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-Reductase Inhibition with Dutasteride and Finasteride on Semen Parameters and Serum Hormones in Healthy MenDepartment of Medicine (J.K.A., B.D.A., A.M.M., W.J.B.), Veterans Affairs-Puget Sound Health Care System (B.D.A., A.M.M.), and Geriatric Research, Education, and Clinical Center (A.M.M.), University of Washington, Seattle, Washington 98195; Department of Clinical Pharmacology (S.E.W., L.J.H., R.V.C.), GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709; and Department of Medicine (R.S.S., C.W.) and General Clinical Research Center (C.W.), Harbor-University of California, Los Angeles Medical Center, Torrance, California 90509
Address all correspondence and requests for reprints to: Dr. Richard V. Clark, Clinical Pharmacology-Metabolic Discovery Medicine, GlaxoSmithKline Research and Development, Five Moore Drive, 17.1356H, P.O. Box 13398, Research Triangle Park, North Carolina 27709-3398.
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Abstract |
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-reductase inhibitors (5ARIs) that dramatically reduce serum levels of dihydrotestosterone (DHT). Objective: Because androgens are essential for fertility, we sought to determine the impact of 5ARI administration on serum testosterone (T), DHT, and spermatogenesis.
Design, Setting, Subjects, and Intervention: We conducted a randomized, double-blinded, placebo-controlled trial in 99 healthy men randomly assigned to receive dutasteride (D; 0.5 mg) (n = 33), finasteride (F; 5 mg) (n = 34), or placebo (n = 32) once daily for 1 yr.
Main Outcome Measures: Blood and semen samples were collected at baseline and 26 and 52 wk of treatment and 24 wk after treatment and were assessed for T, DHT, and semen parameters.
Results: D and F significantly (P < 0.001) suppressed serum DHT, compared with placebo (D, 94%; F, 73%) and transiently increased serum T. In both treatment groups, total sperm count, compared with baseline, was significantly decreased at 26 wk (D, –28.6%; F, –34.3%) but not at 52 wk (D, –24.9%; F, –16.2%) or the 24-wk follow-up (D, –23.3%; F, –6.2%). At 52 wk, semen volume was decreased (D, –29.7%; F, –14.5%, significantly for D) as was sperm concentration (D, –13.2%; F, –7.4%, neither significant). There was a significant reduction of –6 to 12% in sperm motility during treatment with both D and F and at follow-up. Neither treatment had any effect on sperm morphology.
Conclusions: This study demonstrates that the decrease in DHT induced by 5ARIs is associated with mild decreases in semen parameters that appear reversible after discontinuation.
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Introduction |
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-reduction, resulting in the formation of the more potent androgen, dihydrotestosterone (DHT) (1, 2). During embryogenesis, DHT plays a specific and essential role in the development of the male reproductive tract (3). Whether DHT has a crucial function in the adult is unknown; however, DHT does act as the primary androgen in the prostate and hair follicles, actions that tend to accelerate benign prostatic hypertrophy (BPH) and androgenic alopecia (4).
Two isozymes of 5-reductase have been identified in humans (5). Type 2 5-reductase predominates in the reproductive tissues, genital skin, and epididymis, whereas type 1 is predominantly found in the skin, liver (6), and testes (7, 8). The 5-reductase inhibitor, finasteride, effectively inhibits type 2 5-reductase and thereby reduces circulating serum concentrations of DHT by approximately 70% without harmful effects on androgen-responsive end points, such as lipid metabolism, bone mineral density, or general health (9, 10, 11, 12, 13). As a result, finasteride has demonstrated efficacy and a favorable safety profile in large numbers of men for several years for the treatment of BPH (14, 15, 16, 17).
Dutasteride is a dual 5-reductase inhibitor that inhibits both isozymes of 5-reductase and has been approved for the treatment of symptomatic BPH in men with an enlarged prostate. Dutasteride administration causes a 90–95% reduction in serum DHT concentrations (18, 19). In men with BPH, this marked reduction in DHT production leads to a 25% reduction in prostate volume, improvement in symptoms, and a significant reduction in the risk of acute urinary retention and BPH-related surgery (20, 21, 22). It is less clear whether the greater DHT suppression resulting from inhibition of both isozymes of 5-reductase by dutasteride has important effects on other androgen-responsive tissues. Although androgens play a central role in the maintenance of spermatogenesis, the relative importance of T and DHT in spermatogenesis has not yet been fully established. If DHT does play a significant role in spermatogenesis, it is important to determine the level of DHT suppression required to achieve this effect. It is also currently unknown whether type 1 or type 2 5-reductase have specific roles in spermatogenesis.
Therefore, to ascertain the effect of DHT suppression mediated by either a selective or dual 5-reductase inhibitor on spermatogenesis, we conducted a randomized, double-blinded, placebo-controlled study of the effect of finasteride and dutasteride, relative to placebo, on semen parameters and serum levels of reproductive hormones.
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Subjects and Methods |
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Ninety-nine healthy men, 18–55 yr of age, were enrolled in seven centers in the United States. Healthy male volunteers under the age of 55 yr were recruited due to the greater variability in semen characteristics observed in older men (23). Subjects were free of clinically significant conditions as determined by history, physical examination, and clinical laboratory test results and had normal serum testosterone levels.
Subjects who had any significant laboratory abnormalities, an American Urological Association Symptom Index for prostate symptoms score greater than 8, or a history of a vasectomy were excluded from the study. Inclusion criteria for semen parameters on baseline semen analyses were semen volume greater than 1.5 ml, total sperm count greater than 45 million, sperm concentration greater than 30 million/ml, motility greater than 50% (total percent motile sperm), and morphology greater than 10% by strict criteria. These values were purposefully selected to be higher than the lower limit of the normal ranges to allow for some decrease to occur (25–30%) yet still remain within the normal range (Table 1
). Subjects were excluded from participation if they were using any of the following medications: finasteride, dutasteride, saw palmetto, anabolic steroids, estrogen, corticosteroids, spironolactone, cimetidine, tamsulosin, terazosin, or doxazosin. Male-pattern baldness was not an exclusion criterion.
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All subjects gave informed consent before study participation, and the investigational review boards for human studies approved this study at all sites.
Study design
This was a randomized, double-blinded, double-dummy, placebo-controlled, comparative, parallel-group, multicenter study in healthy male subjects. Subjects who met inclusion criteria were randomized by a predetermined schedule with a block size of three to receive one of the following treatments for 52 wk: 1) dutasteride (0.5 mg) daily plus placebo finasteride daily; 2) finasteride (5.0 mg) daily plus placebo dutasteride daily; or 3) placebo dutasteride and placebo finasteride daily. To assess the full effects on the seminiferous epithelium, subjects received study drug for 1 yr, allowing for at least four cycles of spermatogenesis to occur.
Study drugs were overencapsulated so that placebo, dutasteride, and finasteride appeared the same and were administered, orally, once daily for 52 wk.
Blood samples for serum T and DHT and other hormones were collected at screening, wk 0 (baseline), 8, 24, and 52 and 4, 8, 12, and 24 after treatment. Blood samples were allowed to clot at room temperature for 30 min and then centrifuged at a minimum of 1000 x g for 15 min. Serum was stored in a freezer set at –70 C and shipped to a central laboratory for analyses.
Subjects provided three semen samples over 2-wk intervals during the baseline phase before drug administration and again at 26 and 52 wk of active treatment and at 24 wk of follow-up. In addition, a single semen sample was obtained at 8 wk of treatment as an extra safety measure to ensure no unexpected, clinically significant effects on semen parameters occurred that would warrant subject withdrawal or study discontinuation. Semen samples were collected at least 48 h after the time of last ejaculation. Results from the three samples for each interval were averaged to minimize the variability usually seen with serial measurements in a single individual (24, 25, 26).
Measurements
Semen samples were assessed for volume and then analyzed for sperm count, sperm concentration, and motility by computer-assisted semen analysis (Hamilton-Thorn IVOS, Beverly, MA) (27). Sperm count was facilitated using a fluorescent dye (27). All sites had validated andrology laboratories and performed their own quality control procedures. For morphological analyses, a smear was made with a drop of semen placed on a microscope slide, fixed, and sent to a central site for analysis by one of the authors (C.W.). Sperm morphology was assessed using the strict (Tygerberg) criteria (28). These criteria are based on microscopic high-power evaluation of 200 sperm for intactness of membranes of acrosome, head, neck, midpiece, and tail. Using this method, more than 7% of sperm with intact membranes is considered normal.
Serum DHT levels were measured by a validated gas chromatography/mass spectrometry assay, and serum T levels were measured with a validated, solid-phase RIA method. Both of these procedures were performed at a central laboratory as described previously (18). SHBG was measured by a RIA (Delphia; Wallac Oy, Turku, Finland). The sensitivity of this assay was 0.2 nmol/liter, the interassay variation for low, mid-, and high pools was 13.1, 10.6, and 6.8%, respectively, and the intraassay variation was 3.8, 1.7, and 2.2%, respectively. The normal range was 3.2–47 nmol/liter. Serum estradiol was measured by a RIA (Delphia, Wallac Oy). The sensitivity of this assay was 5.5 pmol/liter, the intraassay variation was 5.6 and 5.3% for mid- and high-range values, respectively, and the interassay variation was 7.0% (mid range), and 8.9% (high range). Serum FSH and LH were measured in the Delfia fluoroimmunometric assay (Wallac Oy). The sensitivity of the Delfia assay for FSH was 0.016 IU/liter with an intraassay coefficient of variation of 2.5% and an interassay coefficient of variation of 4.0%. The sensitivity of the Delfia fluoroimmunometric assay for LH was 0.018 IU/liter with an intraassay coefficient of variation of 2.8% and an interassay coefficient of variation of 5.0%.
Statistical analyses
Power calculations were based on the estimated variability for each semen parameter and the magnitude of change in that parameter that was considered to be clinically significant. These values were determined by the study investigators before initiation of the study (Table 1
). The values were designed to be conservative and were derived from human studies comparing semen parameters of fertile and infertile men and changes induced by male hormonal contraceptives, using impairment of fertility as the standard (29, 30). Based on these assumptions, a sample size of 24 subjects in each group provided the power to detect clinically significant differences between treatment groups.
Because increases in semen parameters were not anticipated, comparisons of semen parameters were performed using one-sided hypothesis testing. Total sperm counts (millions), sperm concentrations (million per milliliter), and semen volume (milliliter) were natural log transformed before analysis (31). Measurements of sperm motility (percent motile) and morphology (strict percent normal) were normally distributed and were analyzed without transformation. Model assumptions for this were thoroughly checked through residual analysis. Data were analyzed using ANOVA program (SAS, version 8; SAS Institute, Cary, NC). The analysis model consisted of treatment, baseline, center, and method. Least square means or geometric least square means and a pooled median baseline were used in determining the percentage change from baseline. For all comparisons, P < 0.05 was considered significant. Standard diagnostic tools were used to check assumptions of the models, with formal testing of the residual normality.
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Results |
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Ninety-nine subjects were randomized at baseline to receive dutasteride (0.5 mg) (n = 33), finasteride (5 mg) (n = 34), or placebo (n = 32). There were no significant differences in any baseline characteristics among the study groups (Table 2). Twenty-eight subjects in the dutasteride group, 21 in the finasteride group, and 24 subjects in the placebo group completed both the 52-wk treatment phase of the study and the 24-wk follow-up phase. Twenty-three subjects withdrew from the study prematurely after randomization. Reasons for discontinuation were withdrawal of consent (13 subjects), adverse events (AEs) [six subjects with AEs and one subject with a serious AE (SAE)], lost to follow-up (two subjects), and studies performed off schedule (ended 1 month early, one subject). Of the seven subjects who withdrew due to AEs, two were on placebo (impotence, mood swings), two were on dutasteride (impotence with decreased volume of ejaculate, decreased libido), and three were on finasteride (decreased libido, gynecomastia, and mental status change; the latter was regarded as an SAE by the site investigator). All these AEs were regarded as mild except for the one SAE, which was listed as moderate.
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Mean baseline serum DHT concentrations were not significantly different among groups at baseline (Table 2). There was little change in the serum DHT levels of the placebo group during the study. Both the dutasteride and finasteride treatment groups showed marked and significant reductions in serum DHT concentration at each visit up to wk 52 (Fig. 1A). The mean reductions in serum DHT levels from baseline at 26 and 52 wk were 93.8 and 93.3% in the dutasteride group, and 70.3 and 72.7% in the finasteride group, respectively (P < 0.001 for dutasteride vs. placebo, baseline, and between finasteride and dutasteride, P < 0.05 for finasteride vs. placebo). During the follow-up period, serum DHT concentrations returned to baseline in both the dutasteride and finasteride groups, although the recovery was somewhat more rapid in the finasteride group (at 8 wk vs. 12 wk follow-up).
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). Significant increases in serum T levels of about 25% were observed in both the dutasteride and finasteride treatment groups 8 wk into treatment (Fig. 1B). Thereafter, serum T levels were nonsignificantly elevated throughout the treatment period in the finasteride group, compared with baseline, whereas there was little change in the serum T levels of the dutasteride group from baseline after wk 26; the placebo group was stable throughout. Serum T levels in the finasteride group returned to baseline between wk 4 and 12 of the follow-up period and were at baseline in the dutasteride group at end of treatment and thereafter.
There were no significant changes from baseline or among treatment groups in serum gonadotropins, estradiol (Fig. 1, C–E), or SHBG (data not shown).
Semen parameters
Mean total sperm count, sperm concentration, semen volume, sperm motility, and sperm morphology did not significantly differ between treatment groups at baseline (Table 2).
After 24–28 wk of treatment, the mean total sperm count was significantly reduced from baseline, compared with placebo, by 34.3% in the finasteride group (P = 0.004) and 28.6% in the dutasteride group (P = 0.013) (Table 3 and Fig. 2A). After 52 wk of treatment, the reductions in total sperm counts from baseline with treatment were no longer statistically significant. After 20–24 wk follow-up, the reductions were even smaller. Three subjects demonstrated a decline in total sperm count to less than 10% of baseline at 26 or 52 wk of therapy: one subject on finasteride at 26 and 52 wk, one on dutasteride at 26 and 52 wk, and one on dutasteride at 52 wk only. At the 24-wk follow-up, these three individuals had recovered to 18.8, 28.3, and 32.5%, respectively, of their baseline values. None of the baseline laboratory values or semen parameters for these individuals distinguished them from other subjects.
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and Fig. 2B).
Mean sperm concentration remained relatively constant in each of the treatment groups throughout the study (Table 3 and Fig. 2C). The exception was in the finasteride group at wk 26, when mean sperm concentration was decreased significantly by 21.5% (P = 0.03). Individual subject data showed that two subjects had sperm concentration less than 20 million/ml (dutasteride, 12.0 million/ml after 52 wk of treatment, recovering to 29.2 million/ml at 24-wk follow-up; placebo, 19.3 million/ml at 26 wk follow-up, with values of 42.6 million/ml and 36.9 million/ml at 26 and 52 wk of treatment).
Small but statistically significant reductions in mean sperm motility of 6–12% from baseline were observed in both the dutasteride and finasteride groups, compared with the placebo group at all time points during treatment and follow-up (Table 3 and Fig. 2D). Sperm morphology was not significantly changed with either finasteride or dutasteride (Table 3 and Fig. 2E).
AEs
The total number of AEs was similar in the three treatment groups (Table 4). The most common AEs, reported by 10% or more of subjects in any one treatment group, were common cold, headache, gynecomastia, upper respiratory tract infection, decreased libido, and influenza.
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Discussion |
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-reductase inhibitor has a mild negative impact on spermatogenesis in normal men. This is true using a selective inhibitor, finasteride (inhibiting predominantly the type 2 isozyme of 5-reductase) or a dual inhibitor, dutasteride (inhibiting type 1 and type 2) at their respective therapeutic doses. The average effect on spermatogenesis in normal men appears limited because group means did not fall below preestablished thresholds for clinical significance for total sperm count, sperm concentration, semen volume, sperm motility, and sperm morphology, except for one time point for total sperm count (finasteride at 26 wk). However, statistically significant decreases from baseline were also observed for total sperm count at 26 wk for dutasteride, semen volume at 26 wk for finasteride, and at 26 and 52 wk of treatment and 26 wk of follow-up for dutasteride, for sperm concentration at 26 wk of treatment for finasteride, and for sperm motility for both compounds at all time points. No significant changes were observed for sperm morphology.
Some individuals (approximately 5% of the subjects on active treatment) demonstrated greater sensitivity to the effects of 5-reductase inhibition, with decreases in total sperm count to less than 10% of their baseline values during treatment.
These findings are in contrast to a previous study that concluded that finasteride had no effect on spermatogenesis (32). However, the dose of finasteride used in this previous study was 1 mg, the dose recommended for treatment of alopecia and one fifth of the dose used in the current study, 5 mg, which is the dose recommended for treatment of BPH. Genetic differences between subjects, such as polymorphisms in 5-reductase, which have recently been associated with sperm concentration, may also contribute to the intersubject variability (33).
The impact of these compounds on fertility is unclear, especially because average sperm concentrations decreased only slightly, remaining above 20 million/ml in all but two subjects, one on dutasteride and one on placebo. A recent study suggested that sperm concentrations greater than 12 million/ml are adequate for normal fertility (30). In addition, there are several reports of unexpected pregnancies in partners of men participating in male contraceptive trials, in which sperm concentrations are commonly less than 5 million/ml (34). There was a small (approximately 10%) decrease in sperm motility throughout the study in both the dutasteride and finasteride groups, but the clinical significance of this is unclear and may be minimal. Sperm morphology was unchanged by treatment. The differential effects on sperm motility and morphology suggest no effect on sperm formation but a possible effect on the epididymis in which sperm motility is developed (35). Further investigation into the exact site and mechanism of action underlying the effects of 5-reductase inhibition on spermatogenesis is merited.
Recovery toward baseline was observed for total sperm count, sperm concentration, and semen volume at the follow-up evaluation 24 wk after drug discontinuation. This was more evident in the finasteride group, and this may be related to the shorter half-life of finasteride, compared with dutasteride (36). Both compounds substantially reduced mean DHT levels from baseline, finasteride by 72.7% and dutasteride by 93.4%. These findings, in agreement with previous dutasteride studies, suggest that T alone may be sufficient to maintain qualitatively normal spermatogenesis in most normal men (37). This is also supported by analyses of individuals with congenital type 2 5-reductase deficiency. In nine men with this condition, the semen was characterized by low volume and high viscosity, but two individuals had normal sperm concentrations, and one demonstrated a normal sperm count, whereas the others were severely oligozoospermic. The authors concluded that DHT does not play a major role in spermatogenesis, and the major lesions of congenital type 2 5-reductase deficiency were atrophy of the prostate and seminal vesicles, resulting in very low semen volumes (38).
Studies of drug effects on spermatogenesis are difficult for several reasons including: 1) the 72-d maturation period of sperm, from spermatogonium to ejaculated sperm so that onset of injury and time to recovery can both be delayed; 2) the inherent, large variability in semen parameters, even for a single individual; 3) the large range of normal semen values; 4) the variability of technique and consistency of analyses of semen parameters among different laboratories; and 5) the lack of specific guidelines for what constitutes clinically significant changes in a particular semen parameter or threshold values for impaired fertility (39, 40). Criteria for clinically significant changes must be fairly large because there is an enormous reserve of viable sperm in the normal semen sample. In addition, the guidelines for impairment of fertility are fairly broad, based on the correlation of semen parameters with declines in fertility rates below apparent threshold values.
These issues were addressed in the design of the study. The duration of drug exposure was 1 yr to allow at least four complete spermatogenic cycles to occur, so possible effects, even on early germ cells, could be assessed. To reduce intraindividual variability, subjects provided three semen samples over 2 wk at each of the major sampling points to allow calculation of a representative mean for each individual. Laboratory consistency was accomplished by use of the same, validated CASA system to allow a standardized approach for sperm count and sperm motility, and morphology was assessed at a single site. The predetermined values for mean changes from baseline that could be regarded as clinically significant were chosen to be conservative and were derived from human studies of male fertility and effectiveness of hormonal contraceptives, using impairment of fertility as the standard. As a result, the significant changes in semen parameters observed for both finasteride and dutasteride may not be associated with any impact on fertility in most men. However, the marked sensitivity of some individuals to these compounds could be of importance for some men with infertility and reduced semen quality while using these medications. Indeed, these compounds should be considered as possible etiological agents when evaluating men for infertility.
In conclusion, we have demonstrated that chronic administration of a 5-reductase inhibitor, either dutasteride or finasteride, has demonstrable modest effects on semen parameters in normal men including decreased total sperm count, semen volume, sperm concentration, and sperm motility but no apparent effect on sperm morphology. Partial to nearly complete recovery was observed during the follow-up period for total sperm count and semen volume. Of particular note, approximately 5% of individuals on active treatment showed dramatic declines in total sperm count during treatment, although they demonstrated recovery in the follow-up period. The overall impact of these findings on fertility is currently unknown. Nevertheless, the reduction in semen parameters observed with this class of drugs indicates that they should be considered when evaluating men for unexplained oligospermia, and clinical judgment should be exercised when these drugs are given to men who desire fertility.
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Footnotes |
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Disclosure Summary: J.K.A., C.W., R.S.S., B.D.A., A.M.M., and W.J.B. received grant support (1999–2001) for this study from GlaxoSmithKline (GSK). C.W., R.S.S., A.M.M., and W.J.B. consult for GSK. B.D.A. and A.M.M. have received lecture fees from GSK. S.E.W., L.J.H., and R.V.C. are employees of GSK and have equity interest in GSK.
First Published Online February 13, 2007
Abbreviations: AE, Adverse event; BPH, benign prostatic hypertrophy; DHT, dihydrotestosterone; SAE, serious AE; T, testosterone.
Received October 10, 2006.
Accepted February 1, 2007.
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References |
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-reduced androgens in men and hirsute women: role of adrenals and gonads. J Clin Endocrinol Metab 48:969–975-reductase: two genes/two enzymes. Annu Rev Biochem 63:25–61[Medline]-reductase inhibition in human benign prostatic hyperplasia. Eur Urol 37:367–380[Medline]-reductase. J Clin Invest 89:293–300[Medline]-reductase isozyme expression. J Clin Invest 92:903–910[Medline]-reductase type 1 and 2 isoforms by testosterone and FSH. J Endocrinol 176:393–403[Abstract]-reductase type 1 and type 2 mRNA along the human epididymis. Fertil Steril 69:1116–1121[CrossRef][Medline]-reductase inhibitor, on serum gonadotropins in normal men. J Clin Endocrinol Metab 75:484–488[Abstract]-reductase inhibitor) does not affect bone density and metabolism. Clin Endocrinol (Oxf) 37:432–436[Medline]-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial. J Urol 167:2105–2108[CrossRef][Medline]-reductase inhibitor. J Clin Endocrinol Metab 89:2179–2184-reductase inhibitor dutasteride is well tolerated in men with symptomatic benign prostatic hyperplasia. BJU Int 97:73–79; discussion 79–80[CrossRef][Medline]-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 46:488–494; discussion 495[CrossRef][Medline]-reductase type 2 polymorphisms on sperm concentration and motility. Int J Androl 29:414–420[CrossRef][Medline]-reductase inhibitors on the epididymis. Mol Cell Endocrinol 250:190–195[CrossRef][Medline]-reductase inhibitor. Curr Top Med Chem 6:405–421[CrossRef][Medline]-reductase inhibitor or gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 90:91–97-reductase-2 deficiency. J Clin Endocrinol Metab 79:409–414[Abstract]This article has been cited by other articles:
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  S. T. Page, J. K. Amory, and W. J. Bremner Advances in Male Contraception Endocr. Rev., June 1, 2008; 29(4): 465 - 493. [Abstract] [Full Text] [PDF]
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 J. K. Amory, T. F. Kalhorn, and S. T. Page Pharmacokinetics and Pharmacodynamics of Oral Testosterone Enanthate Plus Dutasteride for 4 Weeks in Normal Men: Implications for Male Hormonal Contraception J Androl, May 1, 2008; 29(3): 260 - 271. [Abstract] [Full Text] [PDF]
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