| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
,
,||
From the * Center for Research in Reproduction and
Contraception, Division of General Internal
Medicine, Department of Medicine and the
Department of Medicinal Chemistry, ||
Divisions of Endocrinology, Metabolism and
Nutrition, University of Washington School of Medicine, Seattle,
Washington.
| Correspondence to: Dr John K. Amory, University of Washington, Box 356429, 1959 NE Pacific St, Seattle, WA 98195 (e-mail: jamory{at}u.washington.edu). |
| Received for publication September 21, 2007; accepted for publication November 28, 2007. |
 |
Abstract |
|---|
 Top Abstract Subjects and MethodsResultsDiscussionReferences |
|---|
Key words: Androgens, FSH, LH, 5
reductase, male fertility
One of the main challenges in the development of a male hormonal
contraceptive is the need for parenteral administration of testosterone, which
has been administered by intramuscular injections or transdermally in
experimental contraceptive trials (Brady et
al, 2006; Page et al,
2006). When surveyed, however, a majority of men state a
preference for an oral form of contraceptive delivery
(Martin et al, 2000;
Weston et al, 2002;
Heinemann et al, 2005).
Unfortunately, in the United States there is currently no safe form of oral
androgen therapy that could be incorporated in a trial of male hormonal
contraception. To address this issue, our group has recently studied oral
testosterone enanthate (TE) combined with the 5-reductase inhibitors
dutasteride and finasteride, which inhibit the metabolism of testosterone to
dihydrotestosterone (DHT). This combination of agents results in elevations of
serum testosterone levels to the normal range for 8–12 hours in
medically castrated men (Amory and Bremner,
2005; Amory et al,
2006). In addition, serum DHT levels are significantly suppressed.
Such long-term DHT suppression could enhance the efficacy, safety, and appeal
of a male hormonal contraceptive regimen, since the inhibition of DHT
production might reduce the risk of diseases, such as prostate hyperplasia
and/or prostate cancer, acne, and male pattern baldness
(Thompson et al, 2003;
Marberger, 2006;
Olsen et al, 2006:
Otberg et al, 2007). Moreover,
chronic administration of dutasteride to normal men significantly decreases
sperm count and could therefore improve suppression of spermatogenesis in a
contraceptive regimen (Amory et al,
2007).
While our initial studies have demonstrated the plausibility of using oral TE plus dutasteride for male hormonal contraception, the degree of gonadotropin suppression mediated by oral testosterone as well as the safety of extended oral administration of TE plus dutasteride are unknown. We hypothesized that 1 month of oral TE plus dutasteride would effectively suppress FSH and LH below the lower limit of the normal range. This degree of gonadotropin suppression has been shown to suppress spermatogenesis when administered to men for at least 12 weeks (Matthiesson and McLachlan, 2006). In addition, we hypothesized that once-daily dosing of oral TE would be as effective as twice-daily dosing in terms of gonadotropin suppression, and that 4 weeks of oral TE would be safe and well tolerated without any significant impact on health, mood, or sexual function. Therefore, to determine the safety and efficacy of chronic oral TE plus dutasteride for male hormonal contraception, we conducted a randomized, double-blinded trial of 4 weeks of oral TE plus dutasteride in healthy men.
|
Subjects and Methods |
|---|
|
TopAbstractSubjects and MethodsResultsDiscussionReferences |
|---|
Study Design
We conducted a randomized, double-blinded, 2-arm study of 4 weeks of oral
TE plus dutasteride in healthy men. For the study, TE in sesame oil
(Delatestryl; Indevus Pharmaceuticals, Lexington, Massachusetts) and placebo
sesame oil were prepared in syringes by the hospital pharmacist at the
University of Washington. Subjects self-administered oral TE once or twice
daily during treatment. There were no restrictions placed on concomitant food
intake. For inhibition of 5-reductase, a loading dose of 24.5 mg
dutasteride (GlaxoSmithKline, Research Triangle Park, North Carolina) was
administered on the first day of the study to achieve rapid inhibition of both
isozymes of 5-reductase (Clark et
al, 2004). Thereafter, subjects self-administered 0.5 mg daily for
the remaining 27 days with their morning TE syringe. Subjects were randomly
assigned to either 1) 400 mg TE in sesame oil by mouth twice daily or 2) 800
mg TE in sesame oil by mouth every morning plus placebo sesame oil every
evening. Dose assignment/randomization was performed by the hospital
pharmacist using a random number sequence. Subjects and study investigators
were blinded to study group so that subjective assessments of mood and sexual
function would not be biased. At the first study visit, the subjects were
instructed on self-administration of the study drug and given a study
medication record to record both the timing of each subsequent dose of study
medication and any illnesses or adverse reactions to study medications. During
treatment, subjects had weekly physical examinations by study personnel and
blood tests for measurement of serum LH, FSH, testosterone, DHT, and estradiol
as well as blood counts and serum chemistries, including liver function tests.
Fasting serum lipids (total cholesterol, high-density lipoprotein [HDL]
cholesterol, low-density lipoprotein [LDL] cholesterol, triglycerides) and
serum PSA were measured at baseline and at after 4 weeks of treatment. In
addition, subjects completed validated questionnaires assessing mood and
sexual function (McNair et al,
1971; O'Leary et al,
1995) at baseline and after 4 weeks of treatment.
On the last day of dosing of the 28-day study period, subjects were admitted to the clinical research center at the University of Washington and underwent 24-hour sampling of their serum concentrations of testosterone, DHT, and estradiol. Blood was drawn before dosing and 1, 2, 4, 8, 12, 13, 14, 16, 20, and 24 hours after their morning dose to allow for analysis of the steady-state pharmacokinetics of oral TE. Three to four weeks after the last dose of oral TE, subjects returned to clinic for a follow-up physical examination and blood tests. The study was designed with the primary endpoint as the suppression of LH and FSH after 28 days of therapy by oral testosterone plus dutasteride. Before the study, it was determined that a sample size of 10 subjects per group conferred an 80% power to detect a difference of greater than 0.4 IU/L in serum LH between the 2 doses of oral TE.
Measurements
FSH and LH levels were measured by immunofluorometric assay (Delfia; Wallac
Oy, Turku, Finland). The sensitivity of the assay for FSH and LH was 0.016
IU/L and 0.019 IU/L, respectively. For low-, mid-, and high-pooled values of
0.05, 1.0, and 21 IU/L of FSH, the intra-assay coefficients of variation were
5.9%, 3.0%, and 3.0%, and the interassay coefficients of variation were 20.7%,
5.0%, and 6.2%, respectively. For low-, mid-, and high-pooled values of 0.06,
1, and 16 IU/L of LH, the intra-assay coefficients of variation were 12.6%,
5.6%, and 4.1%, and the interassay coefficients of variation were 16.5%,
13.9%, and 10.5%, respectively. The normal ranges were 1.2–7.3 IU/L for
LH and 1.1-6.7 IU/L for FSH. Serum total testosterone was measured by a
radioimmunoassay (Diagnostic Products Corp, Webster, Texas). The assay had a
sensitivity of 0.35 nmol/L and interassay variations for low, mid, and high
pools of 13.6%, 6.1%, and 6.8%, and intra-assay variations of 10.0%, 5.3%, and
6.6%. The normal range was 8.7–33 nmol/L. Serum estradiol was measured
using a radioimmunoassay (Diagnostic Products). The assay had a sensitivity of
20 pmol/L and interassay and intraassay coefficients of variation of 8.1% and
7.1%, respectively. The normal value for estradiol in men was <220 pmol/L.
DHT was measured using high-performance liquid chromatography–mass
spectroscopy as described previously
(Kalhorn et al, 2007).
Intraassay coefficients of variation generated using human serum for low-,
mid-, and high-range samples were 15.8%, 4.3%, and 6.3% for DHT. The normal
range for serum DHT was 1.0–3.1 nmol/L.
Statistical Analysis
Serum testosterone, DHT, and estradiol were natural log-transformed prior
to analysis. Due to nonnormal distributions, even after transformation, serum
LH and FSH were analyzed in a nonparametric fashion. Baseline characteristics
and laboratory values were compared using a 2-sample t test. Changes
from baseline in serum hormones were analyzed using a paired t test
(for serum testosterone, DHT, and estradiol) or a Wilcoxon sign-rank test (for
LH and FSH) with a Bonferroni correction for multiple comparisons. Differences
between dose groups were compared with a 2-sample t test with unequal
variances (for serum testosterone, DHT, and estradiol) or a Wilcoxon rank-sum
test (for LH and FSH). Responses on the sexual function and mood
questionnaires from baseline and between groups were compared using an
extended 
2 test. For the analysis of the serum hormone
concentrations during the last 24 hours of dosing, maximum concentration after
dosing (Cmax), time to maximum concentration (Tmax),
area under the curve (AUC), and elimination phase half-life (T1/2)
were calculated for each subject using a computer program (PK Solutions,
Golden, Colorado) after correction for baseline values. Pharmacokinetic
parameters between doses were compared using the Wilcoxon rank-sum test.
Correlations between the degree of gonadotropin suppression and
pharmacokinetic parameters were performed using the Spearman technique. All
statistical analyses were performed using STATA (College Park, Texas). For all
comparisons, an of .05 was considered significant.
|
Results |
|---|
|
TopAbstractSubjects and MethodsResultsDiscussionReferences |
|---|
|
A total of 16 subjects reported 29 adverse events during the study. The most common adverse events were headache (7 subjects), upper respiratory infections (5 subjects), stomach pain/reflux (4 subjects), and back pain (2 subjects). Side effects of particular interest thought to be related to the study medication in included acne (2 subjects) and a transient decrease in libido (1 subject). In addition, 1 subject complained of unusually vivid dreams. There were no serious adverse effects.
Serum Steroid Hormones
During treatment, predose (nadir) serum testosterone remained in the normal
range and did not significantly differ from baseline
(Figure 1A); however, serum DHT
was significantly suppressed (Figure
1B), and serum estradiol was significantly increased
(Figure 1C). There were no
significant differences between groups in predose (nadir) serum testosterone,
DHT, or estradiol. Serum testosterone and estradiol concentrations returned to
baseline values after treatment; however, serum DHT remained significantly
suppressed 14 days after the completion of TE and dutasteride dosing
(Figure 1B).
|
|
|
During the 28th day of treatment, mean serum DHT was significantly increased above baseline by both twice-daily 400 mg TE and once-daily 800 mg TE immediately within 1 hour of dosing (Figure 2C and D), but it remained below the lower limit of normal in the 400 mg twice-daily group. Mean serum DHT remained significantly elevated compared with baseline and within the normal range for 8 hours in the once-daily 800 mg TE group and for 4 hours in the twice-daily 400 mg TE group only after the morning dose. The serum DHT concentrations in the 800 mg TE group were significantly greater than those in the twice-daily 400 mg TE group for 14 hours after the morning dose. As was observed with the serum testosterone concentrations, the evening dose of TE in the twice-daily 400 mg TE group did not result in nearly the postdose elevation of serum DHT observed after the morning dose. The mean Cmax of serum DHT was significantly greater in the once-daily 800 mg TE group compared with the twice daily 400 mg TE group. In addition, the AUC over 24 hours for DHT was significantly greater with 800 mg once daily compared with the 400 mg twice daily (23 ± 3.5 nmol-h/L vs 7.9 ± 1.3 nmol-h/L; P < .01; Table 2).
Mean serum estradiol was significantly increased above baseline by both twice-daily 400 mg TE and once-daily 800 mg TE within 1 hour of dosing (Figure 2E and F). Mean serum estradiol remained significantly elevated for 8 hours in the once-daily 800 mg TE group and for 2 hours in the twice-daily 400 mg TE group after the morning dose. In addition, the serum estradiol concentrations in the 800 mg TE group were significantly greater than those in the twice-daily 400 mg TE group for 4 hours after dosing. In contrast to the marked difference observed for serum testosterone between the morning and evening doses, the serum estradiol concentrations observed after the evening dose of TE in the twice-daily 400 mg TE group were very similar to those observed after the morning dose, and the Cmax and AUC did not differ between treatment groups (Table 2).
Gonadotropin Suppression
There were no significant differences in serum FSH or LH at baseline
between the dose groups (Table
1). During treatment, median serum FSH was significantly decreased
in the once-daily 800 mg TE group throughout treatment, whereas median serum
FSH was significantly decreased only after 4 weeks of treatment with 400 mg TE
twice daily (Figure 3A). In
contrast, median serum LH was significantly suppressed only at 2 weeks of
treatment in the once-daily 800 mg TE group
(Figure 3B). Both FSH and LH
had returned to normal 2 weeks after treatment.
|
After 28 days of treatment in the 400 mg twice-daily TE group, only 1 subject was suppressed below the lower limit of the normal range for serum FSH compared with 6 of 10 subjects in the 800 mg once-daily group (P = .057). Similarly, only 1 subject in the 400 mg twice-daily TE group was suppressed below the lower limit of the normal range for serum LH, compared with 3 of 10 subjects in the 800 mg once-daily group (P = .58). Interestingly, 1 subject in the 800 mg TE once-daily group had his gonadotropins suppressed to below the lower limit of quantitation for both the FSH and the LH assay after 3 weeks of treatment. Intriguingly, this subject exhibited the highest serum concentrations of estradiol but not testosterone during treatment. When all subjects were considered together, the percentage suppression of FSH was significantly correlated with the AUC for estradiol (r = 0.53, P = .01), but not with any other individual pharmacokinetic, hormonal, or anthropomorphic parameter.
Laboratory Monitoring
During treatment, there was a significant decrease in serum PSA observed in
the twice-daily TE group (Table
3). In addition, a significant decrease in serum HDL cholesterol
was noted in both treatment groups (Table
3), but no significant change in total cholesterol, LDL
cholesterol, or triglycerides was noted. Weekly measurements of serum markers
of liver function, liver inflammation, hematocrit, and kidney function did not
change during treatment (Table
3). One subject had an increase in serum alanine aminotransferase
(ALT) of greater than threefold after 2 weeks of treatment, but admitted to
imbibing approximately 10 alcoholic beverages prior to his visit. This
subject's serum ALT normalized despite continued TE treatment.
|
Mood and Sexual Function
There was no significant difference in any parameter of mood
(Table 4) or sexual function at
baseline (Table 5). During
treatment, there was no significant change in mood as determined by the
questionnaire (Table 4). In
addition, no subject complained of worrisome symptoms of depression, anxiety,
or mania. Similarly, there were no significant changes in sexual function as
measured by self-administered questionnaire, excepting a slight increase in
overall satisfaction with sexual activity noted in the once-daily 800 mg TE
group (Table 5). One subject
complained of decreased libido after 2 weeks of treatment; however, this
symptom abated despite continued treatment. At this time, the subject did not
complain of erectile, ejaculatory, or orgasmic dysfunction.
|
|
|
Discussion |
|---|
|
TopAbstractSubjects and MethodsResultsDiscussionReferences |
|---|
The 800 mg once-daily oral dose of TE suppressed FSH and LH to a much greater degree than the 400 mg twice-daily dose of oral TE. This difference between groups was likely due to either the significantly greater serum concentrations of testosterone, DHT, or estradiol during treatment. Which of these hormones is most important for gonadotropin suppression after oral administration is unclear. On one hand, the AUC and Cmax of testosterone and DHT were significantly greater in the 800 mg once-daily group, whereas the estradiol pharmacokinetics were similar between groups. On the other hand, only the AUC for estradiol was the only parameter significantly correlated with the degree of gonadotropin suppression during treatment. Clearly, whether the serum concentration of testosterone, DHT, or estradiol is more important in gonadotropin suppression will require additional study.
A second notable finding of this study was that the suppression of serum
FSH by oral TE was greater than the suppression of serum LH. The reason for
this is likely due to the increases in serum estradiol observed with oral TE.
Estradiol acts to inhibit the hypothalamicpituitary-gonadal axis at both the
hypothalamus and the pituitary and is thought to provide much of the negative
feedback regulation of FSH secretion in men (Hayes et al,
2000,
2001). In contrast, DHT likely
plays a lesser role, since men with idiopathic hypogonadotropic hypogonadism
who are stimulated with pulsatile GnRH do not exhibit feedback inhibition of
gonadotropins when administered an infusion of DHT over 72 hours
(Bagatell et al, 1994). More
likely, DHT exerts its negative feedback effect at the level of the
hypothalamus by inhibiting GnRH pulse amplitude and pulse frequency, since
these are increased in men with congenital 5-reductase deficiency
(Canovatchel et al, 1994).
Therefore, in our study the marked suppression of DHT by dutasteride may be
allowing for the relative preservation of LH compared with FSH, which is well
suppressed by the increased serum levels of estradiol.
As in our prior work, oral TE plus dutasteride results in transient supraphysiologic elevations in serum testosterone. Indeed, in this study, the serum testosterone concentrations were significantly higher than those observed in our previous work with the same doses of oral TE (Amory and Bremner, 2005). Since the predose concentrations of serum testosterone on day 27 were almost identical to the baseline testosterone concentrations, it is unlikely that this is due to accumulation of testosterone. In previous studies, we intentionally inhibited gonadotropin secretion with GnRH analogs prior to treatment, resulting in castrate baseline testosterone concentrations. Since gonadotropin suppression was the primary endpoint in this study, no such suppression was used, and it is likely that the remaining LH, although suppressed, still stimulated some endogenous production of testosterone. Additional studies using oral TE in combination with second agents intended to synergistically suppress gonadotropins will be required to fully determine the pharmacokinetics of oral TE in such a contraceptive setting.
One unanticipated feature of the long-term pharmacokinetics of oral TE was the marked diminution of the postdose testosterone peak with the evening administration of oral TE in the 400 mg twice-daily group. The reason for this is unclear but is not likely due to increased testosterone metabolism at night, since previous studies of metabolism have determined that testosterone metabolism is actually reduced at night (Wang et al, 2004). Our earlier work has demonstrated the concomitant food intake only slightly reduces serum testosterone concentrations achieved after oral dosing of TE in oil (Amory et al, 2006). Since the evening dose was administered after dinner, delayed postprandial absorption may play some role in this difference; however, in general, differences in gastrointestinal transit appear to explain little of the variability in bioavailability with most drugs (Riley et al, 1992). Also, this is not due to the effect of dutasteride "wearing off" by the evening, since the serum DHT peak was similarly attenuated. Obviously, further study of this intriguing phenomenon is required. This observation also suggests the possibility that dosing the oral TE at night might reduce the supraphysiologic Cmax observed with morning doses. Whether this is possible will be the subject of future studies of oral TE plus dutasteride. Importantly, there was no evidence of either liver or kidney toxicity associated with the doses of oral TE administered in this study. While no liver inflammation or other serious adverse events were reported during the 4 weeks of oral testosterone plus dutasteride, it is possible that such effects could be observed with more prolonged treatment. Additional studies administering oral testosterone plus dutasteride for longer periods of time will be required to determine whether this combination is safe long term. In theory, the ability to selectively increase serum testosterone without increasing serum DHT may be attractive in minimizing the risk for DHT-dependent disease, such as benign prostatic hyperplasia, acne, and alopecia, which are associated with testosterone therapy. It is notable that the serum DHT concentration remained suppressed during recovery. This is likely due to the long half-life of dutasteride (Clark et al, 2004).
Notably, no significant changes in mood or sexual function were noted in these healthy volunteers over 1 month. However, since these subjects were still likely producing endogenous testosterone, it is difficult to conclude that oral TE was able to maintain these endpoints. Nevertheless, it can be said that the transient supraphysiologic hormone concentrations observed in this study did not confer apparent psychologic or physiologic alterations, as assessed by self-reported questionnaire.
In conclusion, we have demonstrated that 1 month of oral TE combined with dutasteride can result in suppression of FSH and LH in healthy men. Such gonadotropin suppression would presumably be effective as part of a male contraceptive regimen in combination with either a progestogen or a GnRH analog when administered for periods of at least 12 weeks. Additional, longer-term studies of oral TE plus dutasteride in combination with one of these agents are warranted to determine whether oral TE can be a component of an effective oral form of male contraception.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractSubjects and MethodsResultsDiscussionReferences |
|---|
Amory JK, Page ST, Bremner WJ. Oral testosterone in oil:
pharmacokinetic effects of 5 reduction with finasteride or dutasteride
and food intake in men. J Androl. 2006; 27: 72
–78.
Amory JK, Wang C, Swerdloff R, Anawalt BD, Matsumoto AM, Bremner
WJ, Walker SE, Haberer LJ, Clark RV. The effect of 5-reductase
inhibition with dutasteride and finasteride on semen parameters and serum
hormones in healthy men. J Clin Endocrinol Metab. 2007; 92: 1659
–1665.
Bagatell CJ, Bahl KD, Bremner WJ. The direct pituitary effect of
testosterone to inhibit gonadotropin secretion in men is partially mediated by
aromatization to estradiol. J Androl. 1994; 15: 15
–21.
Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab. 1996;81: 757 –762.[Abstract]
Brady DM, Amory JK, Perheentupa A, Zitzmann M, Hay C, Apter D,
Anderson RA, Bremner WJ, Huhtaniemi I, Nieshclag E, Wu FCW, Kersemaekers WM. A
multi-centre study investigating subcutaneous etonogestrel implants with
injectable testosterone decanoate as a potential long-acting male
contraceptive. Hum Reprod. 2006; 21: 285
–294.
Canovatchel WJ, Volquez D, Huang S, Wood E, Lesser Ml, Gautier T, Imperato-McGinley J. Luteinizing hormone pulsatility in subjects with 5-alpha-reductase deficiency and decreased dihydrotestosterone production. J Clin Endocrinol Metab. 1994; 78: 916 –921.[Abstract]
Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs
S. Marked suppression of dihydrotestosterone in men with benign prostatic
hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J
Clin Endocrinol Metab. 2004; 89: 2179
–2184.
Hayes FJ, Decruz S, Seminara SB, Boepple PA, Crowley WF.
Differential regulation of gonadotorpin secretion by testosterone in the human
male: absence of a negative feedback effect of testosterone on
follicle-stimulating hormone secretion. J Clin Endocrinol
Metab. 2001;86: 53
–58.
Hayes FJ, Seminara SB, Decruz S, Boepple PA, Crowley WF. Aromatase
inhibition in the human male reveals a hypothalamic site of estrogen feedback.
J Clin Endocrinol Metab. 2000; 85: 3027
–3035.
Heckel MJ. Production of oligospermia in a man by the use of
testosterone propionate. Proc Soc Exp Biol Med. 1939; 40: 658
–659.
Heinemann K, Saad F, Wiesemes M, White S, Heinemann L. Attitudes
toward male fertility control: results of a multinational survey on four
continents. Hum Reprod. 2005; 20: 549
–556.
Kalhorn TF, Page ST, Howald WN, Mostaghel EA, Nelson PS. Analysis of testosterone and dihydrotestosterone from biological fluids as the oxime derivatives using high-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2007; 21: 3200 –3206.[CrossRef][Medline]
Marberger M. Drug insight: 5alpha-reductase inhibitors for the treatment of benign prostatic hyperplasia. Nat Clin Pract Urol. 2006;3: 495 –503.[CrossRef][Medline]
Martin CW, Anderson RA, Chang L, Ho PC, van der Spuy Z, Smith KB,
Glasier AF, Everington D, Baird DT. Potential impact of hormonal male
contraception: cross-cultural implications for development of novel male
preparations. Hum Reprod. 2000; 15: 637
–645.
Matthiesson KL, McLachlan RI. Male hormonal contraception: concept
proven, product in sight? Hum Reprod Update. 2006; 12: 463
–482.
McNair DM, Lorr M, Droppleman LF. Profile of Mood States: Manual. San Diego, CA: Education and Industrial Testing Service; 1971.
O'Leary MP, Fowler FJ, Lenderking WR, Barber B, Sagnier PP, Guess HA, Barry MJ. Brief male sexual function inventory for urology. Urology. 1995;46: 697 –706.[CrossRef][Medline]
Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, Wilson T, Rittmaster RS. The importance of dual 5alpha-reductastse inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol. 2006;55: 1014 –1023.[CrossRef][Medline]
Otberg N, Finner WM, Shapiro J. Androgenetic alopecia. Endocrinol Metab Clin North Am. 2007; 36: 379 –398.[CrossRef][Medline]
Page ST, Amory JK, Anawalt BD, Irwig M, Brockenbrough A, Matsumoto
AM, Bremner WJ. Testosterone gel combined with depomedroxyprogesterone acetate
(DMPA) is an effective male hormonal contraceptive regimen but is not enhanced
by the addition of the GnRH antagonist acyline. J Clin Endocrinol
Metab. 2006;91: 4374
–4380.
Riley SA, Sutcliffe F, Kim M, Kapas M, Rowland M, Turnberg LA. The influence of gastrointestinal transit on drug absoprtion in healthy volunteers. Br J Clin Pharmacol. 1992; 34: 32 –39.[Medline]
Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003; 349: 215 –224.[CrossRef][Medline]
Wang C, Catlin DH, Starcevic B, Leung A, DiStefano E, Lucas G, Hull
L, Swerdoff RS. Testosterone metabolic clearance and production rates
determined by stable isotope dilution/tandem mass spectrometry in normal men:
influence of ethnicity and age. J Clin Endocrinol
Metab. 2004;89: 2936
–2941.
Weston GC, Schlipalious ML, Bhuinneasin MN, Vollenhoven BJ. Will Australian men use male hormonal contraception? Med J Aust. 2002;175: 204 –205.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
P < .05 between dose groups at a given time
point.