| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Urology (M.M.), University of Vienna, A-1090 Vienna, Austria; Department of Urology (C.G.R.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Department of Urology (L.S.M.), University of California, Los Angeles, School of Medicine and Urological Sciences Research Foundation, Los Angeles, California 90095; and Departments of Biostatistics (T.W.) and Clinical Development and Medical Affairs (R.S.R.), GlaxoSmithKline, Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Michael Marberger, Department of Urology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: uroldep{at}meduniwien.ac.at
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Objective: The objective of the study was to explore these relationships in a large cohort of men treated with dutasteride for BPH.
Design, Setting, Patients, and Outcome Measures: Among 4254 men with BPH participating in 2-yr placebo-controlled dutasteride trials, 27% had a pretreatment serum testosterone less than 300 ng/dl. These 1162 men were divided into seven groups based on their serum testosterone level (<150, 150–174, 175–199, 200–224, 225–249, 250–274, and 275–299 ng/dl) and compared with men with normal baseline serum testosterone (BST; 
300 ng/dl). Questionnaires were used to assess sexual function, prostate-specific antigen (PSA), and prostate volume to assess androgenic stimulation of the prostate and the American Urological Association Symptom Index to assess clinical responses.
Results: Although lower BST was associated with increased sexual dysfunction, this increase was not seen until BST was less than 225 ng/dl. There was no decrease in baseline PSA and prostate volume at low BST levels. Dutasteride was effective at decreasing PSA and prostate volume and improving BPH symptoms at all BST levels.
Conclusions: In men with BPH, the frequency of sexual dysfunction increases at serum testosterone concentrations less than 225 ng/dl. However, PSA and prostate volume were similar at all testosterone levels, explaining why BPH can occur in men that would otherwise be considered hypogonadal. The fact that dutasteride is also effective in men with normal and low testosterone levels suggests that the high levels of 5
-reductase and dihydrotestosterone in the prostate allow the development and progression of prostatic hyperplasia, even at low circulating testosterone levels.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Although the association between erectile dysfunction (ED) and aging is clear, no such correlation has been established between ED and testosterone level (4, 5). Indeed, in studies of testosterone replacement therapy, approximately 50% of men reported an adequate erectile response while still having a serum testosterone level below the lower limit of normal (3). Furthermore, the overall effect of androgen replacement therapy on sexual function in men with low serum testosterone appears to be variable, suggesting that, although some level of circulating testosterone is necessary for adequate sexual function, other factors are also important (3, 6). Similarly, the impact of variations in serum testosterone on prostate function remains to be fully elucidated.
Despite the observed decrease in testosterone levels with aging, serum dihydrotestosterone (DHT) remains relatively constant, supporting its role in the development of benign prostatic hyperplasia (BPH) (7). Furthermore, high levels of 5-reductase in the prostate may stimulate prostate growth, even at low circulating testosterone concentrations (8). DHT is synthesized from testosterone by 5-reductase, of which there are two isoenzymes, types 1 and 2. Treatment with dutasteride, a dual inhibitor of both 5-reductase isoenzymes, results in a reduction in median serum DHT levels by 93% at 2 yr, with 58% of patients achieving a 90% or greater decrease at 1 month (9). As such, dutasteride has been shown to treat BPH effectively, reducing prostate volume by 26%, improving symptom score by 4.5 U and urinary flow by 2.2 cc/sec, and reducing the risk of acute urinary retention by 57% and BPH-related surgery by 48% (2 yr results) (9, 10). However, to date, the impact of serum testosterone levels on the efficacy and tolerability of dutasteride in men with BPH has not been assessed.
This analysis of data from the dutasteride phase III BPH studies was therefore initiated to further assess the extent to which variation in testosterone contributes to sexual and prostate dysfunction. Given the recognized decline in serum testosterone among aging men, those who are most likely to suffer from BPH, the objective was also to assess the effect of treatment with dutasteride in men with BPH, according to baseline testosterone.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-blocker within 4 wk, or any use of a 5-reductase inhibitor were excluded.
A single blood sample for the evaluation of serum testosterone was drawn from all subjects at baseline. The time of day the samples were drawn was recorded to assess any influence this variable might have on interpretation of the results. Serum concentrations of testosterone were measured by PPD Laboratories (Richmond, VA) using solvent extraction followed by gas chromatography/mass spectrometry (PPD method MS57). Interassay coefficients of variation for standards of 3–750 ng/ml ranged from 4.8 to 12.9%. Serial dilutions of the testosterone standard paralleled the standard curve. Although the reference range for this assay has not been precisely defined, the mean morning testosterone level in this study (14 nmol/liter) is similar to age-matched mean levels determined by RIA in the Baltimore Longitudinal Study of Aging (11). Men with a pretreatment testosterone level of less than 300 ng/dl (10.4 nmol/liter) were divided into seven groups (<150, 150–174, 175–199, 200–224, 225–249, 250–274, and 275–299 ng/dl) and compared with men with a normal baseline serum testosterone (BST; 300 ng/dl).
Androgenic stimulation of the prostate was assessed by measuring prostate volume and PSA. PSA was measured using the Tandem-E immunoenzymetric assay (Hybritech Inc., San Diego, CA); intra- and interassay coefficients of variation were less than 5% and less than 6%, respectively.
The effect of serum testosterone levels on the clinical efficacy of dutasteride was evaluated by assessing changes in prostate volume and AUA-SI. Serum PSA and AUA-SI scores were evaluated at baseline and 1, 3, 6, 12, 18, and 24 months in all three studies. Prostate volume was measured by transrectal ultrasonography at baseline and 1, 3, 6, 12, and 24 months. The baseline and 24-month values were used for this analysis.
In one study (ARIB3003), gonadal function was assessed indirectly by measuring serum LH levels. LH levels were measured by a central laboratory using a validated immunochemiluminescence-based assay (ACS:180, Chiron Corp. Diagnostic, Walpole, MA) with a detection limit of 0.1 IU/liter. The reference range was 1.5–9.3 IU/liter. Interassay coefficients of variation were 6.5–9.0%.
The Sexual Function Inventory (SFI) was administered at baseline and yr 1 in two studies (ARIA3001 and ARIA3002; n = 2555 at baseline) to assess perceptions of problems associated with sexual drive, erection, or ejaculation (three items). The questions asked were as follows: "In the past 30 d, to what extent have you considered a lack of sex drive to be a problem?" "In the past 30 d, to what extent have you considered your ability to get and keep erections to be a problem?" "In the past 30 d, to what extent have you considered your ejaculation to be a problem?" Each question was scored on a 5-point scale, ranging from 0 to 4, with lower and decreasing scores indicating worse sexual function (12). Changes in SFI scores in response to dutasteride treatment were also assessed in these studies.
Statistical tests used to evaluate the relationships between baseline BST level and these variables, at baseline and after treatment, were as follows:
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A total of 4254 men entered the study program and were assessed at baseline. The mean age of participants, 91–92% of whom were Caucasian, was 66 yr. Twenty-seven percent of men enrolled in the studies had testosterone levels below the lower limit of normal for young men (300 ng/dl, 10.4 nmol/liter). There was no significant overall relationship between BST and age, although the mean age of men in the lowest BST category was at least 2 yr older than any other age category (Table 1
). A diurnal variation in BST was observed, with mean values between 394 and 420 ng/dl in the morning, decreasing to 351–395 ng/dl in the afternoon (Fig. 1). The lack of relationship between BST and age persisted when the analysis was restricted to men whose BST levels were drawn between 0700 and 1000 h (n = 897).
|
|
In men with normal BST (300 ng/dl), mean serum LH was 5.3 IU/liter. Lower levels of testosterone were associated with higher proportions of subjects with LH values below the lower limit of the assay normal range (P = 0.001) (Fig. 2). However, the proportion of men with a low LH did not increase significantly until testosterone was less than 250 ng/dl. The proportion of men with LH values above the upper limit of the assay normal range remained constant across all groups of men, with the exception of the lowest serum testosterone group, in which nobody had a high serum LH.
|
Lower levels of BST were associated with lower proportions of subjects who were sexually active (P = 0.004) and a higher prevalence of ED (P = 0.001) and lack of libido (P = 0.001). However, these effects were not observed until the testosterone level was less than 200 ng/dl for reduced sexual activity and less than 225 ng/dl for ED and lack of libido (Fig. 3, A–C). The mean SFI score for men with a normal BST was 6.8, and lower levels of BST were associated with slightly lower baseline SFI scores (P = 0.05) (Table 1
).
|
There were no significant differences in mean PSA across the range of BST categories. Levels ranged from 3.6 to 4.0 ng/ml, and there was no consistent pattern of correlation between PSA level and BST category. In contrast, lower levels of testosterone were associated with higher prostate volume (P = 0.006) and BMI (P < 0.0001) (Table 1). When both BMI and BST were included in the model to predict prostate volume, the contribution of BST was no longer statistically significant (P = 0.28) in contrast to BMI (P < 0.0001).
Relationship between serum testosterone and therapeutic response to dutasteride treatment
Among men with a normal testosterone level, the mean change in SFI in response to dutasteride was a reduction of 1.0 vs. a reduction of 0.3 points for placebo, at month 12. Subjects with lower BST within both treatment groups showed larger decreases in mean SFI from baseline (P < 0.05) (Fig. 4). The mean change in prostate volume at month 24 was a decrease of 25.2% for those treated with dutasteride, compared with an increase of 1.6% for placebo in those with normal BST. Slightly larger differences were noted between placebo- and dutasteride-treated subjects with lower BST (P < 0.05) (Fig. 5). The mean change in PSA at month 24 in dutasteride-treated subjects was a decrease of 52.0%, compared with an increase of 15% in those treated with placebo, in those with normal BST. Overall, percentage change in PSA at month 24 was similar across BST categories in the placebo group but slightly higher reductions in PSA for lower levels of BST were observed in the dutasteride group (P = 0.007). There was no correlation between baseline AUA-SI and BST (data not shown). Among men with normal BST, the mean change in AUA-SI at month 24 in response to dutasteride treatment was a decrease of 4.5 U, compared with a decrease of 2.3 U in men receiving placebo. Dutasteride was equally effective at improving AUA-SI at all BST levels (Fig. 6).
|
|
|
In men with normal BST, drug-related ED (as assessed by the investigator) occurred in 6.7% of the dutasteride group, compared with 4.0% of the placebo group. Analogous figures for decreased libido were 4.2 and 1.8% and for ejaculation disorders, 2.2 and 0.8%. There were no consistent differences (within or between treatment groups) in the incidences of drug-related sexual adverse events according to BST.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Although only a single BST was obtained in each subject, the robustness of the conclusions is supported by the large number of subjects in this study. There was a modest diurnal variation in BST, with levels in the afternoon being about 10% lower than in the morning. No attempt was made to adjust for the time of day of sampling because this would have minimal effect on the BST category into which subjects were placed. Interestingly, in this generally healthy BPH population, there was no evidence of a decrease in serum testosterone with age. This is important because otherwise any relationship between decreased BST and sexual dysfunction could be related to both BST and sexual function decreasing with age.
Neither unbound testosterone nor SHBG was measured in this study. In general, total and unbound testosterone correlate with each other; however, conditions such as obesity, which are associated with decreased SHBG, can selectively decrease total testosterone (11). This effect appears to explain the inverse correlation between prostate volume and BST. When BMI was included as a covariate in the analysis, BMI, but not BST, was a significant predictor of prostate volume. SHBG levels have also been shown to increase with age (11). Therefore, although in this study there was no relationship between total serum testosterone and age, it should be noted that an increase in SHBG levels might have masked a reduction in free testosterone with age.
In the present analysis, an increased incidence of sexual dysfunction was generally not observed until testosterone levels were less than 225 ng/dl, and absolute increases in the rates of sexual dysfunction were small. This indicates that serum testosterone levels below the lower limit of normal do not necessarily indicate symptomatic hypogonadism (14). Previous studies have shown that there does not seem to be a strong cause-and-effect relationship between serum androgen concentrations and erectile function; even in severely hypogonadal men, the erectile response is not always lost and testosterone treatment of hypogonadal men with ED does not necessarily restore lost erectile function (15). Indeed, different types of erection (nocturnal; in response to visual sexual stimulation; in response to sexual partner) may require different degrees of androgenic support (15). In addition, one study showed that erectile capacity may not be totally lost, even in cases of surgical or pharmacologic castration (16). Taken together, these observations suggest that serum testosterone, in isolation, is a rather poor predictor of sexual dysfunction in men with BPH and that testosterone levels are more likely to be only one component of a multifactorial pathophysiology.
The increased frequency of low serum LH seen in the present analysis suggests that, at least in some patients, the low testosterone levels observed reflect a true biological change. Serum LH is also considered low in men with reported normal values, as men with low testosterone levels would be expected to have elevated LH levels. During the studies included in this analysis, serum testosterone levels were not assessed so there was no evaluation of men with low serum testosterone levels unless requested by the patient’s physician as part of the standard medical care and therefore no investigation into the possible causes of hypogonadism. However, the high incidence of low serum LH revealed in the present analysis suggests that the etiology of the hypogonadism may be more commonly secondary to a hypothalamic/pituitary defect, rather than being a primary testicular disorder.
It is clear that many men with normal serum testosterone have sexual dysfunction and that many men with low serum testosterone do not. Furthermore, although one begins to see an increase in the incidence of LH levels below the lower limit of the assay normal range when the testosterone level is less than 250 ng/dl, an increase in sexual dysfunction is not seen until serum testosterone is less than 225 ng/dl. The results of these analyses also reveal that, based on serum PSA and prostate volume measurements, the prostate gland shows evidence of normal androgenic stimulation, even at testosterone levels less than 150 ng/dl, and that BPH can occur in men who would otherwise be considered hypogonadal. However, because this cohort of men was recruited based on the presence of symptomatic BPH in men with enlarged prostates and a serum PSA greater than 1.4 ng/ml, a selection bias is possible. If there is a group of men whose prostate function is more dependent on circulating testosterone levels, they would not have fulfilled the entry criteria for this study. However, these data are consistent with previously published studies showing that prostate volume and serum PSA do not correlate with serum testosterone (17, 18). These observations may reflect the fact that in the prostate, testosterone is converted to the more potent androgen DHT by high levels of 5-reductase, and it is the resultant high levels of DHT that enhance the androgen signal in the prostate (7, 8). Hence, one role of 5-reductase in the prostate may be to allow the prostate to function normally and undergo age-related growth, even in the presence of low circulating testosterone levels. As a consequence, despite the increasing prevalence of low serum testosterone levels among aging men, BPH is common. Furthermore, the beneficial effects of dutasteride on BPH could therefore be expected, even in men with low testosterone levels. The absence of a consistent pattern of treatment differences between dutasteride and placebo across the range of baseline testosterone levels evaluated in these analyses supports this hypothesis.
The 52 men with the lowest BST levels of less than 150 ng/dl behaved differently from the rest of the study population: they were slightly older; had larger prostates and a greater increase in prostate volume over time with placebo; and had higher BMI, greater incidence of ED, altered libido, lower SFI, and greater decrease in sexual function over time with placebo. These findings could be a manifestation of obesity-associated metabolic syndrome and are worthy of further examination in other data sets.
In conclusion, sexual function in men is partially dependent on serum testosterone, but many men have normal sexual function at low circulating androgen levels. Serum testosterone level is therefore a poor predictor of sexual dysfunction in men with BPH. On the other hand, androgenic stimulation of the prostate is largely independent of serum testosterone, at least in the range of testosterone levels examined in this study. This explains why BPH can occur in men who would otherwise be considered hypogonadal. By maximally inhibiting 5-reductase activity, dutasteride is effective at treating BPH, regardless of serum testosterone levels.
|
Footnotes |
|---|
Disclosure statement: M.M., C.G.R. and L.S.M. consult for and have received lecture fees from GlaxoSmithKline. T.W. and R.S.R. are employed by and have equity interests in GlaxoSmithKline.
First Published Online January 24, 2006
Abbreviations: AUA-SI, American Urological Association-Symptom Index; BMI, body mass index; BPH, benign prostatic hyperplasia; BST, baseline serum testosterone; DHT, dihydrotestosterone; ED, erectile dysfunction; PSA, prostate-specific antigen; SFI, Sexual Function Inventory.
Received August 30, 2005.
Accepted January 17, 2006.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
-reductase. Endocrinology 140:4509–4515-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 60:434–441[CrossRef][Medline]-reductase inhibitor dutasteride in men with symptomatic benign prostatic hyperplasia. Eur Urol 46:488–495[CrossRef][Medline]This article has been cited by other articles:
 |
|
 |
|
  O. Canguven and A. L. Burnett The Effect of 5 {alpha}-Reductase Inhibitors on Erectile Function J Androl, September 1, 2008; 29(5): 514 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Krassas, K. Tziomalos, F. Papadopoulou, N. Pontikides, and P. Perros Erectile Dysfunction in Patients with Hyper- and Hypothyroidism: How Common and Should We Treat? J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1815 - 1819. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
