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From the Clinical Research Centers |
Divisions of Endocrinology, Departments of Medicine/Pediatrics, Harbor-University of California-Los Angeles Medical Center and Research and Education Institute (R.S.S., C.W., N.B.), Torrance, California 90509; Veterans Affairs Medical Center, Baylor College of Medicine (G.C.), Houston, Texas 77030; The Johns Hopkins University (A.D.), Baltimore, Maryland 21287; Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; Veterans Affairs Puget Sound Health Care System, University of Washington (A.M.M.), Seattle, Washington 98108; University of Pennsylvania Medical Center (P.J.S.), Philadelphia, Pennsylvania 19104; Duke University Medical Center (T.W.), Durham, North Carolina 27705; Unimed Pharmaceuticals, Inc. (J.L.), Deerfield, Illinois 60015
Address all correspondence and requests for reprints to: Christina Wang, M.D., General Clinical Research Center, Harbor-University of California-Los Angeles Medical Center, 1000 West Carson Street, Torrance, California 90509-2910. E-mail: wang{at}gcrc.humc.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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T and other steroids can also be applied to the skin in open systems.
When T is applied to the skin surface as a hydroalcoholic gel, the gel
dries rapidly, and the steroid is absorbed into the stratum corneum,
which serves as a reservoir. The reservoir in the skin releases T into
the circulation slowly over several hours, resulting in steady state
serum levels of the hormones (22). Our previous short-term
(7–14 days) pharmacokinetic studies of both T and
5
-dihydrotestosterone (DHT) transdermal hydroalcoholic gels showed
that the androgens were absorbed, and peak levels of the applied
androgens occurred 18–24 h after initial application. With continued
application of the gel for 7–14 days, steady serum levels of androgens
were maintained (23, 24). About 9–14% of the T in the
gel applied to the skin is bioavailable (24). We also
demonstrated that application of the T gel (100 mg/day) at a single
site or four separate sites resulted in serum T levels at the upper
limit of the normal range, with about 23% higher serum levels when the
gel was applied at four sites. In the 7- to 14-day studies, neither T
nor DHT gel produced skin irritation in the small number of subjects
studied (23, 24). In the present study we investigated the
detailed pharmacokinetics and tolerability of T gel (AndroGel) at two
dosages (50 and 100 mg/day) and T patch after repeated daily dosing for
180 days in a large number of hypogonadal men (n = 227) recruited
from 16 centers across the United States.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Two hundred and twenty-seven hypogonadal men were recruited,
randomized, and studied in 16 centers in the United States. About one
third of the subjects were randomized into each treatment group (Table 1
). The patients were between 19–68 yr
of age and had single morning serum T levels at screening of 10.4
nmol/L (300 ng/dL) or less. The screening serum T concentrations were
measured at each center’s clinical laboratory. Previously treated
hypogonadal men were withdrawn from T ester injection for at least 6
weeks and from oral or transdermal androgens for 4 weeks before the
screening visit. Aside from the hypogonadism, the subjects were in good
health, as evidenced by medical history, physical examination, complete
blood count, urinalysis, and serum biochemistry. If the subjects were
taking lipid- lowering agents or tranquilizers, the doses were
stabilized for at least 3 months before enrollment. The subjects had no
history of chronic medical illness or alcohol or drug abuse. The
subjects had a normal rectal examination, a prostate-specific antigen
level of less than 4 ng/mL, and a urine flow rate of more than 12 mL/s
before enrollment to the study. They were excluded if they had a
generalized skin disease that might affect T absorption or a prior
history of skin irritability with the nonscrotal T patch
(Androderm). Subjects with body weight of less than 80 or
more than 140% of ideal body weight and subjects taking medications
known to alter the cytochrome P450 enzyme systems were also excluded
from this study.
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T gel (AndroGel) was manufactured by Besins Iscovesco (Paris, France) and supplied by Unimed Pharmaceuticals, Inc. (Deerfield, IL). The formulation is a hydroalcoholic gel containing 1% T (10 mg/g). We have previously shown that about 9–14% of the steroid in the gel applied is available to the body. Thus, 10 g gel applied to the skin contain 100 mg T and delivers approximately 10 mg T to the body (23, 24). Approximately 250 g gel were packaged in multidose glass bottles that delivered 2.27 g gel for each actuation of the pump. Patients assigned to the 50 mg T in 5 g gel group were given one bottle of T gel and one bottle of placebo gel (vehicle only); those assigned to the 100 mg T in 10 g gel were dispensed two bottles of the active T gel. All patients applied T gel or placebo gel at four separate sites each day (right and left upper arms/shoulders and right and left abdomen). On day 1 of the study, the patients were instructed to depress the pump of one of the bottles once, and the gel was applied to the right upper arm/shoulder. Then, using the same bottle, a second dose of gel was delivered and applied to the left upper arm/shoulder. The second bottle was then used with the actuation of the pump for gel to be applied to the right abdomen and the second actuation to the left abdomen. On the following day, the application sites were reversed. Alternate application sites continued throughout the study. After application of the gel to the skin, the gel dried within a few minutes. The patients washed their hands with soap and water thoroughly after gel application. After 90 days the subjects titrated to the 75 mg/day T gel dose were supplied with three bottles, one containing placebo and two containing T gel. The subjects were instructed to apply one actuation from the placebo bottle and three actuations from the T gel bottle to four different sites of the body as described above.
T patches (Androderm) were provided, each delivering 2.5 mg/day T, which is the recommended replacement dose for androgen replacement therapy. The patients were instructed to apply two T patches to a clean dry area of skin on the back, abdomen, upper arms, or thighs once per day. Application sites were rotated, with an approximately 7-day interval between applications to the same site. T gel or patches were applied at approximately 0800 h each morning for 180 days.
In the T gel group, treatment compliance was estimated as the percentage of T gel actually used compared with the theoretical amount of T gel that could have been used. The actual amount of T gel used was measured as the difference in weight of the dispensed and returned T gel bottles. The theoretical weight of T gel that could have been used was calculated as 2.27 g/actuation x days in study x 2, 3, or 4 actuations depending on whether the dose of T gel was 50, 75, or 100 mg, respectively. In the T patch group, the actual number of patches used was compared with the theoretical number that could have been used calculated as days in study x 2 patches/day.
Study design
The study is a randomized, multicenter (16 centers), parallel study including 2 doses of T gel and a single dose of T patches. A placebo group was not included because 6-month placebo treatment of hypogonadal men was not believed to be justifiable, as untreated hypogonadism will result in impaired libido, decreased strength, bone mineral loss, and other clinical defects. The study was double blinded until day 90 with respect to the T gel groups and open label for the T patch group. For the first 3 months of the study (days 1–90), the subjects were randomized to receive 50 mg/day T gel (in 5 g gel delivering about 5 mg T/day), 100 mg/day T gel (in 10 g gel delivering about 10 mg T/day), or 2 patches delivering 5 mg T/day (T patch). In the following 3 months (days 91–180), the subjects were administered 1 of the following treatments: 50 mg/day T gel, 100 mg/day T gel, 75 mg/day T gel, or 5.0 mg/day T patch. Patients who were applying T gel had a single, preapplication serum T measurement made on day 60; if the levels were within the normal range (10.4–34.7 nmol/L; 300-1000 ng/dL), they remained on their original dose. Men with T levels at 60 days of treatment less than 10.4 nmol/L and who were applying 50 mg T gel and those with T levels more than 34.7 nmol/L who had received 100 mg T gel were then assigned to the 75 mg/day T gel group for days 91–180. No changes in dose were made to subjects randomized to T patch.
On days 0, 1, 30, 90, and 180 subjects had multiple blood samples for T and free T measurements at 30, 15, and 0 min before and 2, 4, 8, 12, 16, and 24 h after T gel or patch application. Brief history and physical examinations were performed, and any complaints or adverse events were documented in the subject’s records. In addition, subjects returned to each study center on days 60, 120, and 150 for a single blood sampling before application of the gel or patch. Serum DHT, estradiol (E2), FSH, LH, and sex hormone-binding globulin (SHBG) were measured in samples collected before gel or patch application on days 0, 30, 60, 90, 120, 150, and 180. Sera for hormones were stored frozen at -20 C until assay. All samples for a patient for each hormone were measured in the same assay whenever possible. In addition, the subjects were examined for any adverse effects and skin irritation.
Hormone assays
Except for the screening serum T concentration, which was measured at each center’s clinical laboratory, all hormone assays were performed at the Endocrine Research Laboratory of the Harbor-University of California-Los Angeles Medical Center. Serum T levels were measured after extraction with ethyl acetate and hexane by a specific RIA using reagents from ICN Biomedicals, Inc. (Costa Mesa, CA). The cross-reactivities of the antiserum used in the T RIA were 2.0% for DHT, 2.3% for androstenedione, 0.8% for 3ß-androstanediol, 0.6% for etiocholanolone, and less than 0.01% for all other steroids tested. The lower limit of quantitation of serum T measured by this assay was 0.87 nmol/L (25 ng/dL). The mean accuracy (recovery) of the T assay, determined by spiking steroid free serum with varying amounts of T (0.9–52 nmol/L), was 104% (range, 92–117%). The intra- and interassay coefficients of the T assay were 7.3% and 11.1% at the normal adult male range, which in our laboratory was 10.33–36.17 nmol/L (298–1043 ng/dL). Serum free T was measured by RIA of the dialysate after an overnight equilibrium dialysis, using the same RIA reagents as in the T assay. The lower limit of quantitation of serum free T using this equilibrium dialysis method was estimated to be 22 pmol/L. When steroid-free serum was spiked with increasing doses of T in the adult male range, increasing amounts of free T were recovered, with a coefficient of variation that ranged from 11–18.5%. The intra- and interassay precisions of free T were 15% and 16.8%, respectively, for adult normal male values (121–620 pmol/L, 3.48–17.9 ng/dL).
Serum DHT was measured by RIA after potassium permanganate treatment of
the sample followed by extraction. The methods and reagents of the DHT
assay were provided by Diagnostic Systems Laboratories, Inc. (Webster, TX). The cross-reactivities of the antiserum used
in the RIA for DHT were 6.5% for 3ß-androstanediol, 1.2% for
3-androstanediol, 0.4% for 3-androstanediol glucuronide, 0.4%
for T (after potassium permanganate treatment and extraction), and less
than 0.01 for other steroids tested. This low cross-reactivity against
T was further confirmed by spiking steroid free serum with T (35
nmol/L, 1000 ng/dL) and taking the samples through the DHT assay. The
results even on spiking with over 35 nmol/L T were less than 0.1 nmol/L
DHT. The lower limit of quantitation of serum DHT in this assay was
0.43 nmol/L. All values below this value were reported as less than
0.43 nmol/L. The mean accuracy (recovery) of the DHT assay, determined
by spiking steroid free serum with varying amounts of DHT from 0.43–9
nmol/L, was 101% (range, 83–114%). The intra- and interassay
coefficients of variation for the DHT assay were 7.8% and 16.6%,
respectively, for the adult male range, which in our laboratory was
1.06–6.66 nmol/L (30.7–193.2 ng/dL).
Serum E2 levels were measured by a direct assay without extraction with reagents from ICN Biomedicals, Inc. The intra- and interassay coefficients of variation of E2 were 6.5% and 7.1%, respectively, for normal adult male range (E2, 63–169 pmol/L, 17.1–46.1 pg/mL). The lower limit of quantitation of the E2 was 18 pmol/L. All values below this value were reported as 18 pmol/L. The cross-reactivities of the E2 antibody were 6.9% for estrone, 0.4% for equilenin, and less than 0.01% for all other steroids tested. The accuracy of the E2 assay was assessed by spiking steroid free serum with an increasing amount of E2 (18–275 pmol/L). The mean recovery of E2 compared with the amount added was 99.1% (range, 95–101%).
Serum SHBG levels were measured by assay kits obtained from Delfia (Wallac, Inc., Gaithersburg, MD). The intra- and interassay precisions were 5% and 12%, respectively, for the adult normal male range (10.8–46.6 nmol/L). Serum FSH and LH were measured by highly sensitive and specific fluoroimmunometric assays with reagents provided by Delfia (Wallac, Inc., Gaithersburg, MD). The intraassay coefficient of variations for LH and FSH fluoroimmunometric assays were 4.3% and 5.2%, respectively, and the interassay variations for LH and FSH were 11.0% and 12.0%, respectively (adult normal male range: LH, 1.0–8.1 U/L; FSH, 1.0–6.9 U/L). For both LH and FSH assays, the lower limit of quantitation was 0.2 IU/L. All samples obtained from the same subject were measured in the same assay.
Statistical analyses
Descriptive statistics for each of the hormone levels were calculated. Before analysis, each variable was examined for its distributional characteristics and, if necessary, transformed to meet the requirements of a normal distribution. There were no significant differences between the study sites on any of the parameters; therefore, the data presented were pooled for all of the centers. The pharmacokinetic parameters for each full sampling day were determined by noncompartmental methods. The pharmacokinetics of T gel were assessed using the area under the curve from 0–24 h (AUC0–24) generated by the 24 h of multiple blood sampling for T on days 1, 30, 90, and 180. The AUC was computed using the linear trapezoid method. The average T concentration over the 24 h after gel application (Cavg) was calculated as the AUC0–24 divided by 24 h.
All data in the figures and tables show the treatment mean
(±SEM) by time and/or day for each of the three groups of
subjects based on the treatment from days 0–90 and for each of the
five groups from days 91–180. However, because the final treatment
groups (five groups) for the subjects receiving T gel were no longer
randomized, statistical comparisons between groups were only performed
until day 90 using the original treatment assignments (50 or 100 mg T
gel or patch) as the independent groups. Comparisons between groups
were performed using one-way ANOVA or the Kruskal-Wallace test
(accumulation ratio, fluctuation index) followed by posttest contrasts.
Analysis of the effects was performed using repeated measures ANOVA.
The 
2 test was used to compare rates. Analyses
of change from day 0 to day 180 within treatment groups were performed
within each of the five groups based on pattern using paired
t tests. Comparisons resulting in P 
0.05
were considered statistically significant. SAS version 6.12 was used
for all analyses (SAS Institute, Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 227 patients were enrolled: 73, 78, and 76 were
randomized to the 50 mg/day T gel (T gel 50), 100 mg/day T gel (T gel
100), and T patch groups, respectively (Table 1
). There were no
significant differences in the patients’ characteristics at baseline
(height, weight, and previous T treatment). Thirty-five to 45% of the
patients in each treatment group had primary hypogonadism
(Klinefelter’s syndrome, anorchia, testicular failure); 15–25% had
well defined secondary hypogonadism (Kallman’s syndrome, hypothalamic
pituitary disease, pituitary tumor). The other patients had low serum T
and normal or low normal LH levels. These were ascribed to aging (based
on age >60 yr), or normogonadotropic hypogonadism. These patients did
not have brain imaging to exclude hypothalamic-pituitary disease. Their
primary physician did not deem that brain scans were indicated. After
completion of day 90, 55 of the subjects in the T patch, 67 in the T
gel 50, and 73 in the T gel 100 groups agreed to continue for another 3
months (days 91–180). The discontinuation rate (21 of 76, 27.6%) in
the T patch group was higher (P = 0.0002) than those in
the T gel groups (50 mg: 6 of 73, 8.2%; 100 mg: 5 of 78, 6.4%). Most
of the discontinuation in the T patch group was due to adverse skin
reaction based on the subjects’ complaints and records. After 90 days
of treatment, patients randomized initially to the T gel groups had
dose adjustment if their preapplication serum T level was below 10.4 or
above 34.7 nmol/L on day 60. Twenty subjects who had received 50 mg/day
T gel had their dose increased to 75 mg/day; 20 who had received 100
mg/day T gel decreased their dose to 75 mg/day. The exceptions were 1
100 mg T gel patient who was adjusted to 50 mg/day and 1 50 mg T gel
patient who decreased the dose to 25 mg/day. Before approval of the
long-term follow-up study, 3 patients who were receiving T patch until
day 90 were switched to T gel 50 from days 91–180 because of skin
irritation from the patches. The data for these 3 patients as well as
for the single subject who was changed from 100 to 50 mg/day were
analyzed as the T gel 50 group from days 91–180. The number of
subjects enrolled in the study from days 91–180 was 195, with 51
receiving T gel 50, 40 receiving T gel 75, 52 receiving T gel 100, and
52 continuing on the patch.
Treatment compliance
From days 1–90, the mean treatment compliance rates were 89.8%, 93.1%, and 96.0% for the T patch, T gel 50, and T gel 100 groups, respectively. During days 1–180 (the 6-month study period), the mean compliance rate was 86.3% for the T patch and 93.3%, 111.4%, and 96.5% for the 50, 75, and 100 mg/day T gel groups, respectively.
Pharmacokinetics of serum T concentrations (Table 2 and Fig. 1)
At baseline (day 0) average serum T concentrations over 24 h
(Cavg) were similar in the three groups and were
below the normal adult range (Fig. 1). In all three groups, during the
24-h baseline period the mean maximum T levels
(Cmax) occurred between 0800–1000 h (0–2 h in
Fig. 1), and the minimum (Cmin) T levels occurred
8–12 h later, demonstrating the expected diurnal variation of serum
T.
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On day 1 after the first application of transdermal T, serum T rose most rapidly in the T patch group, reaching a Cmax between 8–12 h (Tmax), plateaued for another 8 h, then declined to the baseline. Serum T rose steadily to the normal range after T gel application, with Cmax achieved by 22 and 16 h in the T gel 50 and T gel 100 groups, respectively.
On days 30 and 90, serum T followed a similar pattern as on day 1 in
the T patch group. In the T gel groups, serum T levels were at steady
state, showing small and variable increases after treatment. After gel
application on both days 30 and 90, the Cavg in
the T gel 100 group was 1.4-fold higher than that in the T gel 50 group
and was 1.9-fold higher than that in the T patch group
(P = 0.0001). The variation in serum concentration over
the day [fluctuation index = (Cmax -
Cmin)/Cavg] was similar in
the three groups. On days 30 and 90, the accumulation ratio, which is
defined as the increase in daily exposure to T with continued
transdermal application (calculated as AUCday 30 or
90/AUCday 1) was 0.94 ± 0.04
for the T patch group showing no accumulation, whereas the accumulation
ratios at 1.53 ± 0.09 and 1.9 ± 0.18 were significantly
higher (P = 0.0001) in the T gel 50 and 100 groups,
respectively. This indicates that the T gel preparations had a longer
effective half-life than the T patch (Table 2 and Fig. 2).
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and
Table 2). For the patients who switched from T gel 50 or 100 to T gel
75, their Cavg on day 180 was 20.84 ± 1.76
nmol/L, midway between the Cavg in the T gel 50
(19.24 ± 1.18 nmol/L) and T gel 100 (24.72 ± 6.08 nmol/L)
groups. Examination of Table 2 and Fig. 1 shows that the patients
titrated to this T gel 75 group were not homogeneous. On day 180, the
Cavg in the patients in the T gel 100 group who
converted to 75 mg/day on day 90 was 1.7-fold higher than the
Cavg in the patients titrated to T gel 75 from 50
mg/day. Despite adjusting the dose up by 25 mg/day in the T gel 50 to
75 group, the Cavg remained lower than for those
remaining in the 50 mg group. In the T gel 100 to 75 group, the
Cavg became similar to those achieved by patients
remaining in the T gel 100 group without dose titration. The increase in AUC0–24 h on days 30, 90, and 180 from the pretreatment baseline (net AUC0–24 h) showed dose proportionality. The mean for the net AUC0–24 h from day 0 to day 30 or 90 was about 1.7-fold higher for T gel 100 than for T gel 50 patients (T gel 50: day 30, 268 ± 28; day 90, 263 ± 29 nmol/L·h; T gel 100: day 30, 446 ± 30; day 90, 461 ± 27 nmol/L·h). A 4.3 nmol/L (125 ng/dL) mean increase in the serum T Cavg level was produced by each 25 mg/day of T gel. The increases in AUC0–24 h from the pretreatment baseline achieved by the T gel 100 and T gel 50 groups were approximately 2.9- and 1.7-fold higher than those resulting from application of the T patch (day 30, 154 ± 18; day 90, 157 ± 20 nmol/L·h).
The preapplication serum T levels in the T patch group remained at the
lower limit of the normal range throughout the entire treatment period.
Serum T levels after T gel application reached steady state at about
1–2 days after the initial application (24). Thereafter,
the mean serum T levels remained at about 17–20 nmol/L in the T gel 50
group and about 22–30 nmol/L in the T gel 100 group (Fig. 2, upper panel).
Pharmacokinetics of serum free T concentration
At baseline (day 0), serum free T Cavg was similar in all three groups (T patch, 167 ± 14; T gel 50, 154 ± 14; T gel 100, 150 ± 13 pmol/L) and was at the lower limit of the adult male range (121–620 pmol/L). The detailed pharmacokinetic parameters of serum free T on days 1, 30, 90, and 180 mirrored those of serum total T as described above (data not shown). Similar to the total T results, the free T Cavg achieved by the T gel 100 group was 1.4- and 1.7-fold higher than those in the T gel 50 and T patch groups, respectively (P = 0.001).
The preapplication mean free T levels throughout the treatment period
in all three groups were within the normal range, with the T gel 100
group maintaining higher free T levels than both the T gel 50 and T
patch groups (Fig. 2, middle panel). The calculated percent
free T (free T/T x 100) remained between 1.6–2.2% before and
throughout the transdermal T treatment period. Exogenous T replacement
did not significantly alter the percent free T in any of the treatment
groups (Fig. 2, lower panel).
Serum DHT concentrations
The pretreatment mean serum DHT concentrations were between
1.24–1.45 nmol/L, which were near the lower limit of the normal range
(1.06–6.66 nmol/L) and were not different among the three groups (Fig. 3, upper panel). After T patch
application mean serum DHT levels rose to about 1.3-fold above the
baseline, whereas serum DHT increased to 3.6-fold (within the normal
range) and 4.8-fold (at the upper limit of the normal range) above the
baseline after application of T gel 50 and 100 (P =
0.0001), respectively, throughout the 180 days. Examination of the DHT
to T ratio (Fig. 3, middle panel) showed that
this ratio was not significantly altered in the T patch group
(P = 0.078), whereas in the T gel 50 and 100 groups,
the DHT to T ratio increased significantly from a baseline of 0.2 to
between 0.23–0.29 and 0.29–0.33, respectively, during the treatment
period (P = 0.0001 for both groups). The mean serum
total androgen levels (calculated as the sum of serum T + DHT levels
for each time point) achieved by T gel 100 throughout the treatment
period were 1.4- and 2.5-fold higher than those in the T gel 50 (
20
nmol/L) and T patch (10 nmol/L) groups, respectively
(P = 0.0001; Fig. 3, lower panel).
Adjustment of the T gel dose on day 90 did not significantly affect the
serum DHT levels, DHT/T ratios, or total androgen levels.
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The baseline mean serum E2 levels were at
the lower normal range and were not different in the three treatment
groups. After transdermal T application, mean serum estradiol increased
to stable levels by an average of 9.2% in the T patch during the
treatment period, 30.9% in the T gel 50 group, and 45.5% in the T gel
100 group (P = 0.001; Fig. 4).
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The serum SHBG levels were similar and within the adult male range in the three treatment groups at baseline. After T replacement, serum SHBG levels showed a small decrease in all three groups (P = 0.0046; data not shown), which was most marked in the T gel 100 group (baseline, 26.6 ± 2.0; day 90, 23.6 ± 2.7; day 180, 24.0 ± 1.7 nmol/L; P = 0.0095).
Suppression of serum gonadotropin levels
Because of the wide variability in the baseline serum LH and FSH
levels, these were expressed as the percent change from baseline in
response to T replacement (Fig. 5). The
mean percent suppression of serum LH levels was least in the T patch
group (between 30–40%), intermediate in the T gel 50 group
(between 55–60%), and most marked in the T gel 100 group (between
80–85%; P < 0.01). The suppression of serum FSH
paralleled that of serum LH levels. In the subjects with primary
hypogonadism, mean serum LH and FSH levels were suppressed to within
the normal range after both doses of T gel administration, but remained
above the normal range after T patch application. The suppression of
serum gonadotropins occurred in all hypogonadal subjects regardless of
the classification of hypogonadism.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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1) with repeated application. The accumulation
ratios were higher in both T gel groups (1.5–1.9) on day 30,
consistent with the longer lasting elevations of serum T. With
continued application of T gel, the accumulation rates showed no
further increases, suggesting no further accumulation on days 90 and
180. Dose titration of T gel to 75 mg was initiated after day 90 in the hypogonadal men who had serum T levels above or below the normal range. Because of study design there was no dose adjustment within the T patch group. Increasing the number of T patches to three or four a day could have resulted in increases in the mean serum T concentrations (16), but might have led to an even higher dropout rate because of skin irritation in some subjects. The patients who were converted from the T gel 50 to 75 mg/day, despite increasing the dose by 50%, had average serum T levels lower than those remaining in the T gel 50 group. It is uncertain whether these lower responders to T gel might be less compliant or are biologically different. The former may be possible in some individuals, as about one third of the subjects had a lower mean compliance rate of 80%, and the average serum T levels attained were related to the mean compliance rate. Alternatively, some patients might have low absorption and high clearance of T either in the basal state or after induction by exogenous T. Downward titration of the T gel dose from 100 to 75 mg/day was effective in decreasing the mean serum T level in the group by 15% and lowering the serum T concentration to the normal range in 16 of 19 of these hypogonadal men.
The present study examined a new transdermal open system, T gel, together with the available standard closed T patch system. A placebo group was not included because of ethical problems associated with withdrawing or delaying T replacement in hypogonadal men for a prolonged 6-month study period. Despite a relatively higher dropout rate, pharmacokinetic data obtained from this large group of hypogonadal men treated with this T patch were similar to those previously reported (14, 15).
Serum free T levels rose after transdermal T gel or T patch application, paralleling those of serum T. The percent free T did not change significantly with T treatment. The results were corroborated by the small decreases, probably not clinically significant, in serum SHBG observed after transdermal T replacement in all three groups. The results indicated that when T is administered by the transdermal route, the lack of the first pass effect of the liver resulted in minor, if any, decreases in SHBG.
T gel application resulted in mean serum DHT that tripled after
application of 50 mg T gel and rose nearly 5-fold with 100 mg T gel
treatment. As 5-reductase is present in nongenital skin
(25), the increase in DHT/T ratios in the 100 and 50 mg
gel groups could be explained by the higher conversion in the skin of T
to DHT as a result of the large area of skin surface exposed to T in
the gel groups compared with the very small area of skin exposed to the
T patch. Increased DHT/T ratios have been observed with the transdermal
scrotal patch, where even greater DHT/T ratios were noted
(11, 12, 13). DHT is a potent androgen that is not
back-convertible to T or aromatizable to E2.
Serum levels of T and DHT are not equivalent in all aspects of
biological action, but certainly both have major actions on multiple
androgen-dependent target organs. The biological impact of the
moderately greater increase in DHT after T gel application is unclear
other than its additive effect on total androgen action. Serum
E2 levels showed small and proportionate
increases after transdermal T application that may be important for the
known beneficial effects of estrogens on serum lipid levels, vascular
endothelium reactivity, and bone resorption.
The biological activity of the T replacement in the hypogonadal men was evidenced by the consistent suppression of serum gonadotropin levels in the patients after transdermal T applications. The suppression of gonadotropins was proportional to the serum T levels achieved by the T patch or T gel. The marked and consistent suppression of gonadotropins observed after T gel 100 treatment suggested that such a modality of T delivery could be used in a male contraceptive regimen.
All patients were diagnosed to have male hypogonadism by their primary
physician. In each of the three treatment groups, the same proportion
(30–35%) of subjects had subnormal serum T levels at screening
(assayed at each center’s clinical laboratory), but their average
serum T levels over 24 h were within the normal range when studied
at baseline (on another day and assayed at the central laboratory).
Serum T in a population of men is to a great extent a continuum. The
selection of men that had serum T levels below 10.4 nmol/L at
screening would inevitably allow some subjects to have serum T above
this arbitrarily defined threshold (approximately <2 SD below the mean
for young adult men) on subsequent measurements. The admission
criterion requiring a serum T concentration of 10.4 nmol/L or less is
arbitrary and necessary for the design of a clinical study; however,
there is no definite evidence that there is a threshold level of T at
which biological response changes. The well known intrasubject
variability from day to day and the differences between T assays using
different reagents and methods might account for this discrepancy
between screening and baseline levels. It is also not uncommon in
clinical practice that on repeat serum T measurements, some hypogonadal
patients would have serum T levels that fluctuate in and out of the
statistical normal range. In practice, if symptomatic, many if not most
of these men received androgen replacement therapy. The situation for
assessment of pharmacokinetic parameters after administration of
naturally occurring substances (e.g. T) poses different
problems from those after administration of non-naturally occurring
substances in the body. Ultimate serum levels attained in dynamic
closed loop endocrine systems are complex and include integration of T
levels (with endogenous serum T decreasing while serum T rises from
exogenous administration), the characteristics of the formulation, the
generic and individualized metabolic factors, and the duration of
treatment. Although serum T levels attained in the groups with low or
normal baseline levels were different, statistical analyses showed that
the relative response to T transdermal treatment was not affected by
the initial value. Thus, inclusion of these subjects did not influence
the treatment comparison.
We conclude that transdermal T gel application can efficiently elevate serum T and free T levels in hypogonadal men into the mid to upper normal range within the first day of application, achieve steady state within a few days, and maintain serum T levels with once daily repeated applications. Although serum DHT/T ratios were raised after T gel applications, these ratios remained within the normal range. Serum E2 levels were increased, and gonadotropin levels were suppressed in proportion to serum T levels. The pharmacokinetic profile and the dose proportionality observed after T gel application indicate that this transdermal delivery system may provide dose flexibility and serum T levels from the low to the high normal adult male range.
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Acknowledgments |
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Footnotes |
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2 The Testosterone Gel Study Group includes: S. Berger, The
Chicago Center for Clinical Research (Chicago, IL); E. Dula, West Coast
Clinical Research (Van Nuys, CA); J. Kaufman, Urology Research Options
(Aurora, CO); G. P. Redmond, Center for Health Studies (Cleveland,
OH); S. Scheinman and H. W. Hutman, South Florida Bioavailability
Clinic (Miami, FL); S. L. Schwartz, Diabetes and Glandular Disease
Clinic, P.A. (San Antonio, TX); C. Steidle, Northeast Indiana Research
(Fort Wayne, IN); J. Susset, MultiMed Research (Providence, RI); G.
Wells, Alabama Research Center, L.L.C. (Birmingham, AL); and R. E.
Dudley, S. Faulkner, N. Rehousky, G. Ringham, W. Singleton, and K.
Zunich, Unimed Pharmaceuticals, Inc. (Deerfield,
IL).
Received December 28, 1999.
Revised March 25, 2000.
Revised June 30, 2000.
Accepted August 30, 2000.
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References |
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reductase isozyme expression. J Clin Invest. 92:903–910.
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, T
patch, 
, T gel 50; •, T gel 100; 
, T gel 50 to 75; 
, T gel
100 to 75.
