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Impact of poor glycemic control of type 2 diabetes mellitus on serum prostate-specific antigen concentrations in men

Background To evaluate the impact of poor glycemic control of type 2 diabetes mellitus (T2DM) on serum prostate-specific antigen (PSA) concentrations in men. Methods We performed a prospective analysis of 215 consecutive patients affected by erectile dysfunction (ED). ED was evaluated using the IIEF-5 questionnaire and the poor glycemic control (PGC) of T2DM was assessed according to the HbA1c criteria (International Diabetes Federation). Patients were divided into PGC group (HbA1c ≥ 7%) and control group (CG) (HbA1c < 6%). Correlations between serum HbA1c levels and various variables were evaluated and multivariate logistic regression analyses were carried out to identify variables for PGC. Results We compared 110 cases to 105 controls men ranging from 44 to 81 years of age, lower PSA concentrations were observed in men with PGC (PGC mean PSA: 0.9 ng/dl, CG mean PSA: 2.1 ng/dl, p < 0.001). Also mean prostate volume was 60% was smaller among men with PGC compared with men with CG (PGC mean prostate volume: 26 ml, CG prostate volume: 43 ml, p < 0.001). A strong negative correlation was found between serum HbA1c levels and serum PSA (p < 0.001 and r = −0.665) concentrations in men with PGC. We also found at the multivariate logistic regression model that PSA, prostate volume and peak systolic velocity were independent predictors of PGC. Conclusion Our results suggest that there is significant impact of PGC on serum PSA levels in T2DM. Poor glycemic control of type 2 diabetes was associated with lower serum PSA levels and smaller prostate volumes.


Introduction
Measurement of prostate-specific antigen (PSA) is widely applied for early detection of prostate cancer. However, several factors influencing serum PSA levels in men include age, benign prostatic hyperplasia, prostatitis, and body mass index (BMI). 1,2 Type 2 diabetes (T2DM) is a complex metabolic disease characterized initially by insulin resistance and hyperinsulinemia. It is estimated that 11% of American men have type 2 diabetes. 3,4 Many studies have investigated the association between T2DM and PSA with most evidence supporting a modest inverse association; the reported reduction in risk ranges from 10% to 20% in diabetics. 5,6 There are several possible explanations as to why PSA may be lower in men with T2DM than in those without, including lower testosterone and higher estrogen concentrations, greater obesity, and more frequent use of medications for dyslipidemia. 7e9 These reports have focused on the relationship between serum fasting glucose values and PSA in men with T2DM but the effect of poor glycemic control [PGC; as assessed by hemoglobin A1c (HbA1c)] on serum PSA concentration was not discussed in those publications. Also, the role of severity of T2DM is yet to be explored as more detailed data are still lacking.
In this study, we examined effect of PGC (HbA1c ! 7%) on serum PSA levels in men with T2DM. We also investigate the relationships between HbA1c levels and prostate volumes and investigated what factors may be associated with serum PSA levels in men with PGC.

Design
Between January 2013 and March 2014, 350 consecutive patients with erectile dysfunction (ED) were prospectively enrolled in this study at a single academic outpatient andrology clinic.
Patients who were taking a-blockers, phosphodiesterase type 5 inhibitors, and 5a-reductase inhibitors and those with neurogenic bladder, postvoid residue >150 mL, prostate cancer, bladder cancer, bladder stone, urethral stricture, men with diabetes who suffered from end organ damage (creatinine levels > 250 mm), or absence of hepatic dysfunction (high transaminase plasma levels) were excluded from the study. Okmeydanı Training and Research Hospital Ethics Committe approval and informed consent from all the participants were obtained. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
All patients' detailed medical and sexual history were evaluated. Patients underwent physical examination including digital rectal examination, genitourinary, endocrine systems, and prostate volume estimated by transrectal ultrasonography. Participants completed a baseline questionnaire that ascertained information on urinary symptoms, medical histories, physical examination (weight, height, BMI, waist circumference, and blood pressure), and various demographic and behavioral characteristics.
Lower urinary tract symptoms were evaluated by culturally and linguistically validated versions of International Prostate Symptom Score (IPSS). ED was evaluated using the International Index of Erectile Function short form (IIEF-5) questionnaire, with normal erectile function as 22e25 points, mild dysfunction 17e21, mild-tomoderate ED 12e16, moderate ED 8e11, and severe ED 5e7 points. 10 Blood samples were drawn from overnight-fasted patients and serum levels PSA, free PSA, fasting blood glucose, HbA1c, highdensity lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, and triglyceride were recorded. A venipuncture was performed between 8:00 AM and 10:00 AM for total testosterone measurement.
After the results of the patients' laboratory testing were finalized, patients were consulted with internal medicine department for the diagnosis of T2DM. Poor glycemic control of T2DM was defined as HbA1c ! 7% according to the standards defined by the American Diabetes Association, 11 and 170 patients were diagnosed with T2DM by the Internal Medicine Department (Okmeydanı Training and Research Hospital) and 110 of those patients were diagnosed with PGC. There were 105 patients with ED who had no diabetes recruited as a control group (CG; HbA1c < 6%).

PSA, HbA1c, and hormone measurements
PSA and HbA1c were measured in blood samples. PSA analyses were done using the total and free prostate-specific antigen test (Cobas 6000; Roche Diagnostics, Indianapolis, IN, USA) on a Modular E-Module of Roche Diagnostics. HbA1c analysis was done using high-performance liquid chromatography on the Premier Hb9210 system (Trinity Biotech, Bray, Wicklow, Ireland). Total testosterone was evaluated by commercial electrochemiluminescence immunoassay methods (Roche Diagnostics). All measurements were done in a central laboratory in blinded fashion and according to the manufacturer's instructions.

Transrectal and penile duplex Doppler ultrasonography measurements
To calculate prostate volume, a prostate transrectal ultrasound analysis was performed with a high-resolution echo-color Doppler (iU22; Philips, Eindhoven, The Netherlands) equipped with a 9e5 MHz Broadband Curved Array Transducer. Prostate volume was calculated using the standard ellipsoid formula (width Â height Â length Â p/6). 12 For penile duplex Doppler ultrasonography measurements, patients received a single intracavernous injection of Bimix (15 mg papaverine and 1 mg phentolamine). The erectile response was evaluated for tumescence and rigidity by palpation of the penis. The penis was scanned by a ventral approach at the base with the probe held transversally or in an oblique-longitudinal position. 13 Peak systolic velocity (PSV) and end diastolic velocity (EDV) within the cavernosal arteries were measured. Patients with PSV > 35 cm/s were considered with a normal arterial response, while < 25 cm/s signified arterial insufficiency. Corporal veno-occlusive dysfunction was defined as EDV > 5 cm/s. 14,15

Metabolic parameters measurements
Plasma fasting glucose was determined by enzymatic test (COBAS C720; Roche Diagnostics), total cholesterol was determined by enzymatic colorimetric test (CHOD-PAP, COBAS C720; Roche Diagnostics), and high-density lipoprotein cholesterol and triglycerides were measured by enzymatic colorimetric test (COBAS C720; Roche Diagnostics). Creatinine was determinate by the Jaffe method. For all parameters, the intra-and interassay coefficients of variation were < 8% and 10%, respectively.

Comparison of the groups
The mean age was 61 years in the PGC group (mean ± standard deviation, 59.5 ± 9.6 years), and 59 in CG (60.1 ± 9.5 years, p ¼ 0.46). BMI of PGC group patients was lower than CG but it was not statistically relevant (p ¼ 0.81). No differences were observed in lower urinary symptoms, which were assessed with IPSS (p ¼ 0.63). Lower free and total PSA concentrations were observed in men with PGC patients compared to Cg (PGC mean total PSA: 0.9 ng/dL, CG mean total PSA: 2.1 ng/dL, p < 0.001; PGC mean free PSA: 0.3 ng/dL, CG mean free PSA: 0.8 ng/dL, p < 0.001). Also, mean prostate volume was 60% was smaller among men with severe PGC compared to control participants (PGC mean prostate volume: 26 mL, CG prostate volume: 43 mL, p < 0.001), total testosterone levels were not significantly different between the groups (p ¼ 0.27). Mean PSV was lower in PGC patients compared to control group (T2DM mean PSV: 12.1 cm/s, CG mean PSV: 19 cm/s, p < 0.001), but there were no differences in terms of mean EDV values and IIEF-5 scores. There were no differences between the groups in terms of serum creatinine and lipid profiles ( Table 2).

Discussion
We observed a significant impact of severe PGC on total PSA concentrations in men with PGC. An inverse relationship between high HbA1c levels and total PSA concentrations were shown in two  groups who enrolled in this prospective study. The association was independent of age, BMI, testosterone concentrations and serum lipid profile, suggesting that PGC itself may affect PSA. Several recent studies reported lower PSA levels with T2DM. For example, Werny et al 5 found that men with self-reported diabetes had a 21.6% lower geometric mean PSA level than men without diabetes after accounting for age. Fukui et al 6 observed that except for age group 40e49 years, serum PSA levels were lower 10e16% in diabetic men than in healthy Japanese men. These studies focused on men with T2DM, but did not examine the effects of severe PGC independent medication use. In our study, no participants reported use of any medical treatment for diabetes prior to and at the time of study recruitment.
Our findings are also consistent with those of studies in men with T2DM specifically examining the correlation between HbA1c and PSA. Sarma et al 16 found that each 10% increase in hemoglobin A1C had accompanied by an 11% reduction in prostate specific antigen (p < 0.0001) and PSA decreased with time-weighted (p < 0.001) mean HbA1c. Also, Muller et al, 17 revealed in his study that men with an HbA1c of 7% or more had 15% (p < 0.004) and 29% (p < 0.003) lower serum PSA concentrations, respectively, than men with a normal HbA1c (< 6.1%). In our study, we did not have any data about the duration of diabetes so we could not observe the time-weighted effect of HbA1c on serum PSA levels. In  addition, in our study we found that prostate volumes of diabetic patients were significantly smaller than the control group. Our study demonstrated a greater impact of current HbA1c on serum PSA concentrations or prostate volume. There are several possible explanations for PSA being lower in men with T2DM than in those without, including greater obesity, more frequent use of medications to treat dyslipidemia, microvascular complications, which contribute to prostate ischemia, and lower serum androgen levels.
BMI and PSA levels have been investigated by Fowke et al 18 ; they found that mean PSA was approximately 22% higher among men with a BMI < 25 kg/m 2 compared with men with BMI > 35 kg/ m 2 . BMI may reflect increasing systemic estrogen levels via CYP19 (aromatase) conversion of androgens in adipocytes and hemodilution among obese men may cause negative correlation between BMI and PSA levels. 18 Also, patients with T2DM have a frequent occurrence of hypogonadotropic hypogonadism as reflected in low plasma concentrations of total testosterone. 19 We did not find any differences between the two groups in the terms of mean BMI and plasma total testosterone concentrations. Reduction in PSA with increased HbA1c was independent of BMI and total testosterone.
The influence of statin medications on prostate-specific antigen levels were investigated by Hamilton et al 20 ; after starting a statin, the median PSA decline was 4.1% (p < 0.001) that changes in PSA concentration were strongly associated with statin dose. Patients using medical treatments for diabetes or dyslipidemia mostly were included in studies that investigate the relationship between diabetes and serum PSA. 21,22 In our study, no patients were included in any group who use medication for diabetes or dyslipidemia and there were no differences between two groups in the terms of lipid profile.
The diabetic population is at high risk of developing microvascular complications including diabetic retinopathy, nephropathy, and neuropathy, which contribute to disabilities and high mortality rates in patients with DM. 23 Thus, in this study, an explanation for the detected low total PSA value and small prostate volumes in T2DM men with PGC might include local microvascular dysfunction and prostate ischemia. There is solid evidence suggesting that the prevalence of ED is much higher in diabetic men. 24 One of the most important mechanisms of diabetes-induced ED is penile vascular dysfunction. Numerous studies in diabetic humans found loss of endothelial cells, more stenosis in pudendal and iliac arteries, and high prevalence of penile arterial insufficiency. 25 The prostate and penis are located anatomically close together and they share the same artery and venous supply. 26 Thus, it is highly possible that prostate vascular function is disrupted by T2DM. As seen in this study, PSV values were lower in patients with severe PGC than nondiabetic patients. These results support the role of microvascular injury to determine the possible prostate vascular function disturbance and penile vascular dysfunction.
In this study, we found a very significant inverse correlation between HbA1c levels and plasma PSA levels. We also found an inverse correlation between HbA1c levels and prostate volumes. However, there were several limitations. Our study demonstrated a significant effect of current HbA1c on PSA, but long-term glycemic control as assessed by time-weighted HbA1c was not measured in this study. Finally, because there were few participants who had a PSA in the range sufficient for referral to biopsy (PSA 4.0 ng/mL), we were unable to evaluate the clinical significance of PSA suppression in prostate cancer detection.

Conclusions
Our results suggest that there is significant impact of severe PGC on serum PSA levels in type 2 diabetic men. Poor glycemic control of type 2 diabetes was associated with lower serum PSA level and smaller prostate volume. This relationship is independent of body mass index, age, or total testosterone concentration, which suggests that factors directly related to glycaemia may affect serum PSA levels. Further studies should be undertaken to elucidate the exact biological mechanism that exist between diabetes and prostate.

Conflicts of interest
All authors have no conflicts of interest to declare.