction. CONCLUSIONS: Urinary bother, but not LUTS severity, is independently associated with incident life-space mobility restriction among older men. To maintain life-space mobility in older men with LUTS, future studies should identify shared mechanisms and interventions that minimize urinary bother.

Musculoskeletal Pain, a Possible Indicator of Central Sensitization, Is Positively Associated With Lower Urinary Tract Symptom Progression in Community-Dwelling Older Men.

BACKGROUND: Musculoskeletal pain, a possible marker of central sensitization, is associated with higher prevalence of lower urinary tract symptoms (LUTS) among older men. We investigated whether musculoskeletal pain is associated with LUTS progression. METHODS: Participants were 5 569 men age ≥65 years enrolled in the prospective, multicenter Osteoporotic Fractures in Men (MrOS) Study. Self-reported musculoskeletal pain within 12 months before baseline was categorized as any pain and multilocation pain. Pain interference within 4 weeks of baseline was assessed with the SF-12 questionnaire. LUTS were assessed repeatedly with the American Urological Association Symptom Index (AUA-SI). Men with severe LUTS at baseline were excluded. LUTS progression was defined as the first occurrence of a ≥4-point AUA-SI increase during a 2-year follow-up interval. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using multivariable pooled logistic regression. RESULTS: LUTS progression was 37% higher among men with any musculoskeletal pain compared with men without pain (IRR 1.37, 95% CI: 1.21, 1.54). Positive associations were also observed between LUTS progression and pain at 1 (IRR 1.31, 95% CI: 1.13, 1.48) and ≥2 locations (IRR 1.42, 95% CI: 1.24, 1.60). Compared with men without pain interference, men with quite a bit/extreme pain interference were most likely to experience LUTS progression (minimal interference IRR 1.15, 95% CI: 1.03, 1.26; moderate interference IRR 1.28, 95% CI: 1.11, 1.45; quite a bit/extreme interference IRR 1.47, 95% CI: 1.22, 1.71). CONCLUSIONS: Among men initially without severe LUTS, musculoskeletal pain is associated with an increased risk of LUTS progression. Studies using validated measures of central sensitization and LUTS progression among men are warranted.

Aging-Related Mitochondrial Dysfunction is Associated with Fibrosis in Benign Prostatic Hyperplasia.

BACKGROUND: Age is the greatest risk factor for lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). While LUTS/BPH can be managed with pharmacotherapy, treatment failure has been putatively attributed to numerous pathological features of BPH (e.g., prostatic fibrosis, inflammation). Mitochondrial dysfunction is a hallmark of aging, however its impact on the pathological features of BPH remains unknown. METHODS: Publicly available gene array data was analyzed. Immunohistochemistry examined mitochondrial proteins in human prostate. The effect of complex I inhibition (rotenone) on a prostatic cell line was examined using qPCR, immunocytochemistry, and Seahorse assays. Oleic acid was tested as a bypass of complex I inhibition. Aged mice were treated with OA to examine its effects on urinary dysfunction. Voiding was assessed longitudinally, and a critical complex I protein measured. RESULTS: Mitochondrial function and fibrosis genes were altered in BPH. Essential mitochondrial proteins (i.e., VDAC1/2, PINK1 and NDUFS3) were significantly (P<0.05) decreased in BPH. Complex I inhibition in cultured cells resulted in decreased respiration, altered NDUFS3 expression, increased collagen deposition and gene expression. Oleic acid ameliorated these effects. Oleic acid treated aged mice had significantly (P<0.05) improved voiding function and higher prostatic NDUFS3 expression. CONCLUSION: Complex I dysfunction is a potential contributor to fibrosis and lower urinary tract dysfunction in aged mice. Oleic acid partially bypasses complex I inhibition and therefore should be further investigated as a mitochondrial modulator for treatment of LUTS/BPH. Hypotheses generated in this investigation offer a heretofore unexplored cellular target of interest for the management of LUTS/BPH.

Skeletal Muscle Health, Physical Performance, and Lower Urinary Tract Symptoms in Older Adults: the Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Lower urinary tract symptoms (LUTS) and mobility limitations are bidirectionally associated among older adults, but the role of skeletal muscle remains unknown. We evaluated cross-sectional associations of muscle health and physical performance with LUTS. METHODS: We used data from 377 women and 264 men age>70 years in the Study of Muscle, Mobility and Aging (SOMMA). LUTS and urinary bother were assessed using the LURN Symptom Index-10 (SI-10;higher=worse symptoms). Muscle mass and volume were assessed using D3-creatine dilution (D3Cr) and magnetic resonance imaging. Grip strength and peak leg power assessed upper/lower extremity physical performance. 400m walk, Short Physical Performance Battery (SPPB), and Four Square Step Test (FSST) assessed global physical performance. Mobility Assessment Tool-short form (MAT-sf) assessed self-reported mobility. We calculated Spearman correlation coefficients adjusted for age, BMI, multimorbidity, and polypharmacy, chi-square tests, and Fisher's Z-test to compare correlations. RESULTS: Among women, LURN SI-10 total scores were inversely correlated with FSST (rs=0.11,P=0.045), grip strength (rs=-0.15,P=0.006), and MAT-sf (rs=-0.18,P=0.001), but not other muscle and physical performance measures in multivariable models. LURN SI-10 was not associated with any of these measures among men. 44% of women in the lowest tertile of 400m walk speed versus 24% in the highest tertile reported they were at least "somewhat bothered" by urinary symptoms (P<0.001) whereas differences among men were not significant. CONCLUSIONS: Balance and grip strength were associated with LUTS severity in older women but not men. Associations with other muscle and physical performance measures varied by LUTS subtype but remained strongest among women.