Prevalence of low testosterone in aging men with benign prostatic hyperplasia: data from the Proscar Long-term Efficacy and Safety Study (PLESS)

Abstract

Objectives: We examined the prevalence of low testosterone (LT) in the subset of men in the Proscar Long-term Efficacy and Safety Study (PLESS) who had serum total testosterone (TT) measured at baseline.

Methods: PLESS enrolled 3040 men with benign prostatic hyperplasia (BPH). Of these men, 299 had TT and body mass index (BMI) measurements at baseline. Patients were classified as having LT if their baseline TT was <300 ng/dl.

Results: Of the 299 PLESS patients with baseline TT and BMI measurements, 65 (21.7%) had LT. The prevalence of LT increased with increasing BMI, occurring in 8/78 (10.3%) normal weight patients (baseline BMI <25 kg/m²), 35/160 (21.9%) overweight patients (baseline BMI ≥25–<30 kg/m²), and 22/61 (36.1%) obese patients (baseline BMI ≥30 kg/m²).

Conclusions: LT was observed in more than one in five PLESS patients with baseline TT and BMI measurements. The prevalence of LT increased with increasing BMI – more than one in three obese PLESS patients with baseline TT measurements had LT.

• Benign prostatic hyperplasia
• low testosterone
• Proscar Long-Term Efficacy and Safety Study

Introduction

Increased body mass index (BMI) is a shared risk factor for benign prostatic hyperplasia (BPH) and low testosterone (LT) in aging men [1–3]. Few studies have examined the prevalence of LT in aging men with BPH. A previous study in 312 aging Austrian men with BPH (mean age: 63 years) reported that more than one in five patients had LT, defined as a total serum testosterone (TT) level of <300 ng/dl [4].

The Proscar Long-term Efficacy and Safety Study (PLESS) was a 4 year, randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of finasteride 5 mg in 3040 men aged 45–78 with symptomatic BPH, enlarged prostates and no evidence of prostate cancer [5]. TT was measured in a randomly selected subset of 10% of the patient population. We examined the prevalence of LT, defined as a baseline TT <300 ng/dl, in these men.

Methods

Details concerning the study design for PLESS, conducted between 1991 and 1996, have been published previously [5]. Briefly, the patient entry criteria included an enlarged prostate by digital rectal examination, moderate to severe symptoms of urinary obstruction, decreased maximal urinary flow rate (<15 ml/s with a voided volume of 150 ml or more), no concurrent use of α-blockers or antiandrogens, no prior prostate surgery, no history of prostatitis or recurrent urinary tract infections, a prostate-specific antigen level of <10 ng/ml, and no evidence of prostate or bladder cancer. A total of 3040 men participated in the trial. Of these 3040 men, a randomly selected subset of 301 had TT measured at baseline. Of these 301 men, 299 had both TT and BMI measurements at baseline; these data were examined in the present post hoc analysis. Blood samples for TT measurement were drawn between 8 am and 12 noon in a nonstandardized manner (i.e. whenever the patient was in the clinic for his visit). TT levels were determined by radioimmunoassay at Endocrine Sciences (Calabasas Hills, CA).

In the present post hoc analysis, men with LT were defined as those with baseline TT <300 ng/dl (i.e. lower limit of eugonadal reference range for young men) [6]. Patients were grouped according to BMI categories, <25 kg/m² (normal weight), ≥25–<30 kg/m² (overweight) or ≥30 kg/m² (obese), and the percentage of patients with LT in each BMI group was evaluated.

Results

Patient characteristics

Baseline characteristics for the 299 patients who had TT and BMI measured at baseline and who were included in the present analysis are shown in Table 1, by BMI subgroup. Within this overall analysis cohort, mean ± SD baseline TT was 424.6 ± 154.3 ng/dl, mean ± SD BMI was 27.4 ± 3.9 kg/m², mean ± SD age was 63.4 ± 6.8 years, 26.1% had normal body weight, 53.5% were overweight and 20.4% were obese. For the cohort who had LT (baseline TT < 300 ng/dl), mean ± SD baseline TT was 260.9 ± 33.8 ng/dl, mean ± SD BMI was 29.0 ± 4.1 kg/m² and mean ± SD age was 63.3 ± 6.2 years. For the cohort with normal baseline TT (baseline TT ≥ 300 ng/dl), mean ± SD baseline TT was 470.1 ± 143.6 ng/dl, mean ± SD BMI was 27.0 ± 3.8 kg/m² and mean ± SD age was 63.4 ± 7.0 years. There was a slight decrease in mean age with increasing BMI (mean age was 65.2, 63.0 and 62.1 years in the <25, ≥25–<30 and ≥30 kg/m² BMI subgroups, respectively).

Table 1. Baseline characteristics.

	n	Mean age ± SD(year)	Mean TT ± SD (ng/dl)	Mean BMI ± SD (kg/m^2)
Total population	299	63.4 ± 6.8	424.6 ± 154.3	27.4 ± 3.9
BMI <25 kg/m^2	78	65.2 ± 6.8	493.1 ± 159.3	23.1 ± 1.6
BMI ≥25 to <30 kg/m^2	160	63.0 ± 7.0	422.0 ± 152.9	27.3 ± 1.4
BMI ≥30 kg/m^2	61	62.1 ± 5.9	343.9 ± 105.7	33.3 ± 3.2

BMI = body mass index, SD = standard deviation, TT = serum total testosterone.

Prevalence of LT

Of the 299 patients with baseline TT and BMI measurements, 65 (21.7%) had LT. In the subgroup of men with baseline BMI <25 kg/m² (normal weight), 8/78 (10.3%) had LT, while 35/160 (21.9%) and 22/61 (36.1%) had LT in the subgroups with baseline BMI ≥25 to <30 kg/m² (overweight) and ≥30 kg/m² (obese), respectively (Figure 1). Of the patients included in this analysis, 74% (221/299 patients) were overweight or obese. Among the 65 patients with LT, 88% were overweight or obese.

Figure 1. Prevalence of LT (baseline serum TT <300 ng/dl), by baseline BMI.

Discussion

The prevalence of LT observed in the present analysis of baseline TT and BMI data from PLESS (65/299 patients, or 21.7%) was similar to that reported in previous analyses evaluating hypogonadism in BPH patients [4] and was within the broad range of LT prevalence reported across the general population of aging males [7–9]. The results of this analysis are also in agreement with previous studies in which LT was observed to be associated with increased BMI [10–15]. As expected given the well-established positive relationship between the prevalence and severity of BPH and increased BMI [1–3], the majority (74%) of patients included in the present analysis were overweight or obese, and most (88%) of the patients with LT were overweight or obese.

There are a number of mechanisms that may explain the inverse relationship between higher BMI and testosterone levels in men. In men, adipose tissue is the main peripheral source of aromatase, which catalyzes the irreversible conversion of T to estradiol. The increased adiposity in obesity may be associated with increased aromatase activity, which could lead to an increase in the conversion of T to estradiol [16]. Obese men have been shown to have elevated serum estradiol levels [17]. Increased estradiol levels may, in turn, cause pituitary suppression [16], which may explain, at least in part, the reduction in gonadotropin release reported in obese men [16,17]. Obesity has also been shown to be associated with reduced sex hormone-binding globulin levels, which could lead to a further reduction in serum testosterone levels [17,18].

In light of the role testosterone plays in maintaining male sexual function [19,20], together with its roles in regulation of bone density, muscle mass and function, fat mass and cardiovascular fitness [21,22], physicians should be aware of the relatively high prevalence (36%) of LT in obese men with BPH observed in this study. Consideration might also be given to the possibility that symptoms associated with LT could exacerbate the general deterioration in quality of life associated with BPH [23,24].

The most widely prescribed treatment for men with symptomatic LT is testosterone replacement therapy. However, significant increases in prostate volume and PSA levels have been reported in some hypogonadal patients receiving testosterone therapy [25–29]. Prostate volume and serum PSA are positively correlated with the risk of the serious urinary outcomes of acute urinary retention and BPH-related surgery in men with BPH [30,31]. Moreover, pharmacologically induced decreases in prostate volume and PSA have been shown to be associated with reductions in the risk of acute urinary retention and BPH-related surgery in BPH patients [5,32,33]. Taken together, these findings raise an obvious concern as to whether some BPH patients with LT who may experience significant testosterone-induced increases in prostate volume and/or PSA would be at risk of a further increase in their already elevated likelihood of developing acute urinary retention or needing BPH-related surgery. To date, no large, long-term, randomized and controlled studies have examined the effect of testosterone therapy on urinary outcome risk in BPH patients with LT. Additionally, testosterone therapies that cause large elevations in serum PSA [25] in some hypogonadal patients could also complicate use of serum PSA as part of screening for prostate cancer, including complicating the interpretation of serum PSA levels in BPH patients treated with 5α-reductase inhibitors. Until prospective studies are done to address these potential areas of concern, it would appear prudent for physicians to monitor urinary function in the subgroup of BPH patients with LT who may experience significant prostate tissue stimulation while receiving testosterone therapy.

In spite of its well-known stimulatory effect on prostate tissue, recent studies have suggested that testosterone therapy can actually improve urinary symptoms in hypogonadal BPH patients. The mechanism(s) by which testosterone produces this apparently paradoxical beneficial effect is not clear [34,35]. Given the important role of androgens in male urinogenital physiology, it is conceivable that the re-normalization of serum and intraprostatic androgen levels with testosterone therapy could lead to re-normalization of intraprostatic architecture and function in hypogonadal BPH patients. Further studies are needed to investigate the effects of testosterone therapy on prostatic function and urinary symptoms in these patients.

Conclusions

In conclusion, this analysis of baseline data from 299 BPH patients participating in PLESS demonstrated that, in these men, LT occurred in more than one out of every five patients. The prevalence of LT was highest (36%) among obese BPH patients. Practitioners concerned with managing aging men with BPH should be mindful of the prevalence of LT in these patients, which may be associated with deleterious effects on muscle mass/strength, bone, fat mass, sexual function and cardio-metabolic risk. Further studies are needed to determine whether testosterone therapy could lead to clinical benefits in BPH patients.

Declaration of interest

PLESS was funded by Merck & Co., Inc. Authors O’Neill, Lowe, Hanson and Meehan are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ. Author Kaplan is a PLESS investigator and an employee of Weill Cornell Medical College, New York, NY.

Acknowledgements

The authors wish to acknowledge the contributions of the many investigators, study coordinators and patients who contributed to PLESS. Editorial support was provided by Kathleen Newcomb (Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ).