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*FINASTERIDE
*TESTOSTERONE
Endocrinology Vol. 138, No. 3 871-877
Copyright © 1997 by The Endocrine Society

Articles

Androgen Metabolism in the Prostate of the Finasteride-Treated, Adult Rat: A Possible Explanation for the Differential Action of Testosterone and 5{alpha}-Dihydrotestosterone during Development of the Male Urogenital Tract1

Fredrick W. George

Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75235-8857

Address all correspondence and requests for reprints to: F. W. George, Ph.D., Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8857. E-mail: george02{at}utsw.swmed.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Previous work has clearly demonstrated that inhibition of 5{alpha}-dihydrotestosterone (DHT) formation in vivo is not as effective as total androgen ablation (castration) in causing involution of the prostate. It is likely that this is due to the fact that testosterone is partially effective in maintaining androgen action. To provide insight into this observation, the androgenic metabolites of testosterone, androstenedione, and 5{alpha}-DHT, were measured in prostate tissue and in blood of 5{alpha}-reductase inhibitor (finasteride)-treated adult male rats. Finasteride treatment caused a significant decrease in prostatic DHT levels and a profound increase in prostatic testosterone and androstenedione levels. Similarly, circulating DHT levels were decreased in finasteride-treated rats (0.02 ng/ml compared with 0.05 ng/ml seen in control rats), and circulating androstenedione and testosterone levels were significantly elevated in finasteride-treated animals compared with controls. The in vitro effects of finasteride were assessed on the metabolism of [3H]testosterone in a tissue-slice assays. In the prostate, the inhibition of 5{alpha}-reductase activity resulted not only in the decreased formation of 5{alpha}-reduced metabolites (primarily DHT and 5{alpha}-androstanedione), but also an increase in the 17-oxo metabolite androstenedione. In contrast, the tissues derived from the embryonic wolffian duct (seminal vesicle and epididymis) formed relatively low amounts of 17-keto steroids. Because DHT is a high affinity ligand for the androgen receptor and androstenedione shows very little, if any, affinity for the receptor, these studies suggest that 5{alpha}-reduction of testosterone may be a mechanism to amplify androgen action in urogenital tissues such as the prostate by preventing catabolism of testosterone to the inactive androgen, androstenedione, at the site of hormone action.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ALTHOUGH TESTOSTERONE is the principal androgen synthesized in testicular Leydig cells and circulating in the plasma of males, the active androgen in many, but not all, target tissues is the 5{alpha}-reduced metabolite of testosterone, 5{alpha}-dihydrotestosterone (DHT) (1). Different roles for testosterone and DHT in androgen action were originally suspected based on the results of androgen metabolism studies in urogenital tissues of embryos. These studies demonstrated that 5{alpha}-reductase activity was detectable in the fetal urogenital sinus before differentiation of the prostate and in the urogenital tubercle before differentiation of the penis and scrotum, but that DHT formation was not detectable in the embryonic wolffian duct until after differentiation of the seminal vesicle and epididymis is complete (2, 3). This concept that the action of two androgens are involved in differentiation of the male urogenital tract is substantiated by studies of patients with a rare form of male pseudohermaphroditism caused by the inability to form DHT at its site of action due to the absence, or inactivity, of the critical 5{alpha}-reductase enzyme (4). Patients are characterized by undervirilization of the external genitalia and prostate; however, virilization of the seminal vesical and epididymis occurs normally (5, 6, 7). These results, therefore, imply that DHT formation is not critical for virilization of the tissues derived from the fetal wolffian duct.

Although two androgens, testosterone and DHT, mediate separate androgenic effects in different target tissues, considerable evidence suggests that both bind to (8) and activate (9, 10) the same intranuclear androgen receptor protein. However, DHT has a much higher affinity for the androgen receptor than does testosterone (8, 11, 12).

There are two distinct genes that code for isoforms of steroid 5{alpha}-reductase in both the rat and the human (13). In the human, mutations in the gene that encodes the type 2 isoform of the enzyme cause the phenotype associated with 5{alpha}-reductase deficiency (14). In the rat, the type 2 enzyme is expressed predominantly in tissues of the male urogenital tract, whereas the type 1 enzyme appears to be ubiquitously expressed (15, 16, 17), suggesting that expression of type 2 enzyme in the rat is also the critical isoform of the enzyme for differentiation of the male urogenital tract. Indeed, treating pregnant rats with a pharmacological dose of the 5{alpha}-reductase 2 inhibitor finasteride during the time of embryonic sexual differentiation causes a phenotype in male offspring that is very similar to humans with 5{alpha}-reductase 2 deficiency (18).

Finasteride is primarily an inhibitor of the steroid 5{alpha}-reductase 2 enzyme (19) and is being promoted as a treatment for benign prostatic hyperplasia (20). The primary effect of finasteride on inhibition of the 5{alpha}-reductase activity has been well studied and characterized in detail, and there is no question that finasteride (or other 5{alpha}-reductase inhibitors) is effective in disrupting androgen action in the intact male rat (21, 22, 23, 24). However, the metabolic fate of androgenic steroids in peripheral target tissues when DHT formation is blocked is largely unreported. Herein are reported in vivo and in vitro studies of the effect of the 5{alpha}-reductase 2 inhibitor finasteride on testosterone metabolism in the urogenital tract of the male rat. The findings have important implications for understanding the physiology of androgen action and suggest a testable hypothesis to explain why two androgens (testosterone and DHT) are involved in virilization of the male urogenital tract at the time of embryonic sexual differentiation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
All experiments were conducted in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals. Male Holtzman-Sprague-Dawley rats weighing approximately 250 g were purchased from Harlan Laboratories, Inc. (Indianapolis, IN) and maintained in our animal resource center under controlled conditions of lighting (12-h light, 12-h dark cycle) and temperature (23 C) and were given free access to standard chow and water. In vivo experiments were done with four groups of rats: intact, intact treated with finasteride, castrated, and castrated treated with finasteride. Castrations were performed under ether anesthesia; finasteride was administered sc at a dose of 25 mg/kg BW/day for 7 days in 20% ethanol in triolein oil. Seven days of castration or finasteride treatment was chosen based on prior studies, although longer periods might have been advantageous (24). When castrated animals were treated with finasteride, the finasteride treatment was started on the day of castration. In vitro studies were done with tissues obtained from intact male rats and varying concentrations (0–1 µM) of the 5{alpha}-reductase 2 inhibitor finasteride.

Enzyme assays
5{alpha}-Reductase and 17ß-hydroxysteroid dehydrogenase (17ß-HSD) activities were measured in the same assay. Briefly, [1,2,6,7-3H]testosterone (New England Nuclear Corp.; 90 Ci/mmol) was dried under nitrogen and reconstituted in Eagle’s MEM (GIBCO-BRL, Gaithersburg, MD), pH 7.4, so that the working concentration was 0.25 µM. After gassing the incubation tubes with 95% oxygen/5% CO2, the tissues (2–5 mg) were incubated, with shaking, at 37 C, for 1 h. At the end of the incubation period, the tubes were transferred to an ice bath and extracted with 5 vol (1 ml) of chloroform. A TLC assay (25) was used to determine 5{alpha}-reductase and 17ß-HSD activities. When appropriate, finasteride was added to the incubation medium in a small (<1/20) volume of ethanol at 1 µM and diluted appropriately in medium.

Other assays and statistical analyses
Androstenedione, DHT, and testosterone levels were measured in the blood and prostate tissue by RIAs as described (26, 27, 28). The androstenedione antibodies are highly specific showing <0.001% cross-reactivity with either testosterone or DHT. The DHT and testosterone antibodies, however, are not specific. Therefore, specificity was acheived by separating the steroids in each sample on celite mini-columns (26, 27, 28). The intraassay coefficients of variation for the three assays were between 3.4 and 5.5%; the interassay coefficients of variation were between 9.6 and 14.7%. Protein was measured in prostatic tissue slices by the method of Lowry et al. (29). The data were analyzed by Welch’s approximation to a one-way ANOVA.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
To more fully understand the role of DHT formation in androgen action, the tissue content of testosterone, DHT, and androstenedione was determined by specific RIAs and expressed as the amounts measured either per prostate or per 100 g prostate (Fig. 1Go). Finasteride treatment caused an 85–90% reduction in the tissue content of DHT, whereas androstenedione and testosterone levels were 3.5- to 5-fold and 12- to 25-fold higher, respectively, in finasteride-treated rats depending on whether the data are expressed per prostate or per 100 g prostate (Fig. 1Go). Castration resulted in a disappearance of all three androgens from the prostates (Fig. 1Go).



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  		Figure 1. Androgen content of the ventral prostate of castrated rats or of intact rats treated with finasteride (25 mg/kg BW·day). Prostates were dissected from rats 7 days after castration or the initiation of finasteride treatment. DHT, androstenedione, and testosterone levels were measured by RIA as described in the text and compared to the levels seen in intact, untreated controls. The data are expressed per prostate or per 100 mg prostate. The bars represent means ± SEM of five to nine independent observations. The DHT levels were significantly reduced, and the androstenedione and testosterone levels were significantly increased in intact animals treated with finasteride (P < 0.01). *, < 0.1 ng/prostate.

 
Figure 2Go depicts the circulating androgens in intact, finasteride-treated, and castrated rats. As shown previously, testosterone is clearly the predominant circulating androgen of intact animals. A 2-fold increase in the circulating testosterone concentration was seen in finasteride-treated animals. It is also of interest that finasteride treatment caused an increase in the circulating androstenedione levels. This finding, in association with the finding that prostatic androstenedione levels are elevated in finasteride-treated animals, suggests that 5{alpha}-reduction of testosterone may not only activate the hormone in the rat prostate but also prevent its conversion to the inactive androgen, androstenedione. Once again, castration resulted in almost a total disappearance of androgen from the circulation.



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  		Figure 2. Serum androgens in castrated or finasteride treated rats. DHT, androstenedione, and testosterone levels were measured by RIAs as described in the text in 7-day castrated rat or in intact rats that had been treated for 7 days with finasteride (25 mg/kg·day). The values are expressed as ng/ml and compared with corresponding values seen in intact controls. Bars represent means ± SEM for eight to ten independent observations. The DHT levels were significantly reduced, and the androstenedione and testosterone levels were significantly increase in intact animals treated with finasteride (P < 0.05)

 
To further understand the mechanism by which finasteride treatment decreases prostatic and circulating DHT while causing an increase in prostatic and circulating androstenedione concentrations, in vitro studies were performed to assess androgen metabolism from [3H]testosterone. The first experiment used a prostate tissue-slice assay in which increasing concentrations of finasteride were added to the incubation medium. The results of this experiment are depicted in Fig. 3Go. A concentration of finasteride of 10 pM was ineffective in blocking 5{alpha}-reductase activity and DHT formation in this assay. However, increasing the concentration of finasteride in the incubation by 100-fold to 1 nM blocked 5{alpha}-reductase activity and the formation of DHT by about 50%; a further 100-fold increase in concentration to 100 nM blocked 5{alpha}-reductase activity by >95%. As illustrated in Fig. 3BGo, although the formation of 5{alpha}-androstanedione is inhibited by increasing concentrations of finasteride in the incubation medium, the formation of androstenedione is increased in a reciprocal manner. Thus, finasteride does not inhibit overall 17ß-HSD activity. Furthermore, as shown in Fig. 3CGo, the inhibition of 5{alpha}-reductase activity results in an inhibition of DHT formation and an almost equimolar increase in the formation of androstenedione. Extensive washing of the tissue fragment after such incubations has demonstrated that androstenedione rapidly diffuses from the tissue, whereas DHT is retained by the tissue (results not shown).



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  		Figure 3. 5{alpha}-Reductase and oxidative 17ß-HSD activities in rat ventral prostate tissue slices in vitro as a function of increasing finasteride concentration in the incubation media. Tissue slices (2–5 mg) were incubated with 0.25 µM [3H]testosterone, and the intracellular and extracellular metabolites were extracted and separated by TLC as described in the text. 5{alpha}-reductase activity was estimated by adding together the four 5{alpha}-reduced metabolites (5{alpha}-androstanedione, DHT, and 5{alpha}-androstan-3({alpha}ß)-diols) of testosterone, and 17ß-HSD activity was estimated by adding together 5{alpha}-androstanedione and androstenedione. A, 5{alpha}-reductase activity; B, 17ß-HSD activity; C, formation of the two proximal metabolites of testosterone (DHT and androstenedione) as a function of increasing finasteride concentration. The experiment was done using three independent prostates, and each bar represents a mean ± SEM for total 5{alpha}-reductase activity (A), 17ß-HSD activity (B), or DHT/androstenedione formation (C). *, Significantly different (P < 0.001) from adjacent doses of finasteride for the same hormone (C) or for the same enzyme activity (A). The androstenedione formation at the 0.001 µM dose of finasteride (C) is not statistically different from DHT formation at the same dose. The rates of 17ß-HSD activity for each dose of finasteride (B) are not statistically different.

 
Finally, an in vitro androgen metabolism experiment was performed in rat seminal vesicle and epididymis to assess 5{alpha}-reductase activity and 17ß-HSD activity in urogenital tissues derived from the fetal wolffian duct which virilize in response to testosterone rather than DHT (1). Figure 4Go depicts the results of this experiment and illustrates the fact that, in contrast to the prostate, the seminal vesicle and epididymis have very low levels of 17ß-HSD activity and therefore would not be expected to form appreciable amounts of androstenedione from testosterone (or, for that matter, 5{alpha}-androstanedione from DHT). This observation is reinforced by the fact that the presence of finasteride in the incubation medium did not uncover any apparent 17ß-HSD activity in the two wolffian duct-derived tissues (seminal vesicle and epididymis) as it did in the prostate which is derived from the urogenital sinus (1).



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  		Figure 4. 5{alpha}-Reductase and oxidative 17ß-HSD activities in prostate, seminal vesicle, and epididymis of 5-week-old rats. Tissue slices (2–5 mg) were incubated with 0.25 µM [3H]testosterone ± 0.1 µM finasteride (5{alpha}-reductase inhibitor) for 1 h at 37 C, and the metabolites were isolated as described in the text. 5{alpha}-Reductase activity was estimated by summing the formation of 5{alpha}-androstanedione, DHT and 5{alpha}-androstan-3({alpha}ß)-17ß-diol, and 17ß-HSD activity was estimated by summing the formation of 5{alpha}-androstanedione and androstenedione. Each bar represents a mean of six independent observations ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study confirms that the predominant androgen in the prostate of the intact rat is DHT, and that the 5{alpha}-reductase 2 inhibitor finasteride effectively blocks the formation of DHT thus depriving the androgen receptor of its preferred ligand (8, 11, 12). Although finasteride treatment clearly interferes with androgen action, it is not as effective as the total androgen deprivation that occurs following castration (21, 23, 24). This suggests that other non-5{alpha}-reduced androgens (most likely testosterone) act to partially maintain the androgenic status of finasteride-treated animals. We cannot, however, rule out the remote possibility that the dose of finasteride used in these experiments did not totally inhibit 5{alpha}-reductase activity at the site of action within the prostatic cell, although the amount of finasteride used in these studies was clearly in the pharmacological range. This study also confirms that finasteride treatment depresses circulating DHT levels, even though DHT represents a minor portion of the circulating androgens (22, 24, 30, 31).

The unique finding in these studies, however, is the fact that the prostatic content and circulating levels of androstenedione were elevated in finasteride-treated animals. Because the rat prostate expresses 17ß-HSD activity, the action of this enzyme also results in an increased metabolism of testosterone to androstenedione (a nonactive androgen) that apparently diffuses from the cell and away from the site of action. It is likely that the increased androstenedione levels in the prostate and circulation are meaningful at the molecular level given the almost one to one relationship of the metabolites between the inhibition of 5{alpha}-reductase activity and the increase in androstenedione formation, under in vitro conditions where substrate (testosterone) is saturating. The net effect is to keep the concentration of androgen at the site of action extremely low regardless of other steroid levels within the tissue. The data, therefore, support the idea that 5{alpha}-reduction of testosterone to DHT in the prostate is a mechanism by which cells of the prostate concentrate androgen at the site of action.

Although previous studies have documented the presence of 17ß-hydroxysteroid oxidoreductase activity in the rat and human prostate (32, 33, 34, 35), the significance of the presence of this enzymatic potential is not clear given that the studies were done under conditions that were not physiological. In this study, hormonal measurements of circulating and prostatic androgens in control and finasteride-treated rats were combined with in vitro androgen metabolism data obtained in tissue slice assays to infer the significance of prostate 17ß-HSD activity.

It seems unlikely that the presence of oxidative 17ß-HSD activity in the rat prostate serves any physiological, other than catabolic, purpose, because under normal circumstances the only 17-keto steroid formed is 5{alpha}-androstanedione that has not been shown to have androgenic activity. In addition, the oxidative nature of the 17ß-HSD in the rat prostate would not only favor the inactivation of testosterone to androstenedione but would inactivate any estrogen formed. Even in the finasteride-treated rat where prostatic androstenedione levels are elevated, it is difficult to conceive of androstenedione serving as a precursor for estradiol given the oxidative nature of the 17ß-HSD in the rat prostate.

Three isozymes of human 17ß-HSD have been identified and cloned. Each is encoded by a gene on a separate chromosome, and each has unique specificity’s for substrate and co-factor (36). The form of the enzyme uncovered in the ventral prostate of the finasteride-treated rat in this study appears to have characteristics similar to the human type 2 17ß-hydroxysteroid dehydrogenase in that it is primarily oxidative in nature (36). Indeed, the isozyme type of 17ß-HSD associated with the rat prostate cells appears to be the type 2 form of the enzyme (37). However, it is of no practical significance to precisely know the identity of the isoform of the enzyme in the rat ventral prostate, only to recognize that it is oxidative and probably acts to inactivate testosterone (and estradiol) in prostate cells. Thus, 5{alpha}-reduction within cells of the prostate probably acts by transforming a relatively weak androgen (testosterone) to a more potent androgen (DHT). In the absence of 5{alpha}-reductase activity, testosterone would be metabolized to an even weaker (and probably totally ineffective) androgen (androstenedione) by the 17ß-HSD enzyme present in the tissue. In this regard, it is significant that the androstenedione levels in the circulation of finasteride-treated rats were elevated over that of controls, suggesting that a substantial portion of the androstenedione formed in the prostates of these animals leaks into the blood stream. A similar finding was reported for the effect of finasteride on the serum androgens of male volunteers (30).

It is important to emphasize that 17ß-HSD activity, as measured in this assay, was relatively low in tissue slices of rat seminal vesicle and epididymis. Although in apparent contradiction to previous findings in the monkey epididymis (38) and in cultured human epididymal cells (39), significant differences in assay procedure and distribution of activity preclude any direct comparisons.

Taken together, these observations provide insight into one of the most puzzling aspects of androgen action, i.e. why two androgens account for the totality of androgen action. It is known that certain aspects of virilization of the male urogenital tract, such as formation of the prostate and male differentiation of the external genitalia, are dependent upon DHT formation, whereas virilization of the wolffian duct into the seminal vesicle and epididymis does not require DHT formation (1). A study of the tissue-specific expression of the two 5{alpha}-reductase isozymes in the fetal rat urogenital tract indicates that expression of the type 2 isozyme is expressed in mesenchymal cells of both the male and female urogenital tract throughout the period of sexual differentiation (17). The lack of similar developmental studies of the expression of 17ß-HSD isozymes preclude insight into the role 17-oxidation in the fetal urogenital tract at the time of sexual differentiation.

A model for androgen action in the differentiation of the male urogenital tract is presented in Fig. 5Go. Testosterone is the principal androgen secreted by the embryonic and adult testis of all known vertebrates, although very limited information suggests that 5{alpha}-reduced androgens may account for a substantial portion of the total androgens formed in the fetal testis (40). It is postulated that testosterone reaches cells of the indifferent wolffian duct and urogenital sinus by different routes and in different concentration. Testosterone reaches and enters cells of the developing urogenital sinus via the circulation and is rapidly converted by the 5{alpha}-reductase enzyme to DHT, which shows a dramatically higher affinity for the androgen receptor than does testosterone (8). On the other hand, it is conceivable that cells of the undifferentiated wolffian duct, which apparently don’t have the capacity to form DHT, are dependent on much higher concentrations of testosterone delivered directly by lumenal transport. It is important to note that, although both DHT and testosterone apparently bind to the same androgen receptor protein within target cells (4, 41, 42), DHT binds to the receptor with much higher affinity (8) and stabilizes it (43). The relatively weak interaction of testosterone with the androgen receptor probably results in a significant amount of the hormone dissociating from the receptor (and the cell) before the androgenic signal is transmitted. Therefore, a higher local concentration of testosterone within cells of the differentiating wolffian duct is probably required to maintain an activated receptor that is capable of interacting with DNA and eliciting an androgenic response. Furthermore, the conversion of testosterone to DHT is probably essential in the prostate because the increased affinity of DHT for the androgen receptor (compared with testosterone) protects this activated androgen from oxidative catabolism by 17ß-HSD (43).



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  		Figure 5. Proposed model for the differential actions of testosterone and DHT in the virilization of the rat urogenital tract. T, testosterone; D, 5{alpha}-dihydrotestosterone; A, androstenedione; AR, androgen receptor; 17ß-HSD, 17ß-hydroxysteroid dehydrogenase; 5{alpha}-R, 5{alpha}-reductase.

 
The finding that cells derived from the urogenital sinus express oxidative 17ß-HSD activity and therefore the capacity to metabolize testosterone to androstenedione adds an important new insight to androgen action. The fact that DHT formation in prostate tissue incubated in the absence of 5{alpha}-reductase inhibitor precisely matches the rate at which androstenedione is formed by the same tissue in incubations with finasteride suggests that the molecular transformations are closely linked. Metabolism of testosterone to androstenedione, rather than DHT, at the site of action might profoundly affect androgen action in the derivatives of the urogenital sinus, such as the prostate, which are exposed to relatively low concentrations of testosterone. However, cells of the undifferentiated wolffian duct that apparently see a relatively high concentration of testosterone directly from the testis and do not inactivate the hormone via oxidation apparently do not require the ability to form DHT for androgen action. Two key assumptions must be met if this model has explanatory meaning for the dual androgenic action in differentiation of the male urogenital tract: 1) testosterone must be delivered to cells of the differentiating wolffian duct in substantially higher concentration (possibly via lumenal transport from the fetal testis) than it is to cells of the urogenital sinus; 2) cells of the wolffian duct should not have the capacity to metabolize testosterone to androstenedione (i.e. lack oxidative 17ß-HSD activity), and therefore fail to inactivate testosterone. Veysierre et al. (44) have provided support for the first assumption, and support for the second assumption is provided herein. Ultimately, similar patterns of androgen metabolism must be established in the fetal urogenital tracts of other species if this model is to be generally applicable.


   Acknowledgments
 
I thank Mary B. Neal for able technical assistance and Drs. D. W. Foster and J. D. Wilson for support and critical review. Finasteride was a gift from Merck Pharmaceuticals.


   Footnotes
 
1 The studies described in this report were supported by USPHS Grants HD-21966, DK-03892, and Research Career Development Award HD-00845. Back

Received July 22, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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