Abstract
Objectives: Erectile dysfunctions (EDs) are in part caused by hormonal causes; but in men over 65 years of age, testosterone deficiency seems to play an important role. However, in population of Polish men over 65 years of age with relative poor health status, the prevalence of testosterone deficiency in patients with ED is unknown. Material and methods: 286 men over 65 years of age with EDs were invited to complete an erectile function questionnaire (IIEF-5), as a diagnostic tool for EDs. Serum total testosterone (TT) levels were measured. Linear regression model was used to analyze the factors that are associated with testosterone deficiency. Results: The prevalence of testosterone deficiency was 17, 33, 42 and 57% for testosterone levels of less than 200, 250, 300 and 350 ng/dL, respectively. Only 47% patients had testosterone levels in the normal range (>350 ng/dL). The degree of ED was significantly higher in men with lowest testosterone levels (p < 0,002), and it was mild in 39.5% of cases, mild-to-moderate in 26.2%, moderate in 18.2% and severe in 16%. There was significant inverse relationship between age and TT (r = −0.3328, p < 0.05), IIEF-5 score and TT (r = −0.3149, p < 0.05) and IIEF-5 score and age (r = −0.3463, p < 0.05). The most common metabolic disorders were: obesity (68% in men with TT levels >350 ng/dL and 91% in men with TT levels <350 ng/dL) and dyslipidemia (54 and 95%, respectively). Obesity, age and hyperlipidemia all correlated with significantly decreased testosterone levels. Impaired fasting glucose did not affect the testosterone levels. Conclusions: Testosterone deficiency was very common in population of Polish men presenting with EDs and correlated negatively with age, obesity and dyslipidemia. These results can be associated with relative poor health status of Polish population.
Keywords::
Introduction
Accompanying the aging process are certain critical conditions that are often associated with decreased testosterone, such as decreased sense of well-being, depression, decreased libido and increased erectile dysfunction (ED). Moreover, metabolic disorders such as osteoporosis, loss of muscle mass or strength, metabolic syndrome and diabetes are often observed in aging males [Citation1]. The decrease of testosterone levels, associated with aging, is named late-onset hypogonadism (LOH) [Citation2] Probably, the most specific symptom of this process is ED. However, testosterone deficiency is linked to multiple causes of metabolic syndrome, as well as ED and may be a central factor in the pathology of ED [Citation3]. The decrease in serum androgen associated with aging in normal males is accompanied by a decline in testicular function, including lower serum testosterone and bioavailable testosterone and increased sex hormone binding globulin (SHBG). It is controversial, whether the age related decline in serum testosterone in men is universal.
EDs in aging males are often and depends on a complex interplay of pathopsychological, neurological, vascular and endocrine factors [Citation4]. Several studies show that aging in men is associated with decreased sexual interest and activity, particularly with an increased prevalence of ED; but there is considerable controversy on the relative importance of each factors in the initiation and maintenance of erection, especially the role of serum testosterone [Citation5]. Testosterone enhance libido, but a causal relationship between altered androgen levels and ED is still discussed [Citation6].
Moreover, management of LOH is difficult because there is no widely accepted low limit of normal testosterone levels. Guidelines from the Endocrine Society have defined LOH as a testosterone level of less than 200 ng/dL. These low levels must occur in conjunction with one or more of the signs and symptoms of hypogonadism [Citation7]. In contrast, the American Society of Andrology has stated that symptomatic men with reliable TT levels less than 300 ng/dL should be considered hypogonadal [Citation8]; and in recommendations of The International Society for the Study of the Aging Male (ISSAM), symptomatic, aged men with reliable testosterone levels less than 350 ng/dL can be considered hypogonadal [Citation2]. The prevalence of testosterone deficiency in men with ED has previously been reported from 7% to above 50% in various age group [Citation4]. However, these date are associated with overall health condition of studied population; and in European Eastern countries, prevalence of testosterone deficiency and EDs is probably higher.
As such, we evaluated the prevalence of low and low-normal testosterone levels in men presenting for an initial ED evaluation in population of Polish men over 65 years of age.
Material and methods
Our study included 286 men treated in Department of Endocrinology, Medical Centre for Postgraduate Education in Warsaw with a primary complaint of ED. Institutional review board approval had been previously obtained. We excluded patients with obvious preexisting conditions that strongly contribute to ED, such as diabetes mellitus, renal failure or a history of surgery in the pelvic cavity and, especially patients with insufficiency of hypophysis and primary hypogonadism. Cardiovascular disease (CVD) was defined as self-reported coronary artery disease, cerebrovascular disease, congestive heart failure or arrhythmia. Obesity is defined as a body mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or more. Hypertension and hyperlipidemia were considered to be present if the participant reported having received the diagnosis or if he was receiving medication for the condition. Impaired fasting glucose (IFG) was considered to be present if glucose fasting levels were ≥6.1 and <7 mmol/l.
Patient age was over 65 years (from 65 to 78 years; mean age 72.2 years). Sexual function was assessed according to the International Index of Erectile Function (IIEF-5). Possible scores on the IIEF-5 are 1–25, and EDs were classified into five categories based on the scores: severe, 1–7; moderate, 8–11; mild-to-moderate, 12–16; mild, 17–21 and none, 22–25. Blood samples were collected between 8:00 and 9:00 a.m. Endocrinological data including luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL) – using Immulite 2000; DPC United States kids, TT – using Coat-a-Coat; Siemens United States kids – were evaluated. TT, LH and FSH were measured by radioimmunoassay, and prolactin was measured by chemiluminescent immunometric assay. The normal value for testosterone in our laboratory is greater than 250 ng/dL (sensitivity: 4 ng/dL), for LH: 2–6 mIU/L (sensitivity: 0.05 mIU/mL), for FSH: 3–10 mIU/L (sensitivity: 0.1 mIU/mL) and for PRL: 12–24 ng/mL (0.16 ng/mL). Before statistical analysis, patients were divided into five groups according to cutpoints of testosterone levels: <250, <300, <350, <350 and >350 ng/dL and also divided into four groups of age.
Statistical analysis was performed using Statistica software. The p values were calculated using the Fisher’s exact test and Student’s t-test. Plus–minus values are means ± SD. All relationships were assessed by linear univariate and multivariate regression analysis to determine factors which affected the testosterone levels and to reduce bias in a cross-sectional study.
Results
A total of 286 men with ED were evaluated in the study. All men had their testosterone, LH, FSH and PRL levels checked at least once. Hormones levels are shown in . Of the 289 men, 49 (17%) had testosterone levels of less than 200 ng/dL, 95 (33%) less than 250 ng/dL, 121 (42%) less than 300 ng/dL and 164 (57%) less than 350 ng/dL. Only 122 men (43%) had testosterone levels above 350 ng/dL. shows the percentage of patients with specific testosterone levels compared with age (divided into: <65, 65–70, 70–75 and >75 years) for all cutpoints. We observed statistically significant differences of testosterone concentrations among all groups, except <65 years and 65–70 years group (p < 0.05) (). Pearson coefficients of age and TT showed a statistically significant inverse relationship (r = −0.3328, p < 0.05, ). The degree of EDs in all group was mild in 39.5% of cases, mild-to-moderate in 26.2%, moderate in 18.2% and severe in 16% (), and there were significant differences between group <65 and >75 years of age (p < 0,02). IIEF-5 score and TT showed a statistically inverse relationship (r = −0.3149, p < 0,05). Moreover, analysis of the variables IIEF-5 score and age showed a statistically significant negative relationship (r = −0.3463, p < 0.05).
Table I. Mean hormones levels and percentage of patients in five cutpoints of testosterone levels in men with erectile dysfunction.
Table II. Serum testosterone concentration in four age groups.
Table III. Degree of erectile dysfunction according to IIEF-5 scale in all group and in different ages.
Figure 1. The prevalence (%) of low and low-normal testosterone concentration in men with erectile dysfunctions in population of Polish men over 65 years of age.
In , we have presented the prevalence of tobacco use, hypertension, dyslipidemia, obesity and impaired fasting glucose levels in all patients with ED. The prevalence of each condition in all group, except tobacco use, was above 60%, and prevalence of obesity, hypertension, ischemic heart diseases and impaired fasting glucose levels was significantly higher in men with testosterone levels below 350 ng/dL compared with patients with testosterone levels more than 350 ng/dL (). The most common metabolic disorders were: obesity (68% in men with testosterone levels >350 ng/dL and 91% in men with testosterone levels <350 ng/dL) and hyperlipidemia (54 and 95%, respectively).
Table IV. Clinical characteristic of patients with ED in all group and in five cutpoints of testosterone levels.
There were also statistical significant negative correlations between the number of medications used by patients and testosterone levels and IIEF-5 score (r = −0.3613; p < 0.02 and r = −0.3749; p < 0.01, respectively). We also observed negative correlation between BMI and IIEF-5 score (r = −0.3143, p < 0.02) but not testosterone levels.
Multivariate linear regression analysis showed that obesity negatively correlated with TT levels with a mean decrease of 28 ng/dL per 1 kg/m2 increase in BMI score (p < 0.005). Moreover, age negatively correlated with testosterone levels with a mean decrease of 1.9 ng/dL for each year of additional age for men over 65 years of age (p < 0.002). Hyperlipidemia (high total or LDJ-cholesterol levels) also was negatively associated with decreasing TT levels (−0.19 and −0.21 ng/dL per 1 mg/dL increase in total and LDJ-cholesterol respectively p < 0.006). Impaired fasting glucose did not affect the testosterone levels (p = 0.1).
Discussion
We evaluated the prevalence of low and low-normal testosterone levels in men presenting for an initial ED evaluation in population of 286 Polish men over 65 years of age, and it was first performed in the relative large population of men in Poland.
We demonstrated that in our cohort of patients with ED, 57% men had testosterone levels less than 350 ng/dL and 47% less than 300 ng/dL. However, 33% men had testosterone levels less than 250 ng/dL, that is below low limit of normal for young, healthy men, when hypogonadism is diagnosed using only TT levels. These one-third of patients should be treated even when they do not suffer from any signs and symptoms of hypogonadism [Citation2], but all men had EDs and were not treated with testosterone replacement therapy. EDs seem to be the most specific and sensitive signs of late-onset hypogonadism in elderly men [Citation9]. The degree of ED according to IIEF-5 scale in all group was from mild in about 40% to severe in about 16% patients. IIEF-5 score and TT, and also IIEF-5 score and age showed a statistically inverse relationship.
The prevalence of testosterone deficiency among patients with EDs was significantly higher in our study than observed in previous studies. In the study of Köhler et al., the prevalence of androgen deficiency was 7, 23, 33 and 47% for testosterone levels of <200, <300, <346 and <400 ng/dL, respectively [Citation10].
EDs are the most important problem in elderly patients with symptoms of LOH. In the Massachusetts Male Aging Study, the prevalence of complete EDs tripled from 5 to 15% between subjects who were aged between 40 and 70 years [Citation11]. Today, it is well accepted that ED is related to aging and it is also believed that serum testosterone concentration decreases with age (about 1% per year) [Citation12,Citation13]. This process is related to aging and was significant in our patients. We observed statistically significant decrease of testosterone concentrations with age and inverse correlation between age and testosterone levels.
LOH is defined by ISSAM as a biochemical syndrome associated with increasing age, and it is characterized by specific signs and symptoms in combination with an unequivocally low TT level of less than 350 ng/dL and decreased levels of free testosterone [Citation1]. However, the Endocrine Society has defined LOH as an entity in which men have consistent signs and symptoms, as previously described, in combination with testosterone level of less than 300 ng/dL [Citation7]. The Polish Endocrine Society guidelines defined LOH similar to ISSAM guidelines [Citation14]. To date, no robust data sets have described of what prevalence of men with ED can be expected to meet these guidelines in Polish population of elderly men.
Only about 8–10% of ED is caused by hormonal causes; but in men ver 65 years of age, testosterone deficiency due to aging seems to play an important role [Citation4,Citation5,Citation15]. In population of Polish men with relative poor health status, the prevalence of testosterone deficiency in elderly men with ED is higher, than in other studies and higher than in other countries.
EDs are not always caused by LOH. In general, psychogenic, neurogenic and vascular factors, drugs, tobacco, alcohol and systematic diseases such as diabetes mellitus, hypertension, heart disease and renal failure also can cause sexual disorders, especially EDs [Citation16]. Endocrinological factors such as primary and secondary hypogonadism, LOH and hyperprolactinemia, as noted previously, are found only in about 8–10% of patients. However, co-morbidity and high prevalence of diseases such as hypertension, dyslipidemia, obesity and impaired glucose metabolism also play an important role in pathogenesis of ED, as they are involved in the process of atherosclerosis and decrease in testicular levels in elderly men. In our patients, we observed high prevalence of tobacco use, hypertension, dyslipidemia, CVD, obesity and impaired fasting glucose levels (over 60% for each condition except current smoking). There was statistical high prevalence of these diseases in men with testosterone levels below 350 ng/dL compared with patients with testosterone levels >350 ng/dL. The most common metabolic disorders were: obesity (68% in men with testosterone levels >350 ng/dL and 91% in men with testosterone levels <350 ng/dL) and dyslipidemia (54 and 95%, respectively). There was also significant negative correlations between the number of medications used by patients and testosterone levels and IIEF-5 score. We also observed negative correlation between BMI and IIEF-5 score.
Multivariate linear regression analysis showed that obesity, age and hyperlipidemia negatively correlated with TT levels in our study.
These results in our opinion showed significant influence of metabolic disorders and atherosclerosis on prevalence of EDs; however, these diseases also may be in part responsible for very high prevalence of testosterone deficiency in our cohort of Polish men over 65 years of age. So EDs may be only in part related to advancing age, but in part may be the symptoms of testosterone deficiency, which is very common in population of Polish elderly men. This high prevalence of LOH in this cohort may be on the other hand associated with relative poor overall health status in our population of men over 65 years of age.
So, if in Polish population erection dysfunctions are so closely connected with testosterone deficiency and with high prevalence of significant metabolic diseases and atherosclerosis, it seems that routine testosterone screening should be performed in all men presenting with ED. Our study results strongly justify this practice. Additional endocrine workup should be performed after hypogonadism has been demonstrated to determine its etiology. In the absence of modifiable etiologies and contraindications to treatment, testosterone replacement therapy can be initiated. Although some controversy still exists regarding the effectiveness of testosterone replacement therapy in hypogonadal men with EDs, many researchers have demonstrated improvement with erections and libido [Citation17].
There is now evidence that testosterone deprivation produces changes in the histological properties of penile structures, leads to loss of elastic fibers in the tunica albuginea and of smooth muscle fibers in the corpus cavernosum that were replaced by collagenous fibers in both structures [Citation18,Citation19]. This process of reducing trabecular smooth muscle content is reversible upon androgen replacement. It was found that testosterone replacement therapy in hypogonadal men leads to increase in muscle mass and decrease in fat mass [Citation20], and an explanation of this mechanism is that the mesenchymal pluripotent cells follow a myogenic lineage or adipogenic lineage depending on circulating levels of testosterone.
It was also found that intracavernosal pressure, expression of α1-adrenergic receptor and phosphodiesterase type 5 activity were dependent on testosterone. About a 50% reduction in circulating testosterone reduced intracavernosal blood pressure, also nitric oxide synthase activity in the corpus cavernosum probably is affected by adequate testosterone levels. The androgen receptors were found in the corpus cavernosum and play an important role in the regulation of phosphodiesterase type 5 expression in muscular and endothelial compartment of the corpus cavernosum [Citation21].
The effects of testosterone treatment on parameters of sexual functioning have been demonstrated [Citation22–24]; but it must be pointed that testosterone treatment is not always sufficient to restore erectile potency. In men with hypogonadism and EDs, after testosterone treatment, there was an improvement in erectile function only in the first month after reaching normal plasma testosterone, which subsequently declined in the following months of the follow-up [Citation25].
Many of the issues affecting its accuracy can be cited as weaknesses in our data set. Previous studies have demonstrated no association among TT and EDs [Citation5,Citation26]. The testosterone measurements were not repeated in our sample set, TT alone might not accurately describe the subject’s bioavailable or free testosterone and our study did not obtain the free testosterone or SHBG levels. So, our results might have overestimated the true prevalence of hypogonadism in our sample. It is also important to remember that our model in no way established a causal link between low testosterone and EDs; the two conditions might simply overlap and they have probably two separate pathophysiologic pathways.
Conclusions
Testosterone deficiency was very common in population of Polish men presenting with ED and correlated negatively with age and IIEF-5 score. This phenomenon may be in part associated with very high prevalence of CVD, obesity, hypertension, tobacco use and dyslipidemia. Clinicians should be aware of the testosterone deficiency in the population of the aging male, especially with EDs, and also should be keenly aware of the large overlap of patients with EDs who might also have LOH. Additional prospective studies evaluating the prevalence of LOH in men with EDs and the effect of testosterone supplementation in these patients are needed.
Declarations of Interest: This study was supported by research grant number 501-2-1-07-21/09 of the Medical Centre for Postgraduate Education, Poland.
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