THE ROLE OF FREE TESTOSTERONE COMPARATIVE WITH TOTAL TESTOSTERONE IN MALE PATIENTS WITH ERECTILE DYSFUNCTION

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1 THE ROLE OF FREE TESTOSTERONE COMPARATIVE WITH TOTAL TESTOSTERONE IN MALE PATIENTS WITH ERECTILE DYSFUNCTION Porav-Hodade Daniel 1, Coman Ioan 2, Boja Radu M 1, Todea Ciprian 1, Georgescu Carmen 2, Crisan Nicolae 3, Feciche Bogdan 4 1 University of Medicine and Pharmacy Târgu-Mureş, 2 University of Medicine and Pharmacy Iuliu Haţieganu Cluj- Napoca, 3 Clinic of Urology, Municipal Hospital Cluj-Napoca, 4 Department of Urology, Satu Mare County Emergency Hospital Address for correspondence: Daniel Porav-Hodade Clinic of Urology, 1 Gheorghe Marinescu str, , Târgu Mureş [email protected] Tel: Received: Accepted: Med Con December 2012, Vol 7, No 4, Abstract Introduction: As men age, their testosterone levels steadily decrease and in a significant percentage of men. Our purpose was to determine if free testosterone is more sensitive that total testosterone in a prostate cancer screening program in patients with erectile dysfunction. Material and methods: We performed an endocrine screening in patients with erectile dysfunction during a prostate cancer screening program. All the patients answered the question: Do you think that you have any sexual problems (erection, libido, orgasm)? All patients who answered positively were included in the study. For all of these patients we performed free testosterone and total testosterone as a standard analysis. The normal range for total testosterone was considered 3-10 ng/ ml and 8-22 pg/ ml for free testosterone. Results: A total of 491 patients answered that they encountered some sexual problems. The average age was 63.2 years old (28-88 years old). Out of these 336 (68%) patients had low level of free testosterone, 122 (25%) patients were between normal range, and 33 (7%) patients had high level of free testosterone. Compare to that only 85 (17%) patients of the patients had low testosterone, 361 (74%) patients were between normal range and 45 (9%) patients were above normal range. Conclusion: The prevalence of low level of free testosterone is 4 times higher than the prevalence of low testosterone in patients with erectile dysfunction and we considered that free testosterone should replace total testosterone in the first line endocrine analysis in this group of patients. Keywords: erectile dysfunction, free testosterone, total testosterone, age. Introduction The high prevalence of erectile dysfunction with age, coupled with the decline in serum testosterone levels, led to the characterization of Late Onset Hypogonadism (LOH) of older men [1]. The main role of testosterone at the external genitalia level is the differentiation and development in the intrauterin period and then at puberty. At the sexually active adults testosterone is responsible for maintaining sexual desire. Testosterone circulates mainly linked by a hepatic globulin, sex hormone binding globulin (SHBG), under 2% of the circulating concentration of testosterone is represented by the free The Role Of Free Testosterone Comparative With Total Testosterone In Male Patients With Erectile Dysfunction 37

2 MEDICAL CONNECTIONS NUMBER 4 (28) DECEMBER 2012 testosterone, active fraction. Influence of total testosterone on sexual function variable, depending largely on the SHBG level. Instead free testosterone action is not influenced, acting directly at the cellular level through its active metabolite, dihydrotestosterone. Unlike females, male testosterone levels decrease happens slowly and gradually, over several decades, but the clinical relevance of this phenomenon is unclear. Gonadostat modifications to elderly men are to reduce the rate of production of testosterone in the endocrine component of the testis, with lower concentrations of free and total hormone, under increased liver production of sex hormone-binding globulin (SHBG) [2]. After 40 years of age, serum testosterone level falls by % per year, reducing the rate of nictemeral hormone secretion, and also the rate and amplitude of gonadotrop releasing hormone (GnRH) pulses which requires gonadostat reset so that 95% of the elderly hypogonadism are central [3]. Approximately 15-20% of elderly males fall within the criteria that define hypogonadism. Subnormal serum bioavailable testosterone levels correlate with the reduction of sexual behavior [4]. In accordance with WHO recommendations androgen substitution therapy is designed to provide plasma concentrations of testosterone as close to physiological [5]. Evaluation of plasma levels of total testostron is required to establish therapeutic behavior in patients with erectile dysfunction. Instead assessing free testosterone is optional. Erectile dysfunction is a disorder of the elderly closely correlated with hormonal changes. The aim of our study was to determine whether modifying the free testosterone level is more sensitive than total testosterone levels in patients with erectile dysfunction examinated in a screening program for prostate cancer and to demonstrate obligation free testosterone dosage, fraction which correlates much better with erectile dysfunction appearance. 38 Material and methods The only inclusion criterion was the presence of erectile dysfunction in the studied patients. These patients were not investigated on other endocrine diseases or other possible causes of erectile dysfunction. The total and free testosterone determinations were performed in a group of 491 patients with erectile dysfunction and were interpreted in terms of statistical values. All patients answered the question: Do you have sexual problems (erection, libido, orgasm)? All Table I. Normal values of total and free testosterone assays by ELISA methode. Total testostrone Free testosterone Low level <3 ng/ml <8 pg/ml Normal level 3-10 ng/ml 8-22 pg/ml High level >10 ng/ml >22 pg/ml patients who responded positively were included in the study. These for all patients were performed free and total testosterone dosage as a standard analysis. Normal value for total testosterone was considered 3-10 ng / ml and 8-22 pg / ml for free testosterone. Clinical data The patients were aged between 40 and 88 years, randomly selected from the group of patients who entered the above mentioned program for prostate cancer screening to which patients aged years with erectile dysfunction were added. All patients agreed to participate in this study. Hormone dosing Hormone dosage was done using ELISA (Enzyme- Linked ImmunoSorbant Assay). The goal of the ELISA method is to determine if a certain protein is present in the serum and if so, what its level is. We used ELISA to determine the level of antibodies present in the analyzed sample. Patients included in the erectile dysfunction screening were selected randomly for blood sampling for ELISA method analysis of total and free testosterone. The normal values for total testosterone and free testosterone are presented in Table I. Were statistically analyzed free and total testostron level at all patients age over 40 years. For patients under 40 years bacause their number is small (N=12) statistical analysis was performed for the whole group. Statistical methods included median, standard deviation, trend line. All patients with low total or free testosterone and who met criteria of Endocrine Society received replacement therapy with testostron. Results Clinical data Of the total of 491 patients with erectile dysfunction, 12 were under the age of 40 years. The group years age comprises 24 patients. In the years group were 134 patients. The most important group was the age group years with 178 patients. There were 116 patients aged years and 27 patients aged over 80 years. The age distribution of the studied group is show in the Figure 1. Porav-Hodade et al

3 MEDICAL CONNECTIONS NUMBER 4 (28) DECEMBER 2012 ORIGINAL ARTICLES ELISA determination For a proper analysis of the data and male hypogonadism, both the level of total testosterone and the level of free testosterone were measured, the latter representing 1-2% of total testosterone, but which is the biologically active fraction that influences sexual function itself. Total testosterone The number of patients who had low levels of total testosterone (TT) has remained relatively constant in all decades of age, only a percentage between 12-15% of patients having total testosterone deficiency. An exception is the group of pots over 80 years where approximately 40% of patients had testosterone deficiency. Elevated testosterone were found that less than 10% of patients, except for the age group below 39 years where 16% had elevations. On the statistical analysis of the entire group of patients (N=491) total testosterone levels showed a mean value of 5.39±3.08 ng/ml. Low values were recorded in 85 (17%) patients, normal in 361 (74%) and increased in 45 (9%) patients Free testosterone When assessing free testosterone level were completely different things. Low free testosterone was seen in 50% of patients in all age groups. Aproximtiv 68% of the total number of patients studied (N=491) had low testosterone. Frequency of patients with low free testosterone increases with age, so at the age group frequency is 55%, while at octogenarian patients is 73.9%. Elevated free testosterone were found in only 7% of all patients. On the statistical analysis of the entire group of patients (N=491) free testosterone levels showed an average of 9.25 pg/ml, with a standard deviation of pg/ml. Low values were recorded in 336 (68%) patients, normal in 122 (25%) and increased in 33 (7%) patients. Trend line equation confirms upward trend (Fig. 2). Discussions Ageing is associated with levels of testosterone that decrease gradually [6]. The International Consensus of Sexual and Erectile Dysfunction recommends that the diagnosis of hypogonadism be made only when changes are both clinical and paraclinical [7]. Aging correlates with reduced libido, erectile function and sexual satisfaction. Epidemiological studies confirm the increased prevalence of erectile dysfunction in the elderly. Thus, at the age of 30 erectile dysfunction Figure 1. Age distribution of the study group Figure 2. The frequency of patients with LOW level of free testosterone according to age groups The Role Of Free Testosterone Comparative With Total Testosterone In Male Patients With Erectile Dysfunction 39

4 MEDICAL CONNECTIONS NUMBER 4 (28) DECEMBER 2012 occurs in less than <1% of men, at the age of 45 in less than 3% and between years about 10% of the subjects examined complain of erectile dysfunction. At 65 the prevalence increases to 25% and at 80 years up to 75% of men exhibit some degree of erectile dysfunction. Age is an independent factor for erectile dysfunction, it increases the relative risk to 2.2 in men aged and 7.9 for those over 75 years. In addition to prevalence, age is accompanied by the worsening of the severity of erectile dysfunction, a tripling of the prevalence of complete form between 40 and 70 years of age [8]. Although there are certain standards on normal blood level of testosterone, the hormone necessary for normal erectile function varies from one person to the other. Some men may have normal sexual function even if the testosterone level is low [9]. In contrast, in patients with erectile dysfunction the dosage of testosterone is recommended for the screening for hypogonadism, so these patients may benefit from hormone replacement therapy [10]. The European Association of Urology Guidelines recommend testing total testosterone in all patients with erectile dysfunction [11]. Practical Guide of the Endocrinology Society makes several recommendations regarding the administration and contraindications of androgen replacement therapy. The main recommendations are the presence of characteristic symptoms of hypogonadism and low testosterone or in men with low testosterone also to improve libidoul. Also men with low testosterone levels and diminished sexual function requires administration of testosterone to improve erection. Not recommended or testosterone therapy is contraindicated in asymptomatic men with low testosterone, with breast or prostate cancer or value of prostate specific antigen (PSA)> 3 ng/ml or the hard nodule in the prostate without further investigation urological [12,13,14]. All patients in our study who met the inclusion criteria and no exclusion criteria received treatment for androgenic substitution. Our results reveal a significant difference between the levels of free and total testosterone in the studied patients. All patients in our study had erectile dysfunction, but according to European Association of Urology Guidelines only 17% of patients would benefit from treatment with testosterone, one with low testosterone. In fact 68% of patients should receive androgen therapy. On a group of 120 patients with erectile dysfunction Yavuz BB revealed a low level of testosterone at a rate of 23% of the men investigated, values close to those of our group [15]. In our group all patients presented 40 erectile dysfunction, but only 17% of them could have benefited from testosterone replacement therapy as indicated by the dosage guidelines regarding the dosage of total testosterone alone. Dosing instead free testosterone as well, which is in fact the circulating active form, almost two thirds of patients required testosterone replacement therapy. This raises the question whether in the guidelines on erectile dysfunction the indication of total testosterone dosage should be replaced by the dosage of free testosterone. Conclusion The prevalence of low level of free testosterone is 4 times higher than the prevalence of low testosterone in patients with erectile dysfunction. We considered that free testosterone should replace total testosterone in the first line endocrine analysis in this group of patients. Acknowledgements This paper is partly supported by the Sectorial Operational Programme Human Resources Development (SOP HRD), financed from the European Social Fund and by the Romanian Government under the contract number POSDRU We certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript. References 1. Ho CK, Beckett GJ. Late-onset malehypogonadism: clinical and laboratory evaluation. J Clin Pathol 2011;64(6): Bassil N. Late-onset hypogonadism. Med Clin North Am 2011;95(3): Mahmoud A, Comhaire FH. Mechanisms of disease: late-onset hypogonadism. Nat Clin Pract Urol 2006;3(8): Barkin J. Erectile dysfunction and low testosterone: cause or an effect? Can J Urol 2010;17(1): Stanworth RD, Jones TH. Testosterone for the aging male; current evidence and recommended practice. Clin Interv Aging 2008;3(1): Handelsman DJ, Zajac JD. Androgen deficiency and replacement therapy in men. Med J Aust 2004;180: Meuleman EJ, Hatzichristou D, Rosen RC, Sadovsky R. Diagnostic tests for male erectile dysfunction revisited. Committee Consensus Report of theinternational Porav-Hodade et al

5 MEDICAL CONNECTIONS NUMBER 4 (28) DECEMBER 2012 ORIGINAL ARTICLES Consultation in Sexual Medicine. J Sex Med 2010;7(7): Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151(1): AACE Male Sexual Dysfunction Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of male sexual dysfunction: a couple s problem update. Endocr Pract 2003;9: Morales A, Buvat J, Gooren LJ et al. Endocrine aspects of sexual dysfunction in men. J Sex Med 2004;1: Wespes E, Amar E, Montorsi F, Pryor J et al. Erectile dysfunction in EAU guideline 2005 update: Rhoden EL, Morgentaler A. Risks of testosteronereplacement therapy and recommendations for monitoring. N Engl J Med 2004;350(5): Curran MJ, Bihrle W 3rd. Dramatic rise in prostatespecific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 1999;53(2): Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ,Swerdloff RS, Montori VM; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95(6): Yavuz BB, Ozkayar N, Halil M, Cankurtaran M, Ulger Z, Tezcan E, Gurlek A, Ariogul S. Free testosterone levels and implications on clinical outcomes in elderly men. Aging Clin Exp Res 2008;20(3):201-6 The Role Of Free Testosterone Comparative With Total Testosterone In Male Patients With Erectile Dysfunction 41