Prostatic disorders in acromegalic patients experience of a Brazilian

ARtIclE INFO _________________________________________________________ ___________________ Vol. 39 (3): 393-401, May June, 2013 doi: 10.1590/S1677-5538.IBJU.2013.03.13 IBJU | proStatic diSorderS in acromegalic patientS experience 394 be concordant with a higher risk of prostate cancer in the general population, and that high-normal serum IGFBP-3 levels are concordant with a lower risk (5-8). Published data suggest that the relationship between prostatic carcinoma and acromegaly is infrequent (9). Patients with acromegaly have an increased prevalence of prostatic disorders compared to age-matched healthy subjects. Increased size of the whole prostate, together with an elevated incidence of other structural changes, such as nodules, cysts, and calcifications were shown in a large proportion of patients (10,11). The presence of an enlarged prostate in acromegalic patients under 40 years suggests a possible role of GH-IGF-I axis on this gland growth (10,11). Only two studies evaluated the effects of acromegaly treatment on prostate volume (PV), and demonstrated that well controlled patients presented significant reduction in PV after treatment of acromegaly (10,12). The IPSS is a symptom index for benign prostatic hyperplasia (BPH), developed and validated by a multidisciplinary measurement committee of the American Urological Association (AUA) (13). The IPSS is widely used to evaluate the severity of urinary symptoms (14,15). Until today, there is no report of the use of IPSS in the evaluation of acromegalic patients. In a recent guideline for acromegaly management (16) there was no information about the BPH evaluation. The aim of this study was to evaluate the prostate of acromegalic patients through digital rectal examination, transrectal US and IPSS, comparing these results with a group of healthy men, above and below 40 years, and after one year of acromegaly treatment. MAtERIAlS AND MEtHODS Patients Forty acromegalic patients, aged 45.2 + 11.3 years (24-69 years), were recruited from the outpatient endocrinology clinic of the University Hospital Clementino Fraga Filho HUCFF, of the Federal University of Rio de Janeiro UFRJ, over a 24-month period. The diagnosis of acromegaly was based on the following criteria: 1) a lack of suppression of GH to below 1 ng/mL after oral administration of 75g glucose or 2) high serum IGF-I levels. Reasons for ineligibility included patients with previous treatment of prostate cancer or BPH. All subjects entered the study after obtaining written informed consent according to a protocol approved by the Ethics Committee of HUCFF. At baseline, 36 patients had active disease (10 were de novo patients) and four had acromegaly cure or control for less than one year before the inclusion in this study. Twenty-six patients were previously submitted to surgery, nine to radiotherapy and 25 to medical treatment with octreotide LAR and/or cabergoline. Hypogonadism, based on low testosterone levels, was present in 27 (67.5%) patients. Seventeen of these patients were not receiving testosterone as replacement therapy because of severe sleep apnea. As control group, thirty healthy and education-matched men were included. Fourteen of them were less than 40 years-old and were paired to the 14 acromegalic patients younger than 40 years. The other 16 were proportionally age-matched with the 26 acromegalics older than 40 years-old. Study design This study was composed of two parts: a) sectional study comparing patients (at baseline) with healthy controls; b) prospective, longitudinal study (at baseline and after one year of treatment). The study protocol included application of IPSS, digital rectal examination, measurements of GH, IGF-I, IGFBP-3, SHBG, prolactin, LH, FSH, total testosterone, total and free PSA levels and transrectal US, both at baseline and after one year of treatment for patients and on baseline for controls. The free testosterone and the bioavailable testosterone were calculated according to the Vermeulen’s formula (17). Urologic evaluation The IPSS is a survey composed of seven questions related to incomplete bladder emptying, urinary frequency, intermittency, urgency, weak stream, straining and nocturia. To each answer is attributed a value in scale (0-5 points), to a maximum of 35 points. A total score of 0-7 indicates mildly symptomatic; 8-19 moderately symptomatic; 20-35 severely symptomatic patients (13). This survey was validated to the Portuguese language in 1999 (18). IBJU | proStatic diSorderS in acromegalic patientS experience 395 The digital rectal examination was performed by the same urologist (LCDM). Hormone assays Serum GH, IGF-I, IGFBP-3, SHBG, prolactin, LH, FSH and total testosterone levels were determined by chemiluminescense immunometric assays. Total and free PSA serum levels were measured by electrochemiluminescense assay. The low detection limit of GH by the Immulite 2000 kit (DPCDiagnostic Products Corporation, Los Angeles, CA) is 0.01 ng/mL and its linear working range is 0.01-40 ng/mL. Standards are calibrated against the International Standard WHO 98/574. The intra-assay CVs at the respective concentrations of 1.7, 7.8 and 31.0 ng/mL are 5.3%, 6.0% and 6.5%, while the inter-assay CVs at 3.0, 9.3 and 18.0 ng/ mL are 5.7%, 6.2% and 6.1%, respectively. The low detection limit of IGF-I measured by Immulite 2000 kit DPC is 20 ng/mL and the intra and inter-assay CVs are 3.6 and 6.6%, respectively. The standards are calibrated against the first International Reference Reagent WHO 87/518 and IGF-I was expressed in mass units and age-related standard deviation scores (SD-scores). All serum samples were collected in the early morning after an eight-hour fasting period. Transrectal US Transrectal US was performed with a HDI 11XE, Phillips, 2008, using a 5.0-7.5 MHz transducer by the same radiologist (SAC). The prostate examination included the anterior-posterior (AP), transversal (T) and longitudinal (L) diameters, the morphology of boundaries, texture, the occurrence of calcifications and/or nodules, and the evaluation of seminal vesicles and bladder. Prostate volume was calculated by the elliptical shape volume formula (π/6 x APD x TD x LD). Prostate hyperplasia was defined as a PV exceeding 30 mL (19-21). Statistical analysis Analyses were performed by SAS System (version 6.11; SAS Institute North Caroline). The results were expressed as median (min-max). Comparisons between categorical variables were done by χ22 test and between numerical variables were carried out using the Mann Whitney test. Comparisons between related samples were done by Wilcoxon test. McNemar’s test was used to compare paired proportions. Correlations were sought by calculating the Spearman’s rank correlation coefficient. P values < 0.05 were considered statistically significant.


INTRODUCTION
Acromegaly is a rare disease caused by GH hyper secretion (1,2).It is well known that GH promotes a stimulatory effect on IGF-I and IGFBP-3.IGF-I stimulates cell proliferation (3), however, IGFBP-3 stimulates apoptosis (4).Therefore, it is not well established whether acromegaly is associated or not with increased relative risk for cancer development.
Several epidemiologic studies have suggested that high-normal serum IGF-I levels may Prostatic disorders in acromegalic patients experience of a Brazilian center _______________________________________________ Lívia L. Corrêa, Giovanna A. Balarini Lima, Suzana A. Cavallieri, Luiz Carlos D. de Miranda, Mônica R. Gadelha Service of Endocrinology, University Hospital Clementino Fraga Filho (HUCFF), Federal University of Rio de Janeiro (UFRJ) (LLC, GABL, MRG); Department of Urology, University Hospital Clementino Fraga Filho (HUCFF), Federal University of Rio de Janeiro (UFRJ) (LCDM) and Labs D'Or Laboratory and Imaging (SAC), Rio de Janeiro, RJ, Brazil be concordant with a higher risk of prostate cancer in the general population, and that high-normal serum IGFBP-3 levels are concordant with a lower risk (5)(6)(7)(8).Published data suggest that the relationship between prostatic carcinoma and acromegaly is infrequent (9).
Patients with acromegaly have an increased prevalence of prostatic disorders compared to age-matched healthy subjects.Increased size of the whole prostate, together with an elevated incidence of other structural changes, such as nodules, cysts, and calcifications were shown in a large proportion of patients (10,11).The presence of an enlarged prostate in acromegalic patients under 40 years suggests a possible role of GH-IGF-I axis on this gland growth (10,11).Only two studies evaluated the effects of acromegaly treatment on prostate volume (PV), and demonstrated that well controlled patients presented significant reduction in PV after treatment of acromegaly (10,12).
The IPSS is a symptom index for benign prostatic hyperplasia (BPH), developed and validated by a multidisciplinary measurement committee of the American Urological Association (AUA) (13).The IPSS is widely used to evaluate the severity of urinary symptoms (14,15).Until today, there is no report of the use of IPSS in the evaluation of acromegalic patients.
In a recent guideline for acromegaly management (16) there was no information about the BPH evaluation.The aim of this study was to evaluate the prostate of acromegalic patients through digital rectal examination, transrectal US and IPSS, comparing these results with a group of healthy men, above and below 40 years, and after one year of acromegaly treatment.

Patients
Forty acromegalic patients, aged 45.2 + 11.3 years (24-69 years), were recruited from the outpatient endocrinology clinic of the University Hospital Clementino Fraga Filho -HUCFF, of the Federal University of Rio de Janeiro -UFRJ, over a 24-month period.The diagnosis of acromegaly was based on the following criteria: 1) a lack of suppression of GH to below 1 ng/mL after oral administration of 75g glucose or 2) high serum IGF-I levels.Reasons for ineligibility included patients with previous treatment of prostate cancer or BPH.All subjects entered the study after obtaining written informed consent according to a protocol approved by the Ethics Committee of HUCFF.
At baseline, 36 patients had active disease (10 were de novo patients) and four had acromegaly cure or control for less than one year before the inclusion in this study.Twenty-six patients were previously submitted to surgery, nine to radiotherapy and 25 to medical treatment with octreotide LAR and/or cabergoline.Hypogonadism, based on low testosterone levels, was present in 27 (67.5%)patients.Seventeen of these patients were not receiving testosterone as replacement therapy because of severe sleep apnea.
As control group, thirty healthy and education-matched men were included.Fourteen of them were less than 40 years-old and were paired to the 14 acromegalic patients younger than 40 years.The other 16 were proportionally age-matched with the 26 acromegalics older than 40 years-old.

Study design
This study was composed of two parts: a) sectional study comparing patients (at baseline) with healthy controls; b) prospective, longitudinal study (at baseline and after one year of treatment).The study protocol included application of IPSS, digital rectal examination, measurements of GH, IGF-I, IGFBP-3, SHBG, prolactin, LH, FSH, total testosterone, total and free PSA levels and transrectal US, both at baseline and after one year of treatment for patients and on baseline for controls.The free testosterone and the bioavailable testosterone were calculated according to the Vermeulen's formula (17).

Urologic evaluation
The IPSS is a survey composed of seven questions related to incomplete bladder emptying, urinary frequency, intermittency, urgency, weak stream, straining and nocturia.To each answer is attributed a value in scale (0-5 points), to a maximum of 35 points.A total score of 0-7 indicates mildly symptomatic; 8-19 moderately symptomatic; 20-35 severely symptomatic patients (13).This survey was validated to the Portuguese language in 1999 (18).
The digital rectal examination was performed by the same urologist (LCDM).

Hormone assays
Serum GH, IGF-I, IGFBP-3, SHBG, prolactin, LH, FSH and total testosterone levels were determined by chemiluminescense immunometric assays.Total and free PSA serum levels were measured by electrochemiluminescense assay.
The low detection limit of GH by the Immulite 2000 kit (DPC-Diagnostic Products Corporation, Los Angeles, CA) is 0.01 ng/mL and its linear working range is 0.01-40 ng/mL.Standards are calibrated against the International Standard WHO 98/574.The intra-assay CVs at the respective concentrations of 1.7, 7.8 and 31.0 ng/mL are 5.3%, 6.0% and 6.5%, while the inter-assay CVs at 3.0, 9.3 and 18.0 ng/ mL are 5.7%, 6.2% and 6.1%, respectively.The low detection limit of IGF-I measured by Immulite 2000 kit DPC is 20 ng/mL and the intra and inter-assay CVs are 3.6 and 6.6%, respectively.The standards are calibrated against the first International Reference Reagent WHO 87/518 and IGF-I was expressed in mass units and age-related standard deviation scores (SD-scores).
All serum samples were collected in the early morning after an eight-hour fasting period.

Transrectal US
Transrectal US was performed with a HDI 11XE, Phillips, 2008, using a 5.0-7.5 MHz transducer by the same radiologist (SAC).The prostate examination included the anterior-posterior (AP), transversal (T) and longitudinal (L) diameters, the morphology of boundaries, texture, the occurrence of calcifications and/or nodules, and the evaluation of seminal vesicles and bladder.Prostate volume was calculated by the elliptical shape volume formula (π/6 x APD x TD x LD).Prostate hyperplasia was defined as a PV exceeding 30 mL (19)(20)(21).

Statistical analysis
Analyses were performed by SAS System (version 6.11; SAS Institute North Caroline).The results were expressed as median (min-max).Comparisons between categorical variables were done by χ 2 2 test and between numerical variables were carried out using the Mann Whitney test.Comparisons between related samples were done by Wilcoxon test.McNemar's test was used to compare paired proportions.Correlations were sought by calculating the Spearman's rank correlation coefficient.P values < 0.05 were considered statistically significant.
Prostate hyperplasia was not found in patients or controls under 40.Structural abnormalities found at US were: calcifications in one patient and one control (7% vs 7%, p = 1.0) and hyperechogenic foci suggesting corpora amylacea in 4 patients and 3 controls (28.6% vs 21.4%, p = 1.0).
Prostate hyperplasia was found in 12 patients and 2 controls.The frequency of BPH was significantly higher in the acromegalic population when compared with the control group (46.15% vs 12.50%, p = 0.015).Structural abnormalities were also more frequent in acromegalics: calcifications in 11 patients and one control (42.31% vs 6.25%, p = 0.018) and hyperechogenic foci suggesting corpora amylacea in 18 patients and 5 controls (69.23%vs 31.25%,p = 0.036).A uthricular cyst of 0.4 cm was found in one patient.

Comparison of the acromegalic patients under 40 years at baseline and after one year of treatment
The main characteristics of the acromegalic population under 40 years before and after treatment are presented in Table-3.
After one year of treatment, there was a significant reduction in GH (4.96 vs 3.28, p = 0.011).Biochemical control of acromegaly, based on random GH < 1 ng/mL and normal IGF-I ( 24), was achieved in five patients, two of them under 40 years, and the four patients initially considered cured/controlled at baseline, persisted with cure/control criteria.The inclusion of these four patients did not influence the outcomes of the research.No significant reduction in PV was observed after treatment (18.50 vs 18.50, p = 0.75) and there was no significant difference in the frequency of prostate hyperplasia (0% vs 7.14%, p = 0.50) neither in the frequency of structural ab-normalities found at transrectal US.The reduction in IPSS achieved borderline statistical significance (2.00 vs 2.00, p = 0.056).

Comparison of the acromegalic patients above 40 years at baseline and after one year of treatment
The main characteristics of the study population above 40 years before and after treatment are presented in Table-4.
After one year of treatment, there was a significant reduction in GH (4.92 vs 1.85, p = 0.015) and IGF-I (466.00 vs 362.50, p = 0.020) levels.Significant reduction in PV was observed after treatment (28.50 vs 25.50, p = 0.001), however there was no significant difference in the frequency of prostate hyperplasia (46.15% vs 30.76%, p = 0.43) neither in the frequency of structural abnormalities found at transrectal US.There was no reduction in IPSS (4.50 vs 4.50, p = 0.65).
The findings of digital rectal examination, both in acromegalics under and above 40 years, were in accordance with transrectal US.

DISCUSSION
There are three important studies in the literature, all of them European, reporting the prevalence of benign prostate hyperplasia and structural abnormalities in acromegalic patients  (10)(11)(12).Two of these studies compared acromegalics to age-matched healthy subjects (10,11).Until today, there is no report of the use of IPSS in the evaluation of acromegalic patients.
Although physiological development and growth of the prostate depend on testosterone and dihydrotestosterone (DHT), androgens action alone seems to be insufficient to explain prostatic diseases (22,25).The existence of important cross-talk among androgens, growth factors and IGF binding proteins at prostatic level has been suggested (26).Patients with acromegaly are an interesting population model to study the possible involvement of IGF-I in the development of prostatic diseases.In our study, the group of acromegalic patients above 40 years presented a higher proportion of BPH (46.15 vs 12.50%) and structural prostatic changes, such as calcifications and corpora amylacea, when compared to age-matched healthy men.Colao et al., in a study that included 30 acromegalics with active disease and a control group, demonstrated that the prevalence of BPH was significantly higher in the group of acromegalics (58% vs 26.6%) and structural abnormalities were shown in a large proportion of these patients (11).Probably, we found less prostate hyperplasia than Colao's group because our patients were younger.Nonetheless, these data suggest a possible role of GH-IGF-I axis on prostate growth.Only one study evaluated the effects of acromegaly treatment on prostatic disorders (12).This study included 23 acromegalics and evaluated PV and structural prostatic abnormalities before and after two years of acromegaly treatment with surgery and/or lanreotide.Considering the whole group of patients, there was no significant change in PV after two years of treatment (34.6 vs 32.5 mL, p = 0.3).However, when analyzing only well controlled patients (n = 16), there was a significant reduction in PV (29.3 vs 25.4 mL, p = 0.03).Regarding the eleven patients that presented BPH at baseline, four had PV < 30 mL at the end of the 2-year follow-up, all of them with controlled acromegaly.In our study, when we analyzed the acromegalics above 40 years, there was a significant reduction in the PV after one year of treatment (28.50 vs 25.50 mL, p = 0.001), independently of disease control.Of the twelve patients that had BPH at baseline, five presented PV < 30 mL at the end of the study and only one of them had the disease controlled.This finding suggests that a significant reduction in GH and IGF-I levels is sufficient to promote reversion of BPH, even though biochemical criteria of acromegaly control was not achieved.
It is well established that prostate enlargement starts approximately at the age of 40 (22).In a community-based group of 502 men aged 55 to 74 years without prostate cancer, the prevalence of BPH was 19% using the criteria of a PV above 30 mL together with a high IPSS score (15).Berry et al. (19) described that the PV in men aged 21 to 30 years is approximately 20 ± 6 mL.Analyzing our patients according to age, 14 (35%) were younger than 40 years-old and prostate hyperplasia was not found at baseline.Five out of 12 patients with prostate hyperplasia (41.6%) were aged from 40 to 50 years-old.Besides, our data shows that PV in acromegalics and the control group younger than 40 years-old is not different, however, IPSS score in the acromegalics is higher than in the control group.In contrast, probably there was no difference in IPSS score in acromegalics and the control group older than 40 years-old because at this age both groups are already exposed to the onset of urinary symptoms.This is the first report of the use of IPSS in the evaluation of acromegalic patients.