==== Front Ann Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 1850018010.5144/0256-4947.2008.174asm-3-174Original ArticleSerum sex steroids, gonadotrophins and sex hormone-binding globulin in prostatic hyperplasia Ansari Mohammad Abdul Jalil abBegum Dilruba bIslam Fakhrul c a Section of Endocrinology, Central Hospital-Sakaka, Al Jouf, Saudi Arabia b Section of Endocrinology, Rajshahi Medical College, Livestock Research Institute, Dhaka, Bangladesh c Department of Urology, Bangladesh Medical College, Dhaka, BangladeshCorrespondence and reprints: Dr. Mohammad Abdul Jalil Ansari, Consultant Endocrinologist, PARAS Central Hospital Sakaka, Al-Jouf, Saudi Arabia, T: +966 557809063, +966 4 625 0771, ansariabduljalil@hotmail.comMay-Jun 2008 28 3 174 178 01 1 2008 Copyright © 2008, Annals of Saudi Medicine2008This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.BACKGROUND Benign prostatic hyperplasia (BPH) develops in elderly males when serum androgens are relatively lower than in healthy younger males, but it is not well understood whether and how sex steroids are altered in prostatic hyperplasia. It is also uncertain whether there is any change in sex steroid levels in males older than 40 years of age. The use of androgens in elderly males is often discouraged because of the probable worsening effect of androgens on prostatism. This study aimed to determine the relationship between prostatic hyperplasia and sex steroid levels and whether there is any significant change in these hormones after the age of 40 years. SUBJECTS AND METHODS We studied healthy males of age ≥40 years with (n=92) or without (n=93) clinical prostatic hyperplasia. Serum testosterone, estradiol, gonadotrophins and sex hormone-binding globulin (SHBG) were compared. The hormones and SHBG were also correlated with age. RESULTS No significant difference was found in any hormone in cases with prostatic hyperplasia as compared with the controls. There was no significant age-related change in any hormone except estradiol where as a negative correlation (P<.003) with age was found. CONCLUSIONS Serum sex steroids and SHBG remained unchanged in symptomatic prostatic hyperplasia and except for estradiol there was no significant age-related change in serum testosterone, gonadotrophins and SHBG in healthy males after the fourth decade. More studies are needed to confirm the age-related decline of estrogens in males. ==== Body The growth and development of the prostate gland is strongly influenced by androgens and their metabolites.1–2 Prostatic hyperplasia is the commonest disorder of the prostate in elderly males. Only minor ethnic or racial variation in its prevalence has been found. Though males start to have prostatic hyperplasia after the fourth decade of life, it is not known why some develop it earlier and some males do not develop it at all. However, the overall incidence increases with age3,4 and its prevalence reaches about 90% in men in their 80s, of whom only a proportion suffer from urinary symptoms. Medical and conservative treatments are used in management, but most patients eventually need surgery to get rid of the troublesome symptoms of prostatism. Until recently little has been known about the etiopathology and risk factors for this disease.5,6 Studies on the etiopathology and risk factors seem insufficient and are derived mainly from animal rather than human studies. Age is the only unmodifiable and established factor known so far, although androgens, estrogens and several intraprostatic factors are believed to be responsible for its development.1,7,8 Serum androgens in elderly males are significantly lower than in young males. Following a relatively sharp pubertal surge, androgens in males rise steadily followed by a slow decline in the mid-30s.9 After the 40s, the levels of androgens either remain constant or there is a slow decline with age. Though androgens, estrogens and their relative concentrations in the peripheral circulation are related to prostatic hyperplasia,10,11 it is not understood why prostatic hyperplasia develops in that period of life when serum androgens and probably estrogens in the peripheral circulation are relatively lower. Whether there is any change in androgens and other sex steroid concentrations in those who develop prostatic hyperplasia is also not clear. A few early studies reported increased androgens in prostatic hyperplasia but this was not reproduced in subsequent studies. For a long time it was commonly believed that androgens in the peripheral circulation can produce or worsen prostatic hyperplasia. Based on this assumption, use of androgens in elderly males is not encouraged despite clinical conditions where androgens are indicated, like partial androgen deficiency in aged males (PADAM).12,13 Recent studies on the etiopathology and risk factors of BPH have focused mainly on intraprostatic factors and have concluded that increased conversion of androgens to dihydrotestosterone (DHT) is mainly responsible for the development of BPH.7 As the main source of androgens to be converted to DHT comes from the peripheral circulation, it is important to find out whether there is any change in the sex steroid levels in prostatic hyperplasia. In addition, the age-related changes in those hormones after 40 years of age need to be examined. We conducted this study to determine whether there is any change in the concentration of sex steroids, sex hormone binding globulins and gonadotrophins in prostatic hyperplasia and also to determine to what extent these hormones change with age. SUBJECTS AND METHODS For this study, we selected 103 BPH cases and 102 well-matched healthy males without BPH as controls from the inpatient and outpatient departments of Bangabandhu Sheikh Mujib Medical University, Dhaka Medical College Hospital and Bangladesh Medical College, all located in the city of Dhaka, Bangladesh during 2003–2004. The study was completed by 92 cases and 93 control subjects aged 40 to 90 years. Voluntary consent was taken from each participant. The ethical clearance for this study was obtained from the ethical committee of the Bangladesh Medical Research Committee. The participants were without any major systemic illness and had not taken any drug within 6 weeks before collection of serum samples. Detailed medical and urological examinations were done on each subject before inclusion. The cases and controls were different only in having and not having BPH. The BPH cases had a prostatic volume ≥30 mL and the controls had a volume ≤25 mL as determined by abdominal ultrasonography. The International Prostate Symptom Score (IPSS) was >8 for the cases and 0 for the controls. The IPSS was determined from the results of the standard questionnaire on incomplete voiding, frequency, intermittency, urgency, weak stream, straining and nocturia under supervision of a urologist. All the questionnaires were converted to the local language.14 The clinical and laboratory characteristics of the cases and controls are shown in Table 1. Venous blood samples were collected from each subject at 8:30 to 9:30 AM, the serum separated and preserved at −40°C until laboratory analysis. Laboratory assays were done within 3 months of collection. Serum samples were assayed for total testosterone, estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) in the laboratory of the Popular Diagnostic Center, Dhaka. The reagents used were supplied by Diagnostic Products Corporation, 5700 West 96th Street, Los Angeles, USA. Each kit was supplied with instructions for hormone assay by IMMULITE 2000 Analyzer. The means of the different variables were compared between the cases and the controls by the unpaired t test and P value<.05 was considered significant. Correlations between the variables were determined by the Pearson’s correlation test. Data entry and statistical analyses were done by the software FOXPRO, SPSS release 6.0 and Excel. RESULTS No significant difference was found in the mean serum concentrations of total testosterone, estradiol, LH, FSH and SHBG between BPH cases and controls (Table 2). Combining the cases and controls, no significant correlation was found in testosterone, estradiol and SHBG with age. A significant negative correlation in serum estrogen concentration with age was found (P<.05) (Table 3). DISCUSSION We found no change in serum testosterone level in prostatic hyperplasia. This differs from earlier studies where raised androgen levels were reported in prostatic hyperplasia.10,11,15,16 This discrepancy is mainly due to differences in subject selection, laboratory analyses and methods of comparison adopted in those studies as compared to the present study. In one of these earlier studies by Vermeulen et al,11 where raised androgens were reported in prostatic hyperplasia, comparisons between the cases and controls were done by dividing the subjects into several small subgroups by age rather than comparing all the cases and controls together. Even in those subgroups, raised androgens were found only in the 70- to 80-year age group. In other age groups, from 40 to 70 years, no significant difference in androgen concentration was found that conforms well with our findings. The number of subjects in the age group where raised androgen was reported also seems too small. In other studies, the method of subject selection was such that asymptomatic BPH cases could not be excluded from the controls due to the unavailability of modern imaging techniques. For example, selecting cases and controls based on the presence or absence of lower urinary tract symptoms (LUTS) and digital rectal examination without measuring prostatic size by imaging technique seems insufficient to exclude or include prostatic hyperplasia. The laboratory methods for hormone assays were also less sensitive than those available now. Because of the fact that the presence or absence of LUTS cannot include or exclude prostatic hyperplasia with certainty, it is possible that there could be a few asymptomatic prostatic hyperplasia cases included within the control group in our study and this might have confounded our results. However, we considered that cases of LUTS with enlarged prostate, excluding prostatic carcinoma, are practically cases of prostatic hyperplasia. With this limitation in mind our comparisons were between symptomatic BPH cases to age-matched males without LUTS and a normal-sized prostate. In a recent study by Tan et al,17 it was concluded that the concentration of sex hormones plays little role in the clinical severity of BPH. In Tan et al, though free testosterone was found to be lower in clinical BPH than in controls, the estrogen to bioavailable testosterone ratio was found to be higher in clinical BPH. Total testosterone was found to be higher in clinical BPH only in those of age >70 years and there was no change in males of age <70 years. Vermeulen et al11 also found raised testosterone in BPH cases only in men 70 to 80 years of age. In the present study, comparisons were made taking all the cases and controls of all ages together as the number of subjects were not sufficient for age grouping. In addition, no obvious reason was found as to why the testosterone level in BPH cases was different only in the males within a particular age range i.e., >70 years. Liu et al18 and Rohrmann et al19 found no significant correlation of prostate volume or IPSS with circulating testosterone level in studies of different design. However, LUTS or BPH was related to other hormonal factors that appear complex. That the occurrence of clinical BPH is indifferent to circulating testosterone level was also found in a recent study by Marberger et al where clinical BPH was found to occur in elderly males with different baseline serum testosterone, ranging from low to high normal levels.20 Hammond et al21 reported the same results for androgen concentration as in our study. In fact most of the recent studies found no or only a weak change in serum testosterone concentration in prostatic hyperplasia. However, there could be other hormonal changes that have not been addressed in our study. Though a few studies reported an altered androgen-estrogen ratio in prostatic hyperplasia,22–24 we found no change either in absolute concentration of estradiol nor in androgen-estrogen ratio in prostatic hyperplasia, for which more studies are needed. The fact that no change in SHBG and gonadotrophins in prostatic hyperplasia was found in our study suggest that binding of the hormones and their pituitary regulations are also unchanged in prostatic hyperplasia. We also studied the correlations of different hormones and SHBG levels with age by combining both the cases and controls together. A significant negative correlation with age was found in estradiol concentration. For all other hormones and SHBG, no age-related change was found. There are few studies that support our finding of no change in serum testosterone and gonadotrophins with age. Most studies report a slow decline of androgens in aging males.25,26 In contrast to those studies where an age-related decline of androgens were reported,27–29 our subjects were healthy except that half had prostatic hyperplasia. Therefore, age-related declines in serum androgens are insignificant in healthy males older than 40 years according to our study. The probable explanation for this difference is that the studies reporting an age-related decline in androgens included males with associated chronic diseases that might have confounded the results. Diminished gonadotrophins and sex steroids due to chronic diseases are also reported in some studies.30,31 Despite a few reports indicating a slow decline of estrogen with age,32–34 a significant age-related decline in serum estradiol level as found in our study needs further study for confirmation. In our study, aged males were found to have a lower body mass index (BMI) (correlation of BMI with age −.15, P=.03 in our study). As peripheral conversion of androgens to estrogens depends on body fat content, a low BMI in aged males in our subjects could be the reason for the low estradiol concentration. In conclusion, from our study and most of the recent studies in this field, it seems there is no significant change in serum levels of testosterone, estradiol, SHBG and gonadotrophins in clinical prostatic hyperplasia as compared with age-matched asymptomatic males with a normal-sized prostate. In addition, after 40 years of age there is no significant age-related change in serum testosterone, SHBG and gonadotrophins in the males without any systemic disease. Age-related declines in serum estradiol need further study for confirmation. Acknowledgment We acknowledge the Bangladesh Medical Research Council and Opsonin Bangladesh for their financial support, the laboratory authorities of the Department of Biochemistry, Bangabandhu Sheikh Mujib Medical University, Popular Diagnostic Center, Department of Urology and Dhaka Medical College Hospital and Livestock Research Institute Mohakhali, Dhaka for their co-operation in this study. Table 1 Clinical and laboratory profile of cases and controls. BPH cases (n=103) Controls (n=102) Age (year) 65.39±0.86 63.28±0.80 BMI (kg/m 2) 22.38±0.38 23.23±0.316 Prostatic symptom score 14 28.11±0.53 - Volume of prostate (mL) 48.24±1.78 21.43±0.246 Pulse (rate/min) 80.53±0.83 78.00±0.673 Systolic blood pressure (mm Hg) 127.36±1.35 127.11±0.10 Diastolic blood pressure (mm Hg) 75.17±0.88 76.95±0.92 Serum creatinine (mg/dL) 1.100±0.02 1.13±0.015 Values are mean. Table 2 Serum gonadal hormones, gonadotrophins and sex hormone-binding globulin concentrations for BPH cases and controls. Hormonal/biochemical parameters BPH cases (n=92) Controls (n= 93) P value Total testosterone (nmol/L) 14.96±.51 14.23±0.69 .392 Estradiol (ng/L) 34.72±1.29 31.84±1.16 .100 SHBG (nmol/L) 58.06±2.54 54.95±2.75 .406 LH (mIU/mL) 6.61±0.38 6.67±0.38 .911 FSH (mIU/mL) 7.59±0.47 8.23±0.63 .419 Estradiol/testosterone ratio 2.75±0.24 3.13±0.38 .395 Values are mean±SEM Table 3 Correlations of sex hormones, gonadotrophins and sex hormone-binding globulin with age (n=185). Correlation coefficient P value Total testosterone −.0619 .403 Estradiol −.1544 .036 Luteinizing hormone .0250 .735 Follicle-stimulating hormone −.0429 .562 Sex hormone-binding globulin −.0867 .241 ==== Refs REFERENCES 1 Horton R Benign prostatic hypertrophy: A disorder of androgen metabolism Am J Geriatrics 1984 32 320 2 Wilson J The pathogenesis of benign prostatic hyperplasia Am J Med 1980 68 745 6155068 3 Guess HA Arrighi HM Metter EJ The cumulative prevalence of prostatism matches the autopsy prevalence of benign prostatic hyperplasia Prostate 1990 17 24 4 Guess HA Epidemiology and natural history of benign prostatic hyperplasia Uro clin North Am 1995 22 247 261 5 Grayhack JT Kozlowski JM Chung Lee The pathogenesis of benign prostatic hyperplasia: a proposed hypothesis and critical evaluation J Urolo 1998 160 2375 80 6 Meigs JB Mohr B Barry MJ Risk factors for clinical benign prostatic hyperplasia in a community based population of healthy aging men J Clin Epidemiol 2001 54 935 44 11520654 7 Mirone Vincenzo Fusco Ferdinando Verze Paolo Androgens and benign prostatic hyperplasia European Urology Suppl 5 2006 410 17 16650924 8 CarsonIII C Ritmaster R The role of dihydrotestosterone in benign prostatic hyperplasia Urology 2003 61 2 7 9 Stearns El Macdonell JA Kauffman BJ Decline of testicular function with age-hormonal and clinical correlates Am J Med 1974 57 761 4140691 10 Lynch AH Benign prostatic hyperplasia-from bench to bedside (editorial) J urolo 1998 159 1978 11 Vermeulen A De Sy W Androgens in patients with benign prostatic hyperplasia before and after prostatectomy J Clin Endocrinol Metab 1976 43 1250 1254 63468 12 Bhasin S Bagatell TJ Bremner WJ Issues in testosterone replacement in older men J Endocrinol Metab 1998 83 3435 48 13 Mass D Jochen A Lalande B Age related changes in male gonadal function. Implications for therapy Drugs aging 1997 11 45 60 9237040 14 Barry MJ Fowler FJ Jr O’Leary MP The American Urological Association Symptom Index for Benign prostatic Hyperplasia J Urol 1992 148 1549 57 1279218 15 Lagiou P Mantzoros CS Tzonou A Serum steroids in relation to benign prostatic hyperplasia Oncology 1997 54 497 501 9394847 16 Hayward SW Donjacour AA Thompson AA Cunha GR Endocrinology of the prostate and benign prostatic hyperplasia DeGroot JL Jonson JL Endocrinology Philadelphia WB Saunders 2001 2357 67 17 Tan MO Karabiyik I Uygur MC Serum concentration of sex hormones in men with severe lower urinary tract symptoms and benign prostatic hyperplasia Int Urol Nephrol 2003 35 3 357 63 15160539 18 Liu CC Huang SP Li WM Relationship between serum testosterone and measures of benign prostatic hyperplasia in aging men Urology 2007 70 677 80 17991536 19 Rohrmann S Nelson WG Rifai N Serum sex steroid hormones and lower urinary tract symptoms in Third National Health and Nutrition Examination Survey (NHANES III) Urology 2007 69 708 13 17445656 20 Marberger M Roehrborn CG Marks LS Relationship among serum testosterone, sexual function and response to treatment in men receiving dutasteride for benign prostatic hyperplasia J Clin Endocrinol Metab 2006 91 1323 28 16434455 21 Hammond GL Kontturi M Vihko P Vihko R Serum steroids in normal males and patients with prostatic diseses Clin Endocrinol (Oxf) 1978 9 2 113 21 81115 22 Grayhack JT Kozlowski JM Chung Lee The pathogenesis of benign prostatic hyperplasia: a proposed hypothesis and critical evaluation J Urolo 1998 160 2375 80 23 Mc Connell JD Prostate growth: new insights into hormonal regulation Br J Urol 1995 76 5 10 24 Weisher H Kreig M Benign prostatic hyperplasia - the outcome of age-induced alteration of androgen estrogen balance? Urologe 1997 36 3 9 9123678 25 Harman SM Tsitouras PD Reproductive hormones in aging men-Measurement of sex steroids, basal leutinizing hormone, and leydig cell response to human chorionic gonadotrophins J Clin Endocrinol Metab 1980 51 35 40 7189758 26 Ferrini RL Barrett-Connor E Sex hormones and age: A cross sectional study of testosterone and estradiol and their bioavailable fractions in community dwelling men Am J Epidemiol 1998 147 750 54 9554416 27 Swerdloff RS Wang C Androgen deficiency and aging in men West J Med 1993 159 579 85 8279155 28 Tenover JL Testosterone and the aging male J andrology 1997 8 103 106 29 Vermeulen A Androgens in the aging males J Clin Endocrinol Metab 1991 221 24 1856256 30 Moroz EV Verkhratsky NS Hypophyseal-gonadal system during male aging Arch Gerontol Geriatr 1985 4 1 13 9 3923957 31 Lewis JG Ghanadian R Chisholm GD Serum 5alpha-dihydrotestosterone and testosterone changes with age in man Acta Endocrinol (Copenh) 1976 82 2 444 8 946928 32 Ferrini RL Barrett-Connor E Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men Am J Epidemiol 1998 15 147 750 4 9554416 33 Simon D Preziosi P Barrett-Connor E The influence of aging on plasma sex hormones in men: the Telecom Study Am J Epidemiol 1992 135 783 91 1595678 34 Orwoll E Lambert LC Marshal LM Testosterone and estradiol among older men J Clin Endocrinol Metab 2006 91 1223 25 16601197