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From the Clinical Research Centers |
The Johns Hopkins Medical Center (A.S.D., P.S.B.), 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 Watson Laboratories, 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., Department of Medicine, The 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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Subjects (aged 21–65 yr) were first studied during prior treatment with im testosterone esters (IM-T), then during an 8-week period of androgen withdrawal resulting in a hypogonadal state (HG), and finally during a 1-yr treatment period with the TTD. Compared with treatment with IM-T, the HG period produced increases in high density lipoprotein [HDL; 12.0 ± 1.6% (±SEM); P < 0.001] and total cholesterol (4.2 ± 1.9%; P = 0.02) and a decrease in the cholesterol/HDL ratio (-9.7 ± 2.8%; P = 0.02). Compared with the HG period, TTD treatment produced decreases in HDL (-7.6 ± 2.5%; P = 0.002) and increases in the cholesterol/HDL ratio (9.0 ± 2.5%; P = 0.01) and triglycerides (20.7 ± 6.4%; P = 0.03). Small decreases in total cholesterol (-1.2 ± 1.8%; P = 0.1) and low density lipoprotein (-0.8 ± 2.6%; P = 0.07) were also observed during TTD, but did not reach statistical significance. Likewise, there were no significant differences between the IM-T and TTD treatments. Serum HDL levels showed a strong negative correlation with body mass index and other obesity parameters in all three study periods (r < -0.45; P < 0.02). During treatment with TTD, serum testosterone levels also correlated negatively with body mass index (r = -0.621; P < 0.001). As a consequence of these relationships, a positive trend was observed between HDL and testosterone levels during TTD treatment (r = 0.336; P = 0.07). Interestingly, the changes in lipoprotein levels during TTD treatment indicated a more favorable profile (decrease in cholesterol and low density lipoprotein levels) with increasing age of the patients.
In hypogonadal men the effects of transdermal testosterone replacement on serum lipoproteins appear consistent with the physiological effects of testosterone in eugonadal men.
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Introduction |
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In women, the levels of estrogenic hormones, whether present endogenously or given exogenously, have been shown to correlate with increasing HDL levels, resulting in a lower cardiovascular risk profile (6). In addition, estrogens have been shown to produce vasodilating effects that are beneficial to cardiovascular function (7).
In men, however, testosterone levels have a more complicated and controversial relationship to HDL levels and cardiovascular risk. During puberty, rising endogenous testosterone levels are associated with a fall in serum HDL (8). HDL levels also decrease with administration of exogenous androgens to healthy young men (9), athletes (10), and hypogonadal patients (11), although in elderly men the effect of testosterone administration on HDL levels appears to be much weaker (12, 13, 14, 15). Conversely, experimental hypogonadism in men, induced by the administration of a GnRH agonist, results in increased serum HDL levels, implying that androgen levels in the normal adult male range have a suppressive effect on HDL levels (16). However, several cross-sectional studies of adult men (17, 18, 19, 20), including patients with coronary artery disease (21), have shown that higher testosterone levels are associated with higher HDL concentrations. Numerous factors could account for the apparent positive correlation between testosterone and HDL in men, including obesity, fat distribution, diet, age, alcohol intake, exercise, and smoking (17, 22).
As part of a multicenter phase III evaluation of the efficacy and safety of Androderm, a permeation-enhanced testosterone transdermal system (TTD), we investigated the interrelationships among serum lipoproteins, sex hormone levels, anthropometric parameters, and age in 29 hypogonadal men. Longitudinal evaluations of these parameters were first made during prior treatment with im testosterone esters (IM-T), then during an 8-week period of androgen withdrawal resulting in a hypogonadal state (HG), and finally during a 1-yr treatment period with TTD. By studying a population of hypogonadal men during periods of androgen replacement and withdrawal, we were able to assess both the effects of exogenous testosterone administration on serum lipoproteins as well as the cross-sectional relationship between lipoproteins and sex hormones in the same individuals.
Other aspects of this multicenter study, including pharmacokinetics, sexual function, prostate evaluations, and overall clinical outcomes have been published previously (23, 24, 25, 26).
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Subjects and Methods |
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Hypogonadal males, 20–65 yr of age, who had been receiving androgen replacement therapy (primarily testosterone ester injections) for at least 3 months were eligible for this study. Hypogonadism was defined as a pretreatment serum testosterone of 8.7 nmol/L or less and was confirmed during the androgen withdrawal period. Patients were excluded from the study for serum prostate-specific antigen levels greater than 3.9 µg/L, prostate volume greater than 30 cm3 on transrectal ultrasound examination, postvoid residual volume greater than 60 cm3, unstable or untreated endocrine disorders, poorly controlled diabetes, psychiatric disturbances, or use of tricyclic antidepressants or any drugs with antiandrogenic properties. Patients were also excluded for severe hyperlipidemia, defined as two or more of the following abnormalities: greater than 95th percentile (for age) of total cholesterol, low density lipoprotein (LDL), or tryglycerides or less than 5th percentile of HDL, based on normative data from the Lipid Research Clinics Program (27).
The study protocol was approved by the institutional review boards of the participating institutions (center 1, University of Utah School of Medicine, Salt Lake City, UT; center 2, Karolinska Hospital, Stockholm, Sweden; and center 3, Johns Hopkins University, Baltimore, MD), and written informed consent was obtained from all patients.
Study design
This was an open label, multicenter study with four consecutive evaluation periods (26). In the first period (denoted IM-T), patients were monitored for 21 days after receiving a final testosterone ester injection. The second period (denoted HG) was an 8-week androgen withdrawal phase in which patients returned to a hypogonadal state. In the third period, lasting approximately 1 month, patients underwent a series of single dose transdermal pharmacokinetic studies using different application sites (23). No lipoprotein or anthropometric measurements were made during this period. In the last period (denoted TTD), patients were treated for 12 months with transdermal testosterone. During the TTD period, inpatient pharmacokinetic studies and physical examinations were performed at months 3, 6, and 12 (26).
Androgen dosing regimens
During the first period, 27 men were treated with IM-T formulations (26 with testosterone enanthate and 1 with testosterone propionate). The average IM-T dose was 229 mg (range, 150–300 mg), and the average dosing interval before the last injection was approximately 26 days (range, 10–44 days). Two additional patients used TTD (2 2.5-mg/day patches nightly) based on participation in an earlier open label trial. During the 12 month TTD period, all patients began treatment with 2 2.5-mg/day patches nightly (total dose, 5 mg/day). Twenty-seven patients were maintained on this regimen, and 2 were changed to a 3-patch nightly regimen (7.5 mg/day) based on their initially low testosterone levels. The TTD systems were applied to the recommended sites (back, abdomen, thighs, and upper arms) on a rotating basis.
Serum hormone measurements
Morning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), estradiol (E2), and sex hormone-binding globulin (SHBG) were measured between 0800 and 1200 h at 1- to 4-week intervals during the IM-T, HG, and TTD periods. Samples were analyzed by Endocrine Sciences, Inc. (Calabasas Hills, CA) using validated hormone assays (23).
Plasma lipoprotein parameters
All plasma samples for lipoprotein measurements were obtained in the morning after a 12-h fast and were assayed at the Lipid Research Unit of The Johns Hopkins School of Medicine using validated methods (28, 29), as described below. Samples from centers 1 and 2 were frozen at -70 C and shipped under dry ice to the laboratory. Samples from center 3 were delivered unfrozen to the laboratory. Total cholesterol and tri- glycerides were measured enzymatically with a Hitachi 704 clinical chemistry analyzer (Roche Molecular Biochemicals, Indianapolis, IN). HDL was measured enzymatically in the clear supernatant after precipitation of the apolipoprotein B-containing lipoproteins with heparin sulfate at 1.3 g/L and manganese chloride at 0.092 mol/L (28). LDL was calculated from cholesterol, HDL, and triglycerides using the Friedewald equation (29). The cholesterol/HDL ratio was computed as an index of cardiovascular risk (30).
Lipoprotein samples were obtained during out-patient visits on days 7 and 21 of the IM-T period, at weeks 4 and 8 of the HG period, and at months 0 (pretreatment), 1, 2, 4, 5, 7, 8, 9, 10, and 11 of the TTD period. Samples obtained during in-patient visits during the TTD period (months 3, 6, and 12) were excluded from statistical comparisons due to differences in posture and activity at the time of sampling, which are known to affect lipoprotein concentrations (31).
Anthropometric measurements
Anthropometric measurements of body weight, height, waist circumference, and hip circumference were made with the patient dressed in underwear and examining gown at the following time points: screening visit of the IM-T period, week 8 of the HG period, and months 3, 6, and 12 of the TTD period. Waist circumference was measured at the level of the umbilicus; hip circumference was measured at the level of the greater trochanter. The waist to hip ratio was computed as an index of upper body adiposity. Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters) squared.
Statistical analysis
Normality was assessed by Kolmogorov-Smirnov tests, and appropriate transformations were used when needed. Data that were measured more than once within a study period were reduced to period averages, defined for each parameter on a pharmacokinetic or statistical basis (no significant trend over time), as follows.
Hormone data. For the IM-T period, the period averages for T, BT, DHT, E2, and SHBG were defined as the AUC from days 0–21 divided by 21, i.e. the time-averaged values. For the HG period, the period averages were defined as the mean of the week 4 and week 8 values. For the TTD period, the period averages were the mean of the 10 morning hormone levels measured from months 3–12.
Lipoprotein data. Triglyceride data were found to be nonnormal and were log-transformed. For the IM-T period, the period averages for all lipoprotein parameters were the mean of the day 7 and day 21 values. For the HG period, the period averages were the mean of the week 4 and week 8 values. For the TTD period, the period averages were the mean of the month 4, 5, 7, 8, 9, 10, and 11 values.
Anthropometric data. For the IM-T and HG periods, the period averages corresponded to the single measurements taken during those periods. For the TTD period, the period average was the mean of the month 3, 6, and 12 values.
Descriptive statistics were computed using Excel. Inferential comparisons of study period averages among the IM-T, HG, and TTD periods were analyzed using repeated measures ANOVA, with clinical center (1, 2, or 3) as a grouping variable. Pairwise comparisons were based on contrasts from the ANOVA, with no adjustments for multiple comparisons. Comparisons between the IM-T and the TTD periods excluded the two subjects who received TTD in the IM-T period. Within each treatment period, Pearson correlation coefficients were computed among the hormone levels, primary lipoprotein parameters, anthropometric parameters, and age using the individual subject period averages. For the TTD period, univariate and multivariate linear regression analyses were performed between HDL, T, and BMI. In addition, Pearson correlation coefficients were computed for the changes in each primary lipoprotein parameter (TTD period minus HG period) vs. age, hormone levels, and anthropometric parameters in the TTD period.
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Results |
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A total of 37 healthy hypogonadal men were enrolled in the study.
Three patients withdrew during the HG period, including 2 who did not
meet the subnormal testosterone level requirement for the study. Of the
34 patients who entered the 1-yr TTD treatment period, 3 patients
withdrew due to skin-related adverse events, 1 for noncompliance, and 1
for personal reasons. Of the 29 patients (mean age, 38.6 yr) who
completed 12 months of TTD treatment, 9 patients had primary
hypogonadism, and 20 had secondary hypogonadism. A summary of the
demographic parameters and hypogonadal diagnoses of the patients is
given in Table 1
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Average morning hormone levels of T, BT, DHT, and
E2 were within the normal ranges during the IM-T
and TTD periods and were subnormal during the HG period (Table 2). Mean SHBG levels increased during the
HG period. There were no significant differences in average morning
hormone levels between the IM-T and TTD periods.
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Compared with treatment with IM-T, the HG period produced
increases in HDL [12.0 ± 1.6% (±SEM);
P < 0.001] and total cholesterol (4.2 ± 1.9%;
P = 0.02) and a decrease in the cholesterol/HDL ratio
(-9.7 ± 2.8%; P = 0.02; Table 3). Triglyceride levels did not change
significantly. Compared with the HG period, TTD treatment produced
decreases in HDL (-7.6 ± 2.5%; P = 0.002) and
increases in the cholesterol/HDL ratio (9.0 ± 2.5%;
P = 0.01) and triglycerides (20.7 ± 6.4%;
P = 0.03; Table 3). Small decreases in total
cholesterol (-1.2 ± 1.8%; P = 0.1) and LDL
(-0.8 ± 2.6%; P = 0.07) were also observed
during TTD, but did not reach statistical significance. There were no
significant differences in any lipoprotein parameter between the IM-T
and TTD treatments.
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Compared with IM-T treatment, there were no significant changes in
any parameter during the HG period (Table 4). However, during the 1-yr TTD
treatment, weight and BMI exhibited small, but significant, increases
compared with values during IM-T treatment and the HG period (Table 4).
In contrast, waist circumference and waist to hip ratio did not change
significantly during TTD treatment.
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During the TTD treatment period, highly significant correlations
(P < 0.001) were found within the individual groups of
anthropometric, lipoprotein, and hormone parameters (Table 5). Significant interrelationships among
the parameter groups were also noted (Table 5 and Fig. 1). HDL levels exhibited strong negative
correlations with obesity parameters, e.g. weight, BMI, and
waist size, as illustrated for BMI in Fig. 1A. Similar correlations
were also found during the IM-T and HG periods (r < -0.45;
P < 0.02; data not shown). T, BT, and DHT levels also
exhibited negative correlations with the obesity parameters, as
illustrated by the relationship between T and BMI in Fig. 1B. In
contrast the E2/T ratio showed highly significant
positive correlations with obesity parameters (r > 0.62;
P < 0.001; Table 5), exhibiting a 5-fold increase over
the BMI range from 20–40 (Fig. 1C). As a consequence of the negative
correlations between HDL and BMI (Fig. 1A) and between T and BMI (Fig. 1B), a positive trend between HDL and T (r = 0.336;
P = 0.07) was observed (Fig. 2). The lack of an independent
correlation between HDL and T was shown by a multivariate regression
analysis of HDL vs. BMI and T, which yielded a regression
slope for T that was close to zero (P = 0.9). With
respect to age, the only significant correlations were obtained with
the waist to hip ratio (r = 0.588; P < 0.001) and
SHBG level (r = 0.459; P < 0.05; Table 5).
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, the changes in HDL were independent of the
anthropometric parameters or hormone levels. Thus, the small reduction
in HDL levels seen during TTD treatment was not significantly different
between men whose BMI was less than the median value of 27 (-0.10
± 0.06 mmol/L) and those whose BMI was greater than 27 (-0.14 ±
0.03 mmol/L; P = 0.5). Interestingly, the only
predictive variable for the changes in lipoprotein levels was the
patient’s age, which had a negative correlation to the changes in
total cholesterol and LDL levels (r = -0.451 and -0.446,
respectively; P < 0.05), but no correlation with the
change in HDL levels (r = -0.045; P = 0.8; Fig. 3, A and B).
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Discussion |
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Studies in male weight lifters using high dosages of androgens and anabolic steroids showed large decreases in HDL levels of approximately -0.78 mmol/L (36, 37). Similar decreases in the HDL2 subfraction were observed with use of oral nonaromatizable androgens and were associated with an increase in hepatic triglyceride lipase activity, which increases HDL catabolism (38). The striking reductions in HDL produced by orally administered androgens may be related to hepatic first pass effects of the steroids (33), their inability to form estrogenic metabolites (34), and/or a direct hepatotoxic effect in some cases (39). The much smaller reduction in HDL levels in our study during both IM-T and TTD therapy, approximately -0.13 mmol/L, is presumably due to the lower doses of testosterone used, the aromatization to estradiol, and the avoidance of hepatic first pass metabolism.
In eugonadal men, administration of testosterone enanthate (
200
mg/week) caused HDL levels to decrease by -0.10 to -0.23 mmol/L
(9, 33, 34). Conversely, experimental hypogonadism,
induced by GnRH agonists or antagonists in eugonadal men, reversibly
increased HDL levels by approximately +0.26 mmol/L (16, 35). In Bagatell’s study (16), the increase in HDL
was prevented by the coadministration of testosterone enanthate at a
dose of 100 mg/week, which maintained testosterone levels in the
physiological range. This finding suggests that physiological levels of
testosterone suppress HDL levels in normal eugonadal men
(16) to the same degree seen in hypogonadal patients
receiving TTD treatment.
In contrast to exogenous testosterone, the relationship between endogenous testosterone and lipoprotein levels is more controversial. A positive correlation between HDL cholesterol and testosterone levels has been demonstrated in several cross-sectional studies (17, 18, 19, 20, 40). Other cross- sectional studies have found a negative correlation (5) or no correlation (22, 41, 42). The cross-sectional data analysis of our study revealed a positive trend between HDL and testosterone levels during TTD treatment. This relationship appears to be due to obesity, which is negatively correlated to both HDL and testosterone.
The interrelationships among body size, body composition, testosterone, and lipoproteins are complex. Cross- sectional studies in men with varying degrees of obesity have shown that total testosterone levels and, to a lesser extent, bioavailable and/or free testosterone levels decrease with increasing BMI values (43, 44, 45, 46, 47, 48). These changes are associated with decreases in SHBG (43, 44, 47) and IGF-I levels (48), increases in insulin and estradiol levels (47, 48), and low/normal levels of LH (48), which are indicative of a state of insulin resistance, increased aromatization of testosterone, and hypogonadotropic hypogonadism. As endogenous testosterone levels were low in our hypogonadal patients, and testosterone absorption from the TTD was independent of weight or BMI (26), the observed decrease in testosterone levels with increasing BMI must be a consequence of increasing testosterone clearance. The latter could result from an increase in the volume of distribution, a decrease in half-life, and/or an increase in metabolic conversion (49). Lower SHBG levels, which showed a negative trend with BMI, would also be expected to increase testosterone clearance rates (49). The striking increase in E2/T ratios with BMI observed in our patients is consistent with data in women that show a positive correlation between obesity and the rates of testosterone aromatization (50). In obese men with intact hypothalamic-pituitary-gonadal axes, the increase in E2/T ratio and the negative feedback effects of circulating E2 levels on LH secretion (51, 52) could be important factors in the development of hypogonadotropic hypogonadism (48).
As a potent inhibitor of abdominal (sc) lipoprotein lipase (53) and a stimulator of muscle protein synthesis (54), exogenous testosterone has been shown to decrease abdominal fat mass and increase muscle mass (55, 56). In the present study the 1.3-kg increase in weight during the TTD period was associated with small (but not statistically significant) decreases in waist size and waist to hip ratio. This suggests that the observed weight gain may have resulted from an increase in lean mass rather than fat mass, as seen in other testosterone replacement studies in hypogonadal men in which body composition was measured (57, 58).
The negative correlation between HDL levels and BMI seen in the present study has been observed in numerous studies of eugonadal men (59, 60, 61) as well as in patients with coronary artery disease (62). Insulin resistance and increased hepatic triglyceride lipase activity have been postulated to explain the metabolic defect in obesity that causes low HDL levels (60, 61, 62).
In contrast to the effects of testosterone replacement on HDL levels and cholesterol/HDL ratios, recent studies suggest that testosterone may have cardioprotective effects in men related to vasodilation (63) and other antiischemic mechanisms (64, 65), and that testosterone may be potentially beneficial as a cardiovascular drug (66, 67). Although some contradictions appear in the literature (68), it is likely that the overall influence of testosterone replacement on cardiovascular risk in men will ultimately involve effects on lipoproteins as well as other factors, similar to current views regarding estrogen replacement and cardiovascular risk in women (7).
Lastly, our findings regarding the influence of age on lipoprotein changes during testosterone replacement are consistent with a number of recent studies conducted in older men that have shown decreases in LDL or total cholesterol during testosterone therapy (12, 13, 14, 15, 69, 70) and little or no change in HDL levels (12, 13, 14, 15). The mechanism by which age moderates the effects of exogenous testosterone on lipoprotein levels remains to be further understood.
In conclusion, the longitudinal component of our study showed a small reduction in HDL levels in hypogonadal men treated with im or transdermal testosterone preparations, whereas the cross-sectional data analysis showed a positive trend between HDL and testosterone levels during transdermal treatment. These seemingly contradictory findings are reconciled by the anthropometric data from our patients, which showed that HDL and testosterone levels were both negatively correlated to BMI and that the positive cross-sectional trend between them was a consequence of these relationships. In regard to our longitudinal observations, the effects of transdermal testosterone replacement on serum lipoprotein levels in hypogonadal men appear to be consistent with the physiological effects of testosterone in healthy eugonadal men.
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Acknowledgments |
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Footnotes |
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Received May 12, 2000.
Revised November 6, 2000.
Accepted November 20, 2000.
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References |
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