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From the Clinical Research Centers |
Johns Hopkins Medical Center (A.S.D.), Baltimore, Maryland 21287; Departments of Medicine (A.W.M.) and Pharmaceutics (N.A.M.), University of Utah, Salt Lake City, Utah 84132; Karolinska Hospital (S.A.), Stockholm, Sweden; and TheraTech Inc. (S.W.S., K.E.C., N.A.M.), Salt Lake City, Utah 84108
Address all correspondence and requests for reprints to: Adrian S. Dobs, M.D., M.H.S., Associate Professor and Vice Chair, Department of Medicine, Johns Hopkins University, 1830 East Monument Street, Room 328, Baltimore, Maryland 21205. E-mail: adobs{at}jhu.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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TTD treatment produced circadian variations in the levels of total T, bioavailable T, dihydrotestosterone, and estradiol within the normal physiological ranges. IM treatment produced supraphysiological levels of T, bioavailable T, and estradiol (but not dihydrotestosterone) for several days after each injection. Mean morning sex hormone levels were within the normal range in greater proportions of TTD patients (range, 77–100%) than IM patients (range, 19–84%). Both treatments normalized LH levels in approximately 50% of patients with primary hypogonadism; however, LH levels were suppressed to the subnormal range in 31% of IM patients vs. 0% of TTD patients. Both treatments maintained sexual function (assessed by questionnaire and Rigiscan) and mood (Beck Depression Inventory) at the prior treatment levels.
Prostate-specific antigen levels, prostate volumes, and lipid and serum chemistry parameters were comparable in both treatment groups. Transient skin irritation from the patches was reported by 60% of the TTD patients, but caused only three patients (9%) to discontinue treatment. IM treatment produced local reactions in 33% of patients and was associated with significantly more abnormal hematocrit elevations (43.8% of patients) compared with TTD treatment (15.4% of patients). Gynecomastia resolved more frequently during TTD treatment (4 of 10 patients) than with IM treatment (1 of 9 patients).
Although both treatments seem to be efficacious for replacing T in hypogonadal men, the more physiological sex hormone levels and profiles associated with TTD may offer possible advantages over IM in minimizing excessive stimulation of erythropoiesis, preventing/ameliorating gynecomastia, and not over-suppressing gonadotropins.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Recently, several transdermal preparations have become available for the treatment of hypogonadal men (5, 6, 7). The Androderm testosterone transdermal system (TTD) (7), designed for application to nonscrotal skin, consists of a central gel-containing reservoir that delivers T across a permeable microporous membrane and a peripheral adhesive region that affixes the system to the skin. Two studies of the pharmacokinetics of the TTD in hypogonadal men have demonstrated that the nightly application of this system can produce physiological concentrations and normal circadian variation of T and its metabolites (8, 9).
In the present randomized, age-matched, open-label, multicenter study, we compared the pharmacokinetics, efficacy, and safety of the TTD with intramuscular injections of T enanthate (IM) administered biweekly in two parallel groups of hypogonadal men treated for 24 weeks. All patients had been receiving intramuscular T treatment before entering this study. Portions of the pharmacokinetic and safety data from this study have been summarized in two previous review articles (10, 11).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Adult hypogonadal males 20 to 65 years of age who had been receiving IM replacement therapy for at least 3 months were eligible for the study. Exclusion criteria included: a history of prostate cancer or treatment for any carcinoma within the past 2 years; serum prostate-specific antigen (PSA) levels >3.9 ng/mL; transrectal ultrasound-determined prostate volumes >50 mL or postvoid residual volumes >60 mL; an unstable or untreated endocrine disorder; clinically significant hyperlipidemia; clinically significant psychiatric disease; or the need for tricyclic antidepressant or antipsychotic therapy. The protocol was approved by the Institutional Review Boards of the participating institutions [Johns Hopkins University, University of Utah, Karolinska Hospital, San Diego Endocrine and Medical Clinic (San Diego, CA), Pharmaco Health Research Center (Austin, TX), and Rush Presbyterean–St. Lukes Medical Center (Chicago, IL)] and written informed consent was obtained from all patients.
During the screening period, prospective patients received up to two
injections of their current T replacement medication (usually T
enanthate, administered biweekly or triweekly). After the last T
injection, they entered a 4- to 6-week washout period. At the end of
the washout period, patients had to exhibit hypogonadal morning serum T
levels of 
300 ng/dL (or 350 ng/dL for patients with Klinefelter’s
syndrome). Qualified patients were randomized in an age-matched fashion
to treatment with either TTD or IM therapy for 24 weeks. The
randomization was done centrally by the sponsor. Patients in the TTD
treatment group applied two investigational Androderm systems (2.5 mg
nominal delivery per patch) to the back, abdomen, thigh, or upper arm
each evening and wore them for 24 hours. Patients assigned to IM
treatment received 200 mg T enanthate (Delatestryl; BTG
Pharmaceuticals, Iselin, NJ) by intramuscular injection every 2 weeks.
Dosage adjustments were allowed for both groups if adverse events
occurred or morning T levels were outside the normal range of 306–1031
ng/dL (9). Three patients in the TTD group had an increase in dosage to
7.5 mg/day (three patches applied nightly), and one patient in the IM
group had a decrease in dosage to 100 mg or 150 mg on separate
occasions. At the time of the pharmacokinetic evaluation (see below)
only two patients (both TTD) had undergone a dosing change. All
patients who satisfactorily completed the study were eligible to
receive TTD treatment in an open-label extension study that followed
the present one.
Pharmacokinetic evaluation
Steady-state pharmacokinetic profiles of T, bioavailable T (BT), dihydrotestosterone (DHT), and estradiol (E2) over the dosing interval were determined at week 16 for each therapy. In the TTD group, blood samples for hormone analysis were collected at 0, 3, 6, 9, 12, and 24 h after application of systems. The systems were then removed and were not replaced for 24 h. An additional sample for determination of endogenous baseline hormone levels was obtained in the evening before resuming patch application. Patients who received IM treatment reported to the study site for an injection and collection of a pretreatment (day 0) blood sample. Thereafter, blood samples were collected on days 1, 2, 4, 7, 10, and 14 following injection. All hormone analyses (including gonadotropins; see below) were performed at a central laboratory (Endocrine Sciences, Calabasas Hills, CA) using validated assays and normal ranges that have been described previously (9). Pharmacokinetic parameters included the maximum concentration (Cmax), minimum concentration (Cmin), the time-average concentration (Cavg; equal to the area-under-the-curve divided by the dosing interval), time of maximum concentration (Tmax), and the percentage of the dosing interval in which the hormone profile remained within the normal range (PTNR).
Efficacy assessments
Serum sex hormone and gonadotropin levels. Morning serum levels of T, BT, DHT, and E2 were measured at weeks 2 (TTD group only), 4, 8, 12, 16, 20, and 24 of randomized treatment at the midpoint of the dosing interval (approximately 12 hours after TTD application or 7 days after IM injection). Assessment of normalization was based on average levels from week 2 (week 4 for IM) to week 24. Serum concentrations of LH and FSH were determined at the same intervals as for sex hormones using double antibody radioimmunoassays (9).
Sexual function and mood parameters. Nocturnal erectile activity was assessed objectively using outpatient RigiScan (Dacomed, Minneapolis, MN) monitoring at week 16. Tracings from the penile tip were quantified using the erectile index (12), an integrated measure of the frequency, duration, and rigidity of erections. Subjective assessments of erectile frequency and sexual function were performed using the Davidson Questionnaire (13) at week 20 and the Watts Sexual Function Questionnaire (14) at weeks 4, 8, 12, 16, 20, and 24. The Beck Depression Inventory (15) was used to evaluate mood at week 24. Treatment responses were assessed as the change from baseline evaluations made during the prior IM treatment.
Safety assessments
All adverse events reported or observed during the study were recorded. Local tolerability at TTD application sites and IM injection sites were assessed at each visit. Prostate safety was evaluated by serum PSA, prostate volume, and postvoid residual urine volume (measured by transrectal ultrasound). Assessments were made during prior IM therapy, at week 12 (PSA only), and week 24. Plasma levels of cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, and the cholesterol to HDL ratio were measured monthly (beginning at week 4 of treatment) at a central laboratory (Dr. Paul Bachorik, Johns Hopkins University). Baseline levels during prior IM therapy were measured at each study center (rather than centrally) and, thus, mean changes during treatment were calculated using week 4 as the reference point. Clinical laboratory evaluations (hematology, serum chemistries) were measured at each study center during the prior IM therapy and every 4 weeks during treatment. Individual patients’ hematocrit values were normalized to a standard reference range (40–52%) based on the reference range at each study center.
Statistical analyses
2 analyses were used to compare the TTD and IM
treatment groups with regard to the percentages of patients with
average morning levels of T, BT, DHT, and E2 within the
normal morning ranges. Other pharmacokinetic and efficacy parameters
were compared using the Mann-Whitney test. The percentage of patients
with elevated hematocrit values (>52%) were compared using Fisher’s
exact test. All comparisons were two-tailed and based on intention to
treat. All other analyses presented, including the comparison of
treatment groups during prior IM therapy, were based on descriptive
statistics. Statistical analyses were performed using SAS (Version
6.08), Stat View software, BIOPAK for pharmacokinetic data, and
Excel for correlation analysis.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 66 hypogonadal men between the ages of 22 and 65 years
were enrolled in the study (33 per treatment group). Demographic
characteristics, hypogonadal diagnostic category, prior IM treatment
regimen, and sex hormone levels after washout are summarized in Table 1
. The treatment groups were comparable
with respect to age, race, weight, and dosing regimens of prior T
therapy at study entry. Mean sex hormone levels were not significantly
different after washout (P > 0.10), with total T
levels of 166 ± 79 (SD) and 182 ± 94 ng/dL in
the TTD group and IM group, respectively. Mean scores for sexual
function parameters and mood assessment during prior IM treatment were
similar in the two groups (see baseline values in Table 5).
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Pharmacokinetic evaluation
Steady-state pharmacokinetic profiles of the sex hormones
were evaluated over a 24-h interval for the TTD group and a 14-day
interval for the IM group, starting at week 16. TTD produced mean 24-h
serum profiles of T, BT, DHT, and E2 that were within the
normal morning reference ranges over the entire 24-h evaluation period
(left panels of Fig. 1).
Moreover, the T concentrations displayed a circadian variation, with a
morning peak and nighttime trough similar to that reported for healthy
young men (3). Based on pharmacokinetic analysis of the individual
patient profiles (Table 2), the peak T
concentration averaged 765 ± 277 ng/dL and occurred 8.2 ±
2.0 h after TTD application. The mean trough concentration was
280 ± 146 ng/dL. The time-average concentration
(Cavg) over the 24-h dosing interval was 517 ± 176
ng/dL.
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).
Pharmacokinetic analysis of the IM injection profiles (Table 2) showed
that peak serum T concentrations averaged 1462 ± 408 ng/dL and
occurred 2.3 ± 1.9 days after injection. The mean trough
concentration was 330 ng/dL, and the time-average concentration over
the 14-day interval was 815 ± 167 ng/dL. Hormone normalization
during the pharmacokinetic study was assessed in terms of the
percentage of the dosing interval in which the hormone profile remained
within the normal morning reference range (the parameter PTNR; Table 2). For the TTD regimen, PTNR averaged 81.8% for T, 87.2% for BT,
75.6% for DHT, and 81.4% for E2. For the IM regimen, PTNR
was significantly lower (P 0.05) for T (72.0%), BT
(38.5%), and E2 (34.8%), but was comparable for DHT
(69.6%). The lower PTNR values during IM treatment reflected the
significant portion of time that the BT and E2 profiles
were elevated in the supraphysiologic range.
The endogenous baseline hormone levels, assessed in the TTD group by
delaying the application of new systems for 24 h after the
pharmacokinetic study (Table 2), were appreciably lower than the
morning levels after the washout period from the prior IM treatment
(Table 1).
Efficacy assessments
Morning sex hormone levels. Over the 24-week study
period, treatment with TTD systems resulted in mean morning serum
levels of T, BT, DHT, and E2 (measured approximately
12 h after system application) that were within the normal ranges
(Table 3). With IM treatment, the mean
morning levels of T and DHT (measured 7 days after injection) were also
within the normal range, but the corresponding mean levels of BT and
E2 exceeded the upper limit of normal. The proportion of
patients with morning hormone concentrations within the normal range
was higher in the TTD group than in the IM group; the differences being
highly significant for BT and E2 (P <
0.0001). In comparison with the pharmacokinetic results (Table 2), the
morning hormone levels measured in both treatment groups were closer to
the time-average concentrations than to the peak levels.
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summarizes the LH and FSH levels
measured after 24 weeks of treatment in the patient subgroups with
primary and secondary hypogonadism. In both subgroups, mean
gonadotropin levels were lower in patients receiving IM injections than
in those receiving TTD therapy. Of the primary hypogonadal patients in
the present study, 50% in the TTD group had normalized morning LH
levels after 24 weeks of treatment and 50% of patients had elevated LH
levels. In the IM group, 13% had elevated levels, 56% were in the
normal range, and 31% had been suppressed to subnormal levels. Of
IM-treated patients with secondary hypogonadism, 56% had suppressed LH
levels, compared with 22% of TTD-treated patients. FSH levels showed
trends similar to LH levels in the patients with primary
hypogonadism.
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). No
clinically significant change from prior IM therapy to week 24 was
observed in the mean Beck Depression Inventory score for either
treatment group. Safety assessments
Adverse events. Twenty patients treated with TTD (60.6%) and 16 patients treated with IM (48.5%) experienced at least one adverse event during the study. The most common adverse events in the TTD group were pruritus (nine patients, 27.3%), local skin reactions (six patients, 18.2%), and allergic contact dermatitis at the application site (two patients, 6.0%). Headache also occurred in four patients (12.1%). In the IM group, the most frequent adverse events were headache (three patients, 9.1%) and pruritus (one patient, 3.0%).
Local tolerability. In the TTD group, approximately 60% of patients experienced mild to moderate erythema or pruritus at an application site at least once during the study. The erythema resolved typically within 24–48 h after patch removal. Only three patients (9%), however, discontinued treatment due to skin reactions. In the IM group, 33% of patients experienced at least one local reaction during the study (e.g., pain/soreness, bruising, erythema, swelling, nodules, or furunculosis). No IM-treated patient discontinued for this reason.
Prostate. Prostate evaluations revealed no clinically relevant changes from prior IM therapy in PSA or prostate volume in either treatment group, with the exception of one patient (age 54) in the IM group whose PSA value increased from 5.0 to 12.6 ng/mL between weeks 12 and 24 of treatment. Despite two normal ultrasound examinations, a biopsy was performed after the study and indicated a microscopic adenocarcinoma of the prostate. Localized prostate adenocarcinoma was also detected in two other patients with normal PSA values, one in the TTD group (age 43) and one in the IM group (age 57), following abnormal prostate ultrasound examinations conducted at the end of the study. All three patients had prostatectomies after the diagnosis was made. In the TTD group, the mean serum PSA values at baseline (during prior IM therapy) and at week 24 were both 0.9 ± 0.6 ng/dL. In the IM group, mean PSA at baseline (during prior IM therapy) was 0.9 ± 0.7 ng/dL and at Week 24 was 1.4 ± 2.2 ng/mL. Mean prostate volumes at the same time points were 21.5 ± 7.9 cc and 20.8 ± 6.8 cc in the TTD group and 22.6 ± 10.4 cc and 22.7 ± 8.4 cc in the IM group.
Lipids. From week 4 to week 24 of treatment, HDL levels and cholesterol to HDL ratio remained essentially unchanged in both treatment groups. At week 24, the mean HDL was 49.3 ± 12.4 mg/dL for the TTD group and 40.8 ± 11.2 mg/dL for the IM group.
Hematocrit. Over the 24-week treatment period, the
distribution of individual patient hematocrit values showed potentially
clinically important differences between the two treatment groups (Fig. 2). At baseline, 3 of 32 patients in the
IM group and 4 of 26 patients in the TTD group had hematocrit values
that exceeded 52%. During the treatment period, 14 patients in the IM
group (43.8%) had at least one occurrence of an elevated hematocrit
value compared with 4 patients in the TTD group (15.4%)
(P = 0.025, two-sided Fisher’s exact test). Of the 14
IM patients with hematocrit elevations, average morning levels of T,
BT, DHT, and E2 were above the normal range in 3, 11, 5,
and 12 patients, respectively. Of the four TTD patients with hematocrit
elevations, average morning levels of T, BT, and DHT were normal in
all; however, the average morning E2 level was elevated in
three patients. Using data from all 58 patients who completed the trial
(unstratified by treatment group), hematocrit levels at week 24 were
significantly correlated to the average morning levels of BT (r =
0.46, P < 0.001) and E2 (r = 0.58,
P < 0.001) and to age (r = 0.36,
P = 0.01), but were not significantly correlated to
average morning levels of T or DHT (P > 0.05) (Fig. 3). Using IM-treated patient data only,
hematocrit values correlated significantly with both E2
(r = 0.52, P < 0.005) and age (r = 0.41,
P = 0.02). For the TTD-treated patients, hematocrit
values correlated significantly with BT (r = 0.40,
P < 0.05) and E2 (r = 0.50,
P < 0.01).
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Gynecomastia. At the start of the study, gynecomastia was present in 10 patients randomized to the TTD group and 9 patients randomized to the IM group. In the TTD group, gynecomastia resolved in three patients, improved in one patient, and developed in another patient. In the IM group, gynecomastia resolved in only one patient and was unchanged in the remaining eight patients.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The current study also provided detailed pharmacokinetic information on the steady-state profiles of T, BT, DHT, and E2 during the respective dosing intervals for the TTD and IM injection regimens. For TTD, the results were consistent with earlier studies (8, 16) that showed that the nightly application of two TTD systems resulted in morning peaks and evening nadirs similar to the circadian profiles observed in healthy young men (3). BT, DHT, and E2 profiles generally paralleled the T profiles obtained with TTD, consistent with the results of single-dose pharmacokinetic studies (9). Biweekly IM treatment with 200 mg T enanthate produced fluctuation in T levels between the supraphysiological and low-normal range, consistent with other pharmacokinetic studies of this regimen (2, 17, 18). BT levels showed an even greater degree of fluctuation into the supraphysiological range, reaching average peak levels that were more than twice the upper limit of normal, presumably due to the saturable binding of T to SHBG, which results in a relative excess of non-SHBG-bound T (e.g., BT). Whereas DHT levels showed modest fluctuation with IM injections, E2 levels showed marked and prolonged increases into the supraphysiological range. The enhancement of E2 formation could be due to a preferential uptake of the T enanthate itself into adipose tissue (including that located intramuscularly at the injection site), where it is aromatized into E2 enanthate and slowly de-esterified and released as circulating E2.
The two treatments differed in their effects on LH levels. Although approximately half of the patients with primary hypogonadism attained LH levels in the normal range, LH levels remained elevated in the remaining TTD patients with primary hypogonadism but were suppressed below the normal range in 31% of patients treated with IM. Because all TTD patients had achieved BT levels within the normal range, the persistence of elevated LH levels is of unclear significance and may indicate an androgen-resistant state at the pituitary and/or hypothalamic levels. Raising the TTD dosage rate from e.g., 5 to 7.5 mg/day could conceivably have normalized LH, but at the expense of supraphysiological BT levels in some patients. The suppression of LH levels below the normal range in the IM group may have resulted from the supraphysiological levels of BT and E2 produced by this treatment. Circulating levels of T (presumably BT) and E2 are both known to exert negative feedback on gonadotropin secretion in men (19, 20). Although the biweekly regimen of 200 mg T enanthate was empirically based on its ability to lower LH in patients with primary hypogonadism (2), the suppression of LH to subnormal levels in about one third of our patients is a nonphysiological effect of this regimen and suggests over-replacement. Lowering the IM dose or increasing the interval between injections could be considered in such patients.
In comparison with the 5 mg/day T dosing achieved with the TTD,
the biweekly administration of 200 mg T enanthate corresponds to a
calculated time-averaged dose of 10.3 mg of unesterified T per day.
This calculated dose exceeds the daily T production of most healthy
young men (3, 8). Although the actual delivered dose of unesterified T
varies daily during the IM dosing interval, the time-averaged BT levels
observed with the IM regimen were approximately 2-fold greater than the
time-averaged BT levels for TTD (Table 2), consistent with the
calculated and nominal daily doses of the corresponding regimens.
Despite the different amounts of T delivered, both treatments
maintained sexual function and mood at the prior treatment levels, as
demonstrated by objective (Rigiscan) and subjective assessments during
the study. These findings are consistent with those of the earlier
study of TTD therapy in hypogonadal men (12). It should be noted,
however, that because patients were aware of the type of treatment they
received some bias in the subjective assessment was possible.
Although the examiners were also not blind to treatment, gynecomastia was observed to resolve more frequently in the TTD group than in the IM group, a finding consistent with the prior study of Arver et al. (16). Gynecomastia has been postulated to occur as a result of high levels of E2 relative to those of T, although this has not been conclusively shown (1, 21). The fewer cases of gynecomastia that persisted in the TTD group may be due to the lower concentrations of E2 associated with TTD therapy.
Whereas the erythropoietic-stimulating effect of androgens (22, 23) has been used to treat a variety of anemias (24), administration of T has also been reported to cause polycythemia in some patients, particularly those >50 years of age (25, 26, 27). By increasing blood viscosity, polycythemia reduces cerebral blood flow and poses an additional risk factor for stroke in patients with underlying cardiovascular disease (25). In the present study, the percentage of patients who had at least one supraphysiological hematocrit elevation was nearly 3-fold higher in the IM injection group compared with the TTD group. This finding seems related to the significantly greater percentage of supraphysiological BT and E2 levels produced by the IM regimen compared with TTD. The statistical association between hematocrit and E2 levels in both treatment groups, which was stronger than the correlation to the patients’ age, has not been reported previously and deserves further investigation. Although none of the patients in the present study with elevated hematocrits experienced any thromboembolic events, such concerns regarding have been raised in other studies (1, 25, 27, 28). Periodic monitoring of hematocrit is, therefore, recommended for patients receiving T replacement therapy (29).
Both TTD and IM treatments were well tolerated by most patients and were not associated with clinically significant elevations in liver enzymes or changes in lipid and prostate parameters. However, end of study PSA and ultrasound evaluations led to the diagnosis of localized prostate cancer in one TTD patient and two IM patients, which were treated surgically. The most frequently reported adverse events with TTD were related to local irritation from the patches, a common finding with transdermal delivery systems (30). Recent clinical studies have shown that applying a small amount of 0.1% triamcinolone acetonide cream to the skin under the Androderm patch reservoir reduces the incidence and severity of skin irritation and does not significantly alter transdermal absorption (7, 31, 32).
In conclusion, transdermal T (Androderm) and IM T enanthate both seem to be efficacious and generally well tolerated for replacing T in hypogonadal men. Although IM T offers the convenience of decreased frequency of administration, the more physiological sex hormone levels and profiles achieved with TTD may offer possible advantages in minimizing excessive stimulation of erythropoiesis, preventing/ameliorating gynecomastia and not over-suppressing gonadotropins.
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Acknowledgments |
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Footnotes |
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Received April 28, 1999.
Revised July 7, 1999.
Accepted July 12, 1999.
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A. Mayo, H. Macintyre, A. M. Wallace, and S. F. Ahmed Transdermal Testosterone Application: Pharmacokinetics and Effects on Pubertal Status, Short-Term Growth, and Bone Turnover J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 681 - 687. [Abstract] [Full Text] [PDF]
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 E. L. Rhoden and A. Morgentaler Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring N. Engl. J. Med., January 29, 2004; 350(5): 482 - 492. [Full Text] [PDF]
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A. Ojumu and A. S. Dobs Is Hypogonadism a Risk Factor for Sexual Dysfunction? J Androl, November 1, 2003; 24(6_suppl): S46 - S51. [Full Text] [PDF]
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C. Steidle, S. Schwartz, K. Jacoby, T. Sebree, T. Smith, and R. Bachand AA2500 Testosterone Gel Normalizes Androgen Levels in Aging Males with Improvements in Body Composition and Sexual Function J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2673 - 2681. [Abstract] [Full Text] [PDF]
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 H. G. Pope Jr., G. H. Cohane, G. Kanayama, A. J. Siegel, and J. I. Hudson Testosterone Gel Supplementation for Men With Refractory Depression: A Randomized, Placebo-Controlled Trial Am J Psychiatry, January 1, 2003; 160(1): 105 - 111. [Abstract] [Full Text] [PDF]
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S. von Eckardstein and E. Nieschlag Treatment of Male Hypogonadism With Testosterone Undecanoate Injected at Extended Intervals of 12 Weeks: A Phase II Study J Androl, May 1, 2002; 23(3): 419 - 425. [Abstract] [Full Text] [PDF]
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 A. M. Matsumoto Andropause: Clinical Implications of the Decline in Serum Testosterone Levels With Aging in Men J. Gerontol. A Biol. Sci. Med. Sci., February 1, 2002; 57(2): M76 - 99. [Full Text]
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 S. Bhasin, L. Woodhouse, R. Casaburi, A. B. Singh, D. Bhasin, N. Berman, X. Chen, K. E. Yarasheski, L. Magliano, C. Dzekov, et al. Testosterone dose-response relationships in healthy young men Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1172 - E1181. [Abstract] [Full Text] [PDF]
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W. M. Hair, K. Kitteridge, D. B. O'Connor, and F. C. W. Wu A Novel Male Contraceptive Pill-Patch Combination: Oral Desogestrel and Transdermal Testosterone in the Suppression of Spermatogenesis in Normal Men J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5201 - 5209. [Abstract] [Full Text] [PDF]
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J. C. Lo and M. Schambelan Reproductive Function in Human Immunodeficiency Virus Infection J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2338 - 2343. [Full Text] [PDF]
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A. Vermeulen Androgen Replacement Therapy in the Aging Male--A Critical Evaluation J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2380 - 2390. [Full Text] [PDF]
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A. M. Kenny, K. M. Prestwood, C. A. Gruman, K. M. Marcello, and L. G. Raisz Effects of Transdermal Testosterone on Bone and Muscle in Older Men With Low Bioavailable Testosterone Levels J. Gerontol. A Biol. Sci. Med. Sci., May 1, 2001; 56(5): 266M - 272. [Abstract] [Full Text]
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C. Wang, R. S. Swerdloff, A. Iranmanesh, A. Dobs, P. J. Snyder, G. Cunningham, A. M. Matsumoto, T. Weber, and N. Berman the Testosterone Gel Study Group Transdermal Testosterone Gel Improves Sexual Function, Mood, Muscle Strength, and Body Composition Parameters in Hypogonadal Men J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2839 - 2853. [Abstract] [Full Text]
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, left panels) and biweekly IM
injections of T enanthate (n = 29; X, right
panels) measured at week 16. Dashed lines denote upper
and lower limits of normal range based on morning serum samples (T,
306–1031 ng/dL; BT, 92–420 ng/dL; DHT, 28–85 ng/dL; E2,
0.9–3.6 ng/dL). Error bars denote ± SD.
