Sage Journals: Discover world-class research

Abstract

Lower urinary tract symptoms (LUTS) are common in older men and are frequently associated with benign prostatic hyperplasia (BPH). The relationship between BPH and endogenous total testosterone (TT) levels has been widely studied. The aim of this post hoc analysis was to determine the association between LUTS and endogenous TT levels in a subset of men participating in the 2013 Prostate Cancer Awareness Week, a U.S. community-based prostate cancer screening program. Men completed the International Prostate Symptom Score (I-PSS) questionnaire, prostate size was estimated by a digital rectal examination, and serum TT and prostate-specific antigen levels were measured. Mean TT levels (ng/dl) did not significantly correlate with prostate size category (r = +.03, p = .69): normal, 419.2 (n = 106); enlarged, 394.7 (n = 71); abnormal, 416.4 (n = 7); and abnormal/suspicious, 515.2 (n = 19). Mean TT levels (ng/dl) did not significantly correlate with I-PSS category (r = −.06, p = .40): none, 468.5 (n = 15); mild, 414.0 (n = 138); moderate, 397.4 (n = 66); and severe, 437.9 (n = 7). Mean TT levels (ng/dl) did not significantly correlate with I-PSS quality of life rating (r = −.13, p = .055): delighted, 474.5 (n = 43); pleased, 424.6 (n = 65); mostly satisfied, 361.2 (n = 63); mixed, 448.2 (n = 29); mostly dissatisfied, 337.2 (n = 17); and unhappy, 435.8 (n = 6). Adjustment for prostate size or prostate-specific antigen levels yielded similar findings. In conclusion, endogenous TT levels did not correlate with LUTS or prostate size, and these findings support the saturation theory in which TT is not able to induce further androgen-stimulated prostate tissue growth due to receptor saturation. Any worsening of LUTS following testosterone replacement therapy in hypogonadal men may be related to stimulation of prostatic cells previously deprived of testosterone.

Keywords

testosterone level lower urinary tract symptoms benign prostatic hyperplasia prostate International Prostate Symptom Score

Introduction

Lower urinary tract symptoms (LUTS) are common in older men, with the prevalence of moderate-to-severe LUTS ranging from 22% in men aged 50 to 59 years to 45% in men aged 70 to 80 years (Rosen et al., 2003). LUTS comprise storage (irritative) symptoms (i.e., urinary frequency, nocturia, urgency, urinary incontinence) and voiding (obstructive) symptoms (i.e., slow-stream, intermittency, hesitancy, straining, postmicturition dribble, and sensations of incomplete emptying). LUTS may result from a complex interplay of pathophysiological influences, including prostatic pathology and bladder dysfunction (Chapple & Roehrborn, 2006).

Benign prostatic hyperplasia (BPH), a nonmalignant proliferation of the epithelial and stromal cells, leads to prostate enlargement, primarily in older men. Prostatic cell proliferation and the development of histological features of BPH are generally considered to be dependent on the bioavailability of testosterone and its metabolite, 5α-dihydrotestosterone. An association between these androgens levels and BPH measures has not been consistently reported. Because of the known effects of androgens on prostate growth, testosterone prescribing information warns that the therapy may worsen BPH symptoms, and clinicians are advised to monitor patients with BPH who are receiving testosterone replacement therapy (TRT) for worsening of signs and symptoms of BPH (Bhasin et al., 2010).

While the association between BPH and endogenous total testosterone (TT) levels has been widely studied, there is less clarity on the effects of endogenous TT levels on LUTS. (Pearl et al., 2013, Yassin, El-Sakka, Saad, & Gooren, 2008). The aim of this post hoc analysis was to study the relationship, if any, between TT level and both prostate size, estimated by digital rectal examination (DRE), and LUTS, as assessed by the International Prostate Symptom Score (I-PSS).

Method

The study sample comprised men who elected to be screened during the 2013 Prostate Cancer Awareness Week (PCAW). PCAW is a U.S. community-based prostate cancer screening program, sponsored by the Prostate Conditions Educational Council, with approval provided by Colorado Multiple Institutional Review Board. Men are offered the opportunity to attend PCAW during the third week of September, with recruitment through media announcements and information posted on the Prostate Conditions Educational Council website. Methodology of PCAW has been previously published in detail (Stone, Miner, Poage, Patel, & Crawford, 2014). Men undergoing screening (N = 3,277) provided written informed consent, completed a series of health questionnaires (including the I-PSS) and received a medical evaluation. A subset of men (N = 1,367) had blood drawn for laboratory assays, including measurement of TT and prostate-specific antigen (PSA) levels. Serum TT levels were measured using the ADVIA Centaur XP immunoassay system (Siemens, Malvern, PA; total TT normal range 300-700 ng/dl, sensitivity 10-1,500 ng/dl); PSA levels were measured using the Hybritech PSA immunoassay and the Beckman Access (Beckman Coulter Inc., Fullerton, CA). Prostate size was estimated by DRE and categorized (see Table 1) based on the opinion of the examiner. Analyses were performed using data from men with TT levels measured from an 8- to 11-a.m. blood draw (n = 229). The self-administered I-PSS questionnaire was used to assess the severity of BPH symptoms over the prior month (Barry et al., 1992). The I-PSS includes seven symptom severity questions (each scored 0-5, higher scores indicate more severe symptoms on a scale of 0-35), which are collectively referred to as the I-PSS total score, and one quality of life (QoL) question that is scored independent of the symptom severity questions. The seven I-PSS symptom severity questions can further be categorized into an irritative symptom subscore (questions on urinary frequency, urgency, and straining) and an obstructive symptom subscore (questions on urinary incomplete emptying, intermittency, weak-stream, nocturia). Spearman correlation coefficients were calculated between TT levels and prostate size categories/PSA values and I-PSS categories and QoL ratings as well as between TT levels and I-PSS total, irritative symptoms, and obstructive symptom subscores. Analysis of covariance was used to adjust the I-PSS variables for prostate size. In all analyses, adjustments were made for age and BMI.

Table 1.

Baseline Characteristics (Men With a Blood Draw Time From 8 to 11 a.m., N = 229).

Mean age (years)	62.6 (35-86)
Caucasian	147 (64%)
Current smoker	17 (8%)
Low exercise (<2× per week)	82 (39%)
Mean weight (lb)	189.2 (123-335)
Overweight (≥20 lb)	39 (18%)
BMI (kg/m²)	27.4 (17-45.1)
High BMI (≥ 30 kg/m²)	55 (25%)
Type 2 diabetes	21 (9%)
Mean testosterone level (ng/dL)	411.7 (15-1246)
Low TT (<300 ng/dL)	69 (30%)
PSA (ng/ml)	1.94 (0.01-37.93)
ED/sexual problems	36 (16%)
Current TRT	6 (3%)
Current ED medication	14 (6%)
Current medication for urinary problems	19 (9%)
Prostate size, determined by digital rectal exam^a
Normal	106 (52%)
Enlarged	71 (35%)
Abnormal	7 (3%)
Abnormal/suspicious	19 (9%)
Patient refused	1 (0.5%)

Note. BMI = body mass index; TT = total testosterone; PSA = prostate-specific antigen; ED = erectile dysfunction; TRT = testosterone replacement therapy. Mean (range) or n (%) are shown.

Categorized based on the opinion of the examiner.

Results

There were no significant correlations between mean TT level and prostate size (r = +.03, p = .69), I-PSS category (r = −.06, p = .40) or PSA level (r = +.03, p = .69) (see Table 2). Although mean TT levels did not significantly correlate with I-PSS QoL rating (r = −.13, p = .055), there was some evidence that patients with a higher QoL had slightly higher testosterone levels. There were no significant correlations between TT level and I-PSS total (r = −.073), irritative symptom subscore (r = −.10) or obstructive symptom subscore (r = −.04; p > .1, in all cases). Adjustment for prostate size yielded similar findings.

Table 2.

Total Testosterone Level by Prostate Size and Measures of Lower Urinary Tract Symptoms.

	n	Total testosterone level (ng/dl)	Spearman correlation	p
Prostate size^a
Normal	106	419.2	+.03	.69
Enlarged	71	394.7
Abnormal	7	416.4
Abnormal/suspicious	19	515.2
International Prostate Symptom Score category (score)
None (0)	15	468.5	−.06	.40
Mild (1-7)	138	414.0
Moderate (8-19)	66	397.4
Severe (20-35)	7	437.9
International Prostate Symptom Score–Quality of Life
Delighted	43	474.5	−.13	.055
Pleased	65	424.6
Mostly satisfied	63	361.2
Mixed	29	448.2
Mostly dissatisfied	17	337.2
Unhappy	6	435.8

Categorized based on the opinion of the examiner.

Discussion

In this analysis, endogenous TT levels did not correlate with prostate size, PSA level, or LUTS. The findings are consistent with an earlier study, using a similar group of men, which concluded that testosterone levels had no impact on LUTS status, PSA level, or prostate volume (Schatzl et al., 2000).

These findings may add support to the saturation theory, which postulates that increased levels of testosterone do not further induce androgen-stimulated prostate tissue proliferation due to receptor saturation (Khera, Crawford, Morales, Salonia, & Morgentaler, 2014). While this study assessed only endogenous TT levels, these data suggest that worsening of LUTS following TRT in hypogonadal men may be related to stimulation of prostatic cells previously deprived of testosterone.

Study limitations include the following: the use of a community-based study of relatively small sample size (n = 229), which was not prospectively designed or powered to determine the relationship between TT levels and prostate size or LUTS; the population was not restricted to hypogonadal men or men with LUTS; prostate size was determined by DRE; free/bioavailable testosterone levels were not determined; and only a single TT measurement was made, without consideration for day-to-day variability.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AN, DAP, SAD, and DM are salaried employees at Eli Lilly and Company; EDC is a consultant for Bayer, Inc MDx, Genomic Health Jansen Pharmaceuticals, Dendreon, and Ferring Pharmaceuticals; WP is a collaborator/contractor with MDx Health, Strand Diagnostics, Genomic Dx, Abbott Laboratories, and Bayer, Inc.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The analyses were performed by Eli Lilly and Company

References

Barry

M. J.

Fowler

F. J.

Jr. O’Leary

M. P.

Bruskewitz

R. C.

Holtgrewe

H. L.

Mebust

W. K.

Cockett

A. T.

(1992). The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. Journal of Urology, 148, 1549-1557.

Bhasin

Cunningham

G. R.

Hayes

F. J.

Matsumoto

A. M.

Snyder

P. J.

Swerdloff

R. S.

Montori

V. M.

(2010). Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism, 95, 2536-2559.

Chapple

C. R.

Roehrborn

C. G.

(2006). A shifted paradigm for the further understanding, evaluation, and treatment of lower urinary tract symptoms in men: Focus on the bladder. European Urology, 49, 651-658.

Khera

Crawford

Morales

Salonia

Morgentaler

(2014). A new era of testosterone and prostate cancer: From physiology to clinical implications. European Urology, 65, 115-123.

Pearl

J. A.

Berhanu

Francois

Masson

Zargaroff

Cashy

McVary

K. T.

(2013). Testosterone supplementation does not worsen lower urinary tract symptoms. Journal of Urology, 190, 1828-1833.

Rosen

Altwein

Boyle

Kirby

R. S.

Lukacs

Meuleman

Giuliano

(2003). Lower urinary tract symptoms and male sexual dysfunction: The Multinational Survey of the Aging Male (MSAM-7). European Urology, 44, 637-649.

Schatzl

Brossner

Schmid

Kugler

Roehrich

Treu

Madersbacher

(2000). Endocrine status in elderly men with lower urinary tract symptoms: Correlation of age, hormonal status, and lower urinary tract function. Urology, 55, 397-402.

Stone

N. N.

Miner

Poage

W. L.

Patel

Crawford

E. D.

(2014). Male Androgen Deficiency Syndrome Screening Questionnaire: A simplified instrument to identify testosterone-deficient men. Journal of Men’s Health, 11, 28-37.

Yassin

A. A.

El-Sakka

A. I.

Saad

Gooren

L. J.

(2008). Lower urinary-tract symptoms and testosterone in elderly men. World Journal of Urology, 26, 359-364.

Effects of Testosterone Level on Lower Urinary Tract Symptoms