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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 5 1373-1377
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

MK-386, an Inhibitor of 5{alpha}-Reductase Type 1, Reduces Dihydrotestosterone Concentrations in Serum and Sebum without Affecting Dihydrotestosterone Concentrations in Semen1

Jules I. Schwartz, Wesley K. Tanaka, Daniel Z. Wang, David L. Ebel, Lori A. Geissler, Aimee Dallob, Barry Hafkin and Barry J. Gertz

Merck Research Laboratories (J.I.S., W.K.T., D.Z.W., D.L.E., L.A.G., A.D., B.J.G.), Rahway, New Jersey 07065; and Pharmaco:International, Inc. (B.H.), Austin, Texas 78704

Address all correspondence and requests for reprints to: Barry J. Gertz, M.D., Ph.D., Merck Research Laboratories, P.O. Box 2000, RY33–600, Rahway, New Jersey 07065-0900.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Two isozymes (types 1 and 2) of 5{alpha}-reductase (5{alpha}R; EC 1.3.99.5), with differential tissue distribution, catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT) in humans. This study examined sequentially increasing oral doses of MK-386 (4,7ß-dimethyl-4-aza-5{alpha}-cholestan-3-one), an azasteroid that specifically inhibits the human 5{alpha}R1 isozyme in vitro. Finasteride, a selective inhibitor of 5{alpha}R2, was included for comparison. One hundred men were evaluated in a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group trial. Ten to 20 subjects received MK-386, and 2 to 5 received placebo in each of 6 panels. In 1 panel, 10 subjects received finasteride (5 mg), and 5 received placebo. Treatments were given once daily for 14 days, except in 1 panel in which MK-386 was administered 10 mg twice daily for comparison to 20 mg daily. Serum, sebum, and semen DHT concentrations and serum and sebum T concentrations were measured before and after treatment.

The mean changes from baseline on day 14 for serum DHT after placebo and 0.1, 0.5, 5, 20, and 50 mg MK-386 were 6.9%, 4.6%, -2.7%, -1.2%, -14.1% (P < 0.05 vs. placebo), and -22.2% (P < 0.05 vs. placebo), respectively. No significant alterations in serum T were observed after any dose of MK-386. Serum DHT fell 65.8% from the baseline 14 days after finasteride treatment (P < 0.05 vs. placebo). The mean changes from baseline on day 14 in sebum DHT were 5.0%, 3.0%, -25.4% (P < 0.05 vs. placebo), -30.1% (P < 0.05 vs. placebo), and -49.1% (P < 0.05 vs. placebo) for the placebo and 0.5, 5, 20, and 50 mg MK-386 groups, respectively. Finasteride also reduced sebum DHT, but to a lesser extent (-14.9%; P < 0.05 vs. placebo). Reciprocal increases in sebum T concentration were noted at doses of 5 mg or more of MK-386, but not with finasteride. The mean reduction in semen DHT with 5 mg finasteride was approximately 88% (P < 0.01 vs. placebo); no significant change in semen DHT was noted with 20 or 50 mg MK-386. Serum 3{alpha}-androstanediol glucuronide values were also reduced after the 20- and 50-mg MK-386 treatments in parallel with the changes in serum DHT. No meaningful changes were observed in serum LH after MK-386 treatment. MK-386 was generally well tolerated by all subjects; reversible aspartate aminotransferase/alanine aminotransferase elevations were observed in two subjects at the 50-mg dose.

The differential responses in serum, sebum, and semen DHT concentrations associated with MK-386 and finasteride treatments are consistent with those changes anticipated for selective inhibitors of the human 5{alpha}R isozymes. Dose-dependent suppression of sebum DHT by a 5{alpha}R1 inhibitor suggests the potential utility of such compounds in the treatment of acne.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ENZYME 5{alpha}-reductase (5{alpha}R; E.C. 1.3.99.5) catalyzes the reduction of testosterone (T) to dihydrotestosterone (DHT) (1, 2, 3, 4). The primary androgen, T vs. DHT, varies from one organ to another (5, 6, 7, 8). Whether androgen-related disorders such as acne, hirsutism, and male pattern baldness are dependent on DHT or T is currently under investigation (9, 10, 11, 12, 13).

There are two genes encoding two distinct isozymes of 5{alpha}R that are differentially expressed in human tissues and referred to as 5{alpha}R1 and 5{alpha}R2 (14, 15, 16, 17, 18, 19). 5{alpha}R2 predominates in the prostate as well as the epididymis and seminal vesicles (16, 17, 20) and is selectively inhibited by the 4-azasteroid finasteride. The IC50 values of finasteride for the two human isozymes in vitro are 540 and 4.0 nmol/L for 5{alpha}R1 and 5{alpha}R2, respectively (21).

The observation that finasteride maximally reduced serum concentrations of DHT by only approximately 70% (22, 23) suggested that tissues rich in 5{alpha}R1, such as skin and liver, probably remained a source of circulating DHT. Confirmation of the contribution of 5{alpha}R1 to serum DHT was demonstrated in a study of healthy men with MK-386 (4,7ß-dimethyl-4-aza-5{alpha}-cholestan-3-one) (24), a potent and selective inhibitor in vitro of human 5{alpha}R1 (IC50 values of 20 and >1000 nmol/L for human 5{alpha}R1 and 5{alpha}R2, respectively) (21). The addition of 25 mg MK-386 to 5 mg finasteride for 2 days decreased DHT, on the average, by 90% vs. baseline, or essentially to the limit of detection for the assay (24), consistent with the recent report by Hermann et al. for GI 198745, a dual 5{alpha}R1 and 5{alpha}R2 inhibitor, which reduced circulating DHT from the baseline by nearly 95% (25).

Tissue concentrations of DHT may be more relevant than those of serum DHT to explain a specific organ response to 5{alpha}R inhibition. In the present study, the sebum DHT concentration was used as a noninvasive surrogate for sebaceous gland DHT, an organ that predominantly expresses 5{alpha}R1 (26), and semen DHT was used as a marker of DHT generation in the prostate gland, seminal vesicles, and epididymis, where 5{alpha}R2 predominates (16, 17, 20).

The primary objective of the present clinical trial was to assess whether MK-386 behaves in a manner anticipated for a selective inhibitor of 5{alpha}R1 in man based on the differential response of three compartments (serum, sebum, and semen DHT concentrations) to 5{alpha}R1 inhibition compared to those responses after finasteride treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials

[3H]T ([1,2,6,7,16,17-N-3H]T; 157 Ci/mmol) and [3H]DHT ([1,2,4,5,6,7-N-3H]DHT; 110 Ci/mmol) were obtained from New England Nuclear (Wilmington, DE). Pure T and DHT were purchased from Sigma Chemical Co. (St. Louis, MO). Ether-washed linen facial blotters (Andrea FRESH-UPS, Los Angeles, CA) were used to collect forehead sebum. Antiserum used in the T and DHT assays was obtained from Endocrine Sciences (catalog no. DT3–351, Calabasas Hills, CA). C8 solid phase extraction columns (500 mg) were purchased from Varian (Harbor City, CA). All other reagents were of the highest grade commercially available.

Study design

One hundred nonsmoking healthy males (mean age, 28 yr; range, 18–45 yr), weighing 59–91 kg (mean, 75 kg), with normal clinical and laboratory profiles (based on medical history and routine hematology, chemistry, and urinalysis), including screens for serum T within the reference range, took part in the study. Each subject gave written informed consent to the study, which was approved by the local human research committee.

The study was a double blind, randomized, placebo-controlled, sequential, increasing dose, parallel group design (Fig. 1Go). Subjects were randomly assigned to 1 of 7 panels (A–G), each consisting of 10 subjects receiving either MK-386 capsules or finasteride tablets (and their respective placebos in a "double dummy" fashion) and 2–5 subjects receiving both matching MK-386 placebo capsules and placebo tablets matching finasteride. Treatments were, with one exception (panel F), given once daily for 14 days in the following manner [panel, dose of MK-386 (number of subjects: MK-386/placebo): A, 0.1 mg (10/2); B, 0.5 mg (10/2); C, 5.0 mg (10/2); D, 20.0 mg (10/2); and E, 50.0 mg (10/2)]. In panel F, 10 subjects received 20 mg MK-386 once daily, 10 subjects received 10 mg MK-386 twice daily, and 5 subjects received placebo. Panel G consisted of 10 subjects given finasteride (5 mg) once daily and 5 given placebo; panel G was studied simultaneously with panel F. The investigator and subjects were blinded with respect to treatment (active drug vs. placebo, finasteride vs. MK-386), but not to dose level. The decision to proceed to the next panel was based on acceptable safety and tolerability data from the previous panel, as revealed by clinical assessment of adverse experiences, laboratory safety tests (blood chemistry, hematology, and urinalysis), and physical exam.



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  		Figure 1. Schematic of study design and allocation of subjects to study panels. Lower dose panels completed treatment before initiation of the next higher dose panel.

 
Venous blood samples were collected for serum T and DHT at the following times: two samples before the first day of treatment at least 48 h apart (mean = baseline) and pretreatment on days 1, 4, 10, 14, 15, 18, 21, and 28. Samples were collected between 0600–0900 h on each day and centrifuged, and serum was harvested and stored at -20 C within 30 min of collection.

Serum 3{alpha}-androstanediol glucuronide (3{alpha}AG) values were measured pretreatment (day 1) and posttreatment (day 15) for subjects in panels B, C, D, and E plus the two subjects in panel A who received placebo (n = 10 receiving placebo and each active treatment). Serum LH was assayed in all subjects from panels D and E plus the two subjects receiving placebo in panels A, B, and C (n = 10 receiving active and placebo). Blood for LH assay was drawn before treatment on day 1 and after treatment on day 15 as three consecutive collections 15 min apart between 0600–0900 h. The pretreatment and posttreatment means of the three determinations served as the values for comparison.

Sebum samples for assay of DHT and T concentrations were collected by absorbing sebum for 24 h into an ether-washed paper blotter held against the forehead with an elastic headband. Baseline collections were made on 2 occasions approximately 48 h apart before initiating treatment, and the mean served as the baseline. A 24-h collection was repeated at the end of treatment (day 14). Adequate pre- and posttreatment specimens were available for analysis in 9–10 subjects receiving 0.5, 5, and 50 mg MK-386; 19 subjects receiving 20 mg MK-386; 9 subjects receiving finasteride; and 16 given placebo.

Semen samples were collected by masturbation twice before treatment (mean of two pretreatment DHT determinations = baseline) and once at the end of treatment (day 14).

Measurement of serum T, DHT, LH, and 3{alpha}AG

Serum concentrations of T and DHT were measured by Endocrine Sciences. Serum T and DHT were measured by RIA after extraction and alumina column chromatography for T (27) and chemical oxidation for DHT. The lower limits of reliable quantitation based on the lowest concentration that can be measured with a coefficient of variation of 20% are approximately 6.0 and 2.4 ng/dL for T and DHT, respectively. The interassay precisions for serum T were 5.3% and 7.1% at 278 and 510 ng/dL, respectively. The interassay precisions for serum DHT were 9.6% and 8.0% at 5.0 and 47 ng/dL, respectively. Determinations of LH and 3{alpha}AG concentrations were also performed by Endocrine Sciences, using their standard laboratory procedures.

Measurement of sebum T and DHT

Sebum was collected for 24 h onto a 3.8 x 10.2-cm, 4-ply, ether-washed linen facial blotter covered with cotton gauze and held in place with a self-adherent bandage. Blotters were handled by gloved staff to prevent contamination during handling. Before each sebum collection, subjects washed their hair with Johnson and Johnson Baby shampooTM (Johnson and Johnson, Skillman, NJ) and their faces with NeutrogenaTM facial soap (Neutrogena, Los Angeles, CA). At the end of the 24-h collection period, blotters were removed and stored at -20 C or below before analysis of T and DHT. For analysis, blotters were warmed to room temperature, spiked with [3H]T and [3H]DHT as internal standard, and extracted three times with 5 mL ethyl acetate. Extracts were dried in preweighed siliconized glass vials, weighed, and analyzed for T and DHT as previously described (28). Briefly, this procedure involved solid phase extraction on a C8 column, separation on high performance liquid chromatography (HPLC) using a mobile phase containing 42.5% methanol-42.5% H2O-15% acetonitrile, and quantitative measurement of immunoreactive material using a competitive binding RIA. Overall recoveries of [3H]T and [3H]DHT were 61.4% and 46.9%, respectively. The lower limit of reliable quantitation based on the lowest analyte concentration that could be measured with a coefficient of variation of 20% was estimated to be approximately 0.58 pg/mg sebum (assuming a 45-mg sample) for both T and DHT based on measurements with blotters spiked with authentic T and DHT. The interassay precision for T was 10.7% for a quality control sample containing 62.4 pg T (1.39 pg/mg based on a 45-mg sebum sample). The interassay precision for DHT was 12.5% for a quality control sample containing 64.4 pg DHT (1.43 pg/mg based on a 45-mg sebum sample).

Measurement of seminal plasma DHT

Semen samples were collected at various times by masturbation at the subject’s home or at the clinic and stored on ice until transfer within 2 h to the clinic laboratory. Samples were frozen at -20 C or below until analysis. For analysis of DHT, samples were thawed and spun at 2750 x g for 10 min at 4 C. A 1.0-mL aliquot of seminal plasma was taken, spiked with [3H]DHT internal standard, and extracted three times with 5 mL ethyl acetate. The dried ethyl acetate extract was resuspended in a HPLC mobile phase, filtered in a microfilterfuge tube (0.45-µm nylon filter, Rainin Instruments, Woburn, MA), chromatographed on HPLC, and assayed by RIA as previously described (28). Overall recovery of [3H]DHT was 59.8%. The limit of detection based on the amount of DHT that yields 80% of the maximum binding in the RIA (4 pg) corresponds to 2.25 ng/dL. The interassay precision for semen DHT was 16.8% for a semen quality control sample containing 13.7 ng/dL.

Statistical analysis

Using the average of the predose measurements as the baseline, the percent changes from baseline for serum DHT, T, 3{alpha}AG, and LH and sebum DHT were calculated for each subject. Subjects receiving placebo were pooled across panels for analysis as a single placebo group. The 2 panels of 10 subjects receiving 20 mg MK-386 once daily were also pooled for statistical analysis. Each of the active treatment groups was compared to the placebo group using Dunnett’s t test at an {alpha} = 0.05 level of significance (two-tailed). The two-sample t test was used for the comparison between 20 mg MK-386 daily vs. 10 mg MK-386 twice daily. All values are presented as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Serum DHT and T

Mean pretreatment serum DHT values ranged from 44.3–52.3 ng/dL for all treatment groups. The mean changes from baseline in serum DHT on day 15 of the study were +4.6% (6.2%), -2.7% (4.0%), -1.2% (6.5%), -14.1% (2.9%; P < 0.05 relative to placebo), -22.2% (5.2%; P < 0.05 relative to placebo), -65.8% (2.5%; P < 0.05 relative to placebo), and +6.9% (5.4%) for the 0.1, 0.5, 5, 20, and 50 mg MK-386, finasteride, and placebo treatments, respectively. There was no significant difference after MK-386 treatments of 20 mg once daily and 10 mg twice daily (data not shown). Figure 2Go illustrates the time course for the reduction in DHT upon treatment with 50 mg MK-386, 5 mg finasteride, and placebo.



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  		Figure 2. Percent change from baseline (mean ± SE) in serum DHT after administration of 50 mg MK-386, 5 mg finasteride, or placebo over the 14-day treatment interval and for the 14 days posttreatment (n = 10 receiving MK-386, n = 9 receiving finasteride, and n = 19–20 receiving placebo). *, P < 0.05 vs. placebo.

 
Mean pretreatment serum T values in all panels ranged from 519–628 ng/dL. After 2 weeks of MK-386 or finasteride treatment there were no significant changes in serum T relative to placebo (data not shown).

Sebum DHT and T

Mean pretreatment sebum DHT concentrations were 4.8 (0.4), 4.6 (0.6), 6.2 (0.5), 6.6 (1.7), 6.1 (0.9), and 5.8 (0.6) pg/mg for the 0.5-, 5-, 20-, and 50-mg MK-386; 5-mg finasteride; and placebo treatments, respectively (sebum samples from the 0.1 mg MK-386 group were not assayed). After 2 weeks of treatment, sebum DHT concentrations were significantly suppressed for the 5-, 20-, and 50-mg MK-386 and the 5-mg finasteride treatments. The mean percent changes from baseline for sebum DHT after 0.5-, 5-, 20-, and 50-mg MK-386; 5-mg finasteride; and placebo treatments are illustrated in Fig. 3Go.



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  		Figure 3. Percent change from baseline (mean ± SE) in sebum DHT after treatment with 0.5–50 mg MK-386, 5 mg finasteride, or placebo for 14 days (n = 9–10/group, except n = 19 for 20 mg MK-386 and n = 16 for placebo). *, P < 0.05 vs. placebo.

 
Mean pretreatment sebum T values in all panels (with the exception of 0.1-mg MK-386 samples, which were not assayed) were 2.2 (0.3), 2.1 (0.4), 3.0 (0.5), 3.1 (0.6), 2.6 (0.6), and 2.4 (0.3) pg/mg sebum for the 0.5-, 5-, 20-, and 50-mg MK-386; 5-mg finasteride; and placebo treatments, respectively. The mean percent changes from baseline for sebum testosterone after 2 weeks of 0.5-, 5-, 20-, and 50-mg MK-386; finasteride; and placebo treatments were 12.6% (10.5%), 55.7% (8.4%; P < 0.05), 96.7% (18.6%; P < 0.05), 90.3% (22.8%; P < 0.05), 30.7% (23.0%), and 8.55% (9.27%), respectively. Increases in the sebum T concentration were significantly different from those in the placebo group for the 5-, 20-, and 50-mg MK-386 groups only.

Semen DHT

The only treatment groups for which semen DHT was assayed were those who received 20 and 50 mg MK-386, 5 mg finasteride, and placebo (n = 10/group). Mean pretreatment semen DHT values for these groups were 35.2 (4.9), 41.3 (5.8), 22.4 (4.2), and 38.0 (6.7) ng/dL seminal plasma, respectively. Only finasteride treatment was associated with a statistically significant change from baseline (P < 0.01 for within-group change) and vs. placebo (P < 0.01). Finasteride reduced semen DHT concentrations, on the average, by nearly 88%, which approached the limits of the assay, whereas the 20- and 50-mg MK-386 treatments were ineffective in this regard. Placebo treatment was associated with a 24% difference from baseline (P = NS vs. baseline).

Serum 3{alpha}AG and LH

Mean pretreatment 3{alpha}AG concentrations were 552.7 (86.5), 379.1 (84.4), 360.2 (84.5), 713.8 (96.3), and 546.4 (94.9) ng/dL for the 0.5-, 5-, 20-, and 50-mg MK-386 and placebo treatments, respectively (n = 9–10/group). Mean percent changes from baseline after 2 weeks of therapy were 8.7% (4.4%), -8.6% (7.9%), -48.6% (9.4%; P < 0.05 vs. change on placebo), -72.7% (2.8%; P < 0.05 vs. change on placebo), and 13.6% (9.3%) for the 0.5-, 5-, 20-, and 50-mg MK-386 and placebo groups, respectively.

Mean pretreatment serum LH values were 5.2 (1.2), 7.0 (1.1), and 7.0 (1.7) mIU/mL for the 20- and 50-mg MK-386 and placebo groups, respectively (n = 10/group). The percent changes from baseline after 2 weeks of treatment for the 20- and 50-mg MK-386 and placebo treatments were 16.2% (10.2%), -16.5% (11.1%), and 16.3% (11.0%), respectively (P < 0.05 for 50 mg MK-386 vs. placebo).

Safety

The most common adverse experiences reported were mild to moderate headache and symptoms associated with upper respiratory tract viral infections. All adverse experiences were transient. Two subjects at the 50-mg dose level experienced transiently elevated aspartate aminotransferase and alanine aminotransferase values up to 2–4 times the upper limit of normal. These increases were reversible after discontinuation of treatment and were not associated with any other laboratory abnormalities or clinical symptoms suggestive of hepatic dysfunction.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Fourteen days of treatment with MK-386 resulted in a dose-dependent suppression of serum and sebum DHT without affecting semen DHT concentrations. These findings are in contrast to the results obtained after 2 weeks of finasteride (5 mg/day), which resulted in a substantial reduction in serum and semen DHT, with only a modest reduction in sebum DHT. These differential alterations in DHT concentrations in these three distinct compartments are consistent with selective inhibition of 5{alpha}R1 by MK-386 and 5{alpha}R2 by finasteride and the current understanding of the tissue predominance of these 5{alpha}R isozymes (14, 15, 16, 17, 18, 19, 20, 22, 26).

Serum DHT concentrations were maximally reduced ~22% by 50 mg MK-386, with no significant change in serum T, whereas 5 mg finasteride reduced serum DHT by ~70%. These results are consistent with previous observations (23, 24, 25).

Sebum is generated by an androgen-dependent holocrine process in the sebaceous glands as sebocytes mature and release their contents into the follicle, which are then extruded at the skin surface (28, 29, 30, 31, 32, 33). Sebum DHT was used as a surrogate for sebaceous gland 5{alpha}R activity that has been recently shown to be almost exclusively 5{alpha}R1 (26). One would then predict that a 5{alpha}R1-selective inhibitor would reduce sebum DHT concentrations as a reflection of inhibited sebaceous gland 5{alpha}R activity. The current results revealed a dose-dependent suppression of sebum DHT concentrations after 2 weeks of treatment with MK-386. Sebum DHT was reduced by 55% after 50 mg MK-386, substantially more than the change in serum DHT after this dose of MK-386, consistent with the more limited contribution of 5{alpha}R1 to the latter compartment. A plateau in the reduction in sebum DHT was not achieved in the present study at the highest dose of MK-386 tested. Higher doses could not be evaluated based on the observation of reversible elevations in serum transaminases in subjects receiving 50 mg and the limited toxicological experience. The reciprocal elevations in sebum T after MK-386 are probably due to substrate accumulation after 5{alpha}R1 inhibition. The small (~15%) reduction in sebum DHT after 5 mg finasteride could be a result of 5{alpha}R2 inhibition in the root sheath of the hair follicle where this isozyme has been identified (34) or could result from the large reduction (~70%) in serum DHT, which could affect 5{alpha}R activity through a reduced "feed-toward" activation described for this enzyme (35) or could reflect the possibility that a component of sebum DHT is passively derived from serum.

There was greater variability in semen DHT concentrations, as evident from the measurements over time in the placebo group. Nonetheless, it is clear that finasteride substantially suppressed semen DHT levels, whereas even the highest doses of MK-386 studied did not. Given that the tissues of origin for semen, prostate, epididymis, and seminal vesicles have predominately 5{alpha}R2 (20), it is not surprising that finasteride would affect DHT concentrations in this fluid, whereas MK-386 would not.

Serum 3{alpha}AG concentrations were decreased to a substantially greater extent than serum DHT after 20 and 50 mg MK-386. 3{alpha}AG, a metabolite of DHT, has been considered by some investigators to be a better reflection of skin 5{alpha}R activity (36, 37, 38, 39). Thus, the greater suppression observed in serum 3{alpha}AG with increasing doses of MK-386 are consistent with the greater effects observed on sebum DHT after MK-386 treatment.

Changes in serum LH concentrations after the 50-mg MK-386 dose were small in absolute terms (~1.2 mIU/mL decrease vs. baseline), and the statistical significance of this change relative to the value in the placebo group was due in part to the mean change in the latter group (+16%; 1.1 mIU/mL). These differences probably reflect a chance observation and are unlikely to be clinically meaningful. However, this remains to be confirmed in future investigations.

The current findings are consistent with the hypothesis that an inhibitor of 5{alpha}R1 may benefit conditions associated with excess skin androgen activity, such as acne, androgenetic alopecia, and hirsutism. Specifically, if the reduction in sebum DHT is associated with a fall in sebaceous gland activity and decreased sebum excretion rate, one might anticipate an improvement in acne. Other hormonal treatments that reduce the sebum excretion rate, such as antiandrogens or estrogens, have demonstrated antiacne activity (40, 41, 42, 43, 44).

In conclusion, MK-386 is a selective 5{alpha}R1 inhibitor in man and is associated with a substantial suppression of sebum DHT without an influence on semen DHT. Further clinical trials examining the potential therapeutic benefits of 5{alpha}R1 inhibitors that are well tolerated on chronic exposure are needed to explore the clinical utility of these agents.


   Acknowledgments
 
We wish to acknowledge the assistance of Ms. Shanna Norris and Ms. Carmen Inoa in the preparation of the manuscript.


   Footnotes
 
1 Presented in part at the 10th International Congress of Endocrinology, San Francisco, CA, June 12–15, 1996. This work was supported by a grant from Merck Research Laboratories (Rahway, NJ). Back

Received November 7, 1996.

Revised January 22, 1997.

Accepted January 31, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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