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The Male Contraceptive Regimen of Testosterone and Levonorgestrel Significantly Increases Lean Mass in Healthy Young Men in 4 Weeks, but Attenuates a Decrease in Fat Mass Induced by Testosterone Alone

Population Center for Research in Reproduction, Department of Medicine, University of Washington (K.L.H., B.D.A., J.K.A., A.M.M., W.J.B.); Geriatric Research, Education and Clinical Center (A.M.M.); and Medical Service, Department of Veteran Affairs, Puget Sound Health Care System (B.D.A., A.M.M.), Seattle, Washington 98195

Address all correspondence and requests for reprints to: Karen L. Herbst, M.D., Ph.D., Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University, Room 3069 Third Floor, 1731 East 120th Street, Los Angeles, California 90059. E-mail: kaherbst{at}cdrewu.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In hypogonadal men, testosterone (T) in replacement dosages is known to increase fat-free mass (lean mass) and decrease fat mass. In young eugonadal men, similar dosages of T increase lean mass, but much higher dosages of T are required to decrease total body fat mass. Current T-based male hormonal contraceptive regimens include a second agent, such as a progestin, to maximize inhibition of pituitary gonadotropins and improve efficacy. To study the effect of such combinations on body composition, we randomized healthy, young, eugonadal men into four combinations of exogenous T and the progestin, levonorgestrel (LNG): 1) 100 mg T enanthate, im, weekly plus 125 µg LNG, orally, daily (T+LNG); 2) T plus placebo LNG (T alone); 3) placebo T plus LNG (LNG alone); and 4) placebo T plus placebo LNG (placebo). We then analyzed body composition by dual energy x-ray absorptiometry after 4 and 8 wk of treatment. T+LNG significantly increased total lean mass after 4 and 8 wk of treatment (3.5 ± 0.9% and 4.2 ± 1.2%, respectively; P < 0.05) and truncal lean mass after 4 and 8 wk of treatment (4.7 ± 0.9% and 5.0 ± 0.9%, respectively; P < 0.05) compared with baseline and placebo. T alone also increased total and truncal lean mass significantly compared with placebo after 4 wk of treatment, but not compared with baseline (3.3 ± 1.4% and 3.2 ± 2.3%, respectively; P < 0.05 vs. placebo), suggesting an additive effect of T and LNG to increase lean mass. Fat mass significantly decreased in the abdomen in men administered T alone compared with LNG alone (-4.9 ± 2.8%; P < 0.05). Fat mass significantly increased in the abdomen with LNG alone (4.1 ± 1.0%; P < 0.05) compared with baseline and was unchanged with the combination of T+LNG, suggesting that LNG attenuates the decrease in fat mass seen with T alone. There was no change in weight or body mass index in any group during the study. This study shows that in young eugonadal men 1) T alone rapidly increases lean mass and decreases fat mass in 4–8 wk; 2) T+LNG rapidly increases lean mass, but has no effect on fat mass; and 3) LNG alone increases fat mass. The favorable profile on body composition by T is, therefore, partially attenuated by the progestin, LNG. These findings suggest that androgen-based male hormonal contraceptives might have favorable effects on body composition. The impact of these changes on cardiovascular risk in normal men needs further study.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE COMBINATION OF testosterone (T) and a progestational agent has been used in male hormonal contraceptive regimens, effectively suppressing gonadotropins and spermatogenesis in healthy young men (1, 2, 3). In these studies the usual dosage for T administration is 100 mg, im, weekly of T enanthate or T cypionate, regimens that normalize serum T in hypogonadal men (4, 5, 6). T is known to increase lean mass and decrease fat mass when analyzed by dual energy x-ray absorptiometry (DEXA) in hypogonadal men at replacement doses (7, 8, 9). Bhasin et al. (10) demonstrated increases in lean mass by DEXA after 20 wk with 125 mg T, im, weekly, but a decrease in total body fat mass required much higher doses of T (600 mg weekly for 20 wk).

Levonorgestrel (LNG) is an androgenic progestin that is frequently combined with T in hormonal male contraceptive regimens (3, 11). We hypothesized that changes in body lean and fat mass with the combination of T plus LNG would be greater and occur earlier than with T alone because of the androgenicity of LNG (12, 13). In this study we examined the effects of T plus LNG, T alone, LNG alone, or placebo for 8 wk on the body composition of normal young men.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Men between the ages of 18 and 45 yr were recruited by flyers, newspaper ads, and radio advertisement and through the University of Washington Clinical Research Study Internet Site. After informed consent, subjects were accepted into the study during the control phase with a normal medical history and physical examination, normal serum levels of T, estradiol (E₂), FSH, and LH. Exclusion criteria were chronic systemic disease, regular medication use, tobacco use, and use of steroid hormones in the past 12 months, including androstenedione and dehydroepiandrosterone. The University of Washington Human Subjects Committee Institutional Review Board and the V.A. Research and Development Committee approved this study.

Protocol

The study consisted of a 4-wk control phase, an 8-wk treatment phase, and an 8-wk recovery phase. Nurses and investigators were blinded to treatment conditions. Thirty-seven healthy young men (average age, 32.7 ± 1.4 yr) who met screening criteria were randomized into one of four groups for an 8-wk treatment phase: 1) T+LNG: 100 mg T enanthate (Delatestryl, manufactured for BTG Pharmaceuticals Co. by Bristol-Myers Squibb Co., Princeton, NJ), im, weekly plus 125 µg LNG, orally, daily (formulated as a white powder in a clear capsule; Wyeth Ayerst, Philadelphia, PA); 2) T alone: 100 mg T enanthate, im, weekly and oral placebo (lactose as a white powder in a clear capsule) daily; 3) LNG alone: placebo T (sterile sesame seed oil), im, weekly plus 125 µg LNG, orally, daily; and 4) placebo: placebo T, im, weekly plus placebo LNG, orally, daily. Assignment for each consecutively enrolled subject was made by a research pharmacist using a predetermined assignment sheet created using a random number generator.

Subjects were asked to consume an average of one or fewer alcoholic beverage per day and to use an approved contraceptive throughout the study. Subjects were also asked not to change their diet or exercise patterns during the study. Dietary and exercise habits were reviewed at each study visit.

Three subjects discontinued the study after two or fewer T injections, one because of mood changes, one due to scheduling conflicts, and one because of noncompliance. Thirty-four subjects completed the treatment phase of the study. Two subjects did not complete the recovery period because they moved out of the state. One subject in the placebo group completed the study, but was eliminated from analysis because of a body mass index (BMI, 35.8 kg/m²) that was 3 SD above that in the rest of the study participants (25.2 ± 3.5 kg/m²). This subject was not obese, but had a very muscular body habitus. Exclusion of data from this subject did not change any of the statistically significant results.

Hormone assays

Serum hormone levels were obtained between 1700–1900 h. T, FSH, and LH levels were measured by immunofluorometric assay (Delfia, Wallac, Inc., Turku, Finland). Peak levels (24 h after injection) and trough levels (immediately before next injection) of hormones were measured during treatment wk 8. The assay sensitivity for T was 0.35 nmol/liter; the intraassay coefficient of variation was 4.5%, and the interassay coefficient of variation was 9.5% for a mean low range pooled T value of 6 nmol/liter, a mean midrange pooled T value of 11.4 nmol/liter, and a mean high range pooled T value of 24 nmol/liter. E₂ was measured with a standard DSL-39100 kit (Diagnostic Systems Laboratories, Inc., Webster, TX) with 0.75 pg/ml sensitivity and 6.0% coefficient of variation for interassay variability for a pooled low range value of 29 pmol/liter and 4.6% coefficient of variation for intraassay variability for a midrange pooled value of 110 pmol/liter. The sensitivities of the assay for FSH and LH were 0.016 and 0.019 IU/liter, respectively. The intraassay coefficient of variation was 12.0%, and the interassay coefficient of variation was 22.3% for a low range pooled value of FSH of 0.045 IU/liter; these values were 2.9% and 6.1%, respectively, for a midrange pooled value of 0.96 IU/liter. The intraassay coefficient of variation was 6.5%, and the interassay coefficient of variation was 17.7% for a low range pooled LH value of 0.074 IU/liter, and 3.2% and 12.5% for a midrange pooled value of 1.15 IU/liter. Samples from each participant were run in duplicate in the same assay to avoid interassay variability.

Body composition

Weight using the same scale and BMI were monitored throughout the study. During the last week of the control period, all subjects had a DEXA scan to assess body composition. The DEXA scans were performed on a QDR-4500A (Hologic, Inc., Waltham, MA) using Hologic software version 9.03 with a precision error of less than 1% for regional and total body scans. One technician with certification from the International Society for Clinical Densitometry was assigned to this project and verified the accuracy of each scan. The standard whole body DEXA examination included total body and regional measurements. Soft tissue regions measured outside of bone included two of the trunk, one of the pelvis, one of the abdomen, and one for each limb. The window of measurement for the total abdomen by DEXA was from lumbar vertebrae 1 (L1) through to the pelvic sacrum. The DEXA scan was repeated at wk 4 and 8 during treatment and once during the recovery phase. Abdominal and limb soft tissue mass were measured during the control period and treatment wk 8 only.

General laboratories

Blood sampling for determinations of complete blood count and differential, electrolytes and glucose (chemistry 7), calcium, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, bilirubin, total protein, creatinine, calcium, uric acid, phosphate, nonfasting total cholesterol, triglycerides, high density lipoprotein, and low density lipoprotein as well as urinalysis were performed three times during the control period, once during treatment, and once during recovery. Laboratory values were analyzed by Dynacare Laboratories (Seattle, WA).

Statistics

Data are presented as the mean ± SEM. Subjects who did not complete both treatment phase DEXA scans have been excluded from the analysis to present data at each time point from the same individuals. There originally were eight subjects in the placebo and T alone groups, seven subjects in the LNG alone group, and nine subjects in the T+LNG group. Excluding one subject in the placebo group, three subjects in the T alone group, and two subjects in the T+LNG group did not change the statistical significance of any of the reported changes in hormones or body composition. Changes from baseline within a group were analyzed with an unpaired one-sample t test. Differences between groups were assessed by ANOVA and verified by Kruskal-Wallis test. Differences between treatment groups were further compared using a paired two-tailed t test. We used Duncan’s comparison measure as our post hoc test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
All data presented are from individuals that completed the baseline and treatment phase DEXA scans (see Subjects and Methods).

Hormones

T. Trough levels of T did not increase significantly in the placebo or T+LNG group, but were significantly higher in the T alone group than baseline values and significantly lower in the LNG alone group than baseline or placebo group values (P < 0.05; Table 1). Peak levels of T significantly decreased in the LNG alone group vs. baseline and the placebo group (P < 0.05; Fig. 1). Peak levels of T increased significantly in the T alone and T+LNG groups compared with baseline and the placebo group (P < 0.05; Table 1). Trough and peak T levels did not significantly differ between the T alone and T+LNG groups. There were no significant differences in T levels among groups at baseline or during the recovery period.

View larger version (25K): [in this window] [in a new window]   Figure 1. Change in serum hormone levels. Data are the percent baseline (±SEM) changes in T, E2, FSH, and LH levels at 8 wk of treatment. T and E2 are peak levels. , Placebo; , LNG alone; , T alone; , T+LNG. *, P < 0.05 vs. baseline; , P < 0.05 vs. placebo; , P < 0.05 vs. LNG alone.

Gonadotropins. Serum gonadotropins were measured during treatment wk 8 at the same time as a trough level of T was measured. FSH did not change significantly in the placebo group. FSH decreased significantly in the LNG alone, T alone, and T+LNG groups compared with baseline and placebo group values (P < 0.05; Table 1 and Fig. 1).

LH did not change significantly in the placebo or LNG alone group, although LH tended to decrease in the LNG alone group vs. baseline (P = 0.07). LH decreased significantly in the T alone and T+LNG groups compared with baseline and the placebo groups (P < 0.05; Table 1 and Fig. 1).

There were no significant differences in gonadotropin levels between the T alone group and the T+LNG group. There were no significant differences in gonadotropin levels between groups at baseline or during the recovery period.

Body composition

Total lean mass increased significantly by 3.5 ± 0.9% (1.8 ± 0.4 kg; P < 0.05) above baseline in the T+LNG group after 4 wk of drug administration (Table 2 and Fig. 2). Total lean mass remained significantly elevated to 4.2 ± 1.2% (1.9 ± 0.6 kg; P < 0.05) above baseline after 8 wk of drug and returned to baseline values during the recovery phase. The increase in total lean mass at 4 and 8 wk of treatment in the T+LNG group was significantly higher than that in the placebo group (P < 0.05). T alone tended to increase total lean mass above baseline after 4 and 8 wk (P = 0.06 and 0.09, respectively; Table 1 and Fig. 2). The increase in total lean mass in the T alone group was significant vs. that in the placebo group at 4 wk of treatment (P < 0.05). There were no significant changes in total lean mass in the placebo group or LNG alone group during treatment or the recovery phase. There were no significant differences in total lean mass between groups at baseline or during the recovery period.

View larger version (12K): [in this window] [in a new window]   Figure 2. Change in total lean mass. T increases total lean mass in 4 wk in healthy young men. Data are the percentage of baseline ± SEM. •, Placebo; , LNG alone; , T alone; , T+LNG. *, P < 0.05 vs. baseline; , P < 0.05 vs. placebo; , P < 0.05 vs. LNG alone.

T+LNG and T alone significantly increased limb lean mass (right arm and leg) after 8 wk of treatment (3.2 ± 1.2% and 3.3 ± 1.0% increase vs. baseline, respectively; P < 0.05) after 8 wk of treatment. There was no significant change in lean mass in the limbs in the placebo or LNG alone groups. There were no significant differences in lean mass in the limbs between groups at baseline or during the recovery period.

There was no significant change from baseline or between groups for total percent fat mass in the placebo, LNG alone, or T+LNG groups over the 8-wk treatment period. T alone significantly decreased total percent fat mass vs. baseline at wk 8 of treatment (-5.6 ± 2.0%; P < 0.05; Table 2).

T+LNG did not affect abdominal fat mass. T alone significantly decreased abdominal fat mass after 8 wk of treatment compared with LNG alone (-4.9 ± 2.8%; P < 0.05; Table 2) and tended to decrease abdominal fat mass compared with baseline and placebo (P = 0.09). Treatment with LNG alone significantly increased abdominal fat mass vs. baseline (4.1 ± 1.0%; P < 0.05; Fig. 3). There was no change in abdominal fat mass in the placebo group during the treatment or recovery phase.

View larger version (15K): [in this window] [in a new window]   Figure 3. Change in abdominal fat mass. T decreases, LNG increases, but T+LNG does not affect abdominal fat mass in 8 wk in healthy young men. , Placebo; , LNG alone; , T alone; , T+LNG. Data are the percentage of baseline ± SEM. *, P < 0.05 vs. baseline; , P < 0.05 vs. LNG alone.

Laboratory tests, and physical and vital signs

There were no changes in the routine laboratory tests monitored throughout the study (see Materials and Methods), including hematocrit. There were no changes in heart rate, blood pressure, gynecomastia, or testicular size throughout the study (data not shown).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
T when administered with LNG to healthy young men significantly increased total lean mass and regional lean mass in the trunk and limbs in only 4 wk. The rapidity of the change suggests a direct and potent link between T and body composition in men.

T alone tended to increase total lean mass and significantly increased limb lean mass within 4–8 wk. That the increase in total lean mass in the T alone group had only a trend to significance vs. baseline might reflect the small number of subjects (n = 5) in this group. Alternatively, the T+LNG group might have had a greater androgen stimulus to increase lean mass than the T alone group. LNG is a T-derived progestin known to bind with high affinity to the androgen receptor. Although it has less affinity for the androgen receptor than does dihydrotestosterone (13), LNG binds with greater affinity to the androgen receptor than do other progestational agents (12). The ability of LNG to bind to the androgen receptor suggests that the effect of LNG on lean body mass would be additive to that of T. LNG alone, however, did not have any effect on lean mass; therefore, although LNG might potentiate the effects of T on lean mass, T is the more potent stimulus to increasing lean mass.

Exogenous T+LNG and T alone also significantly increased truncal lean mass by DEXA. A number of other studies have also monitored changes in truncal lean mass with various interventions (14, 15). DEXA has been verified by computed tomography (CT) as an accurate measure of total and regional lean mass in the limbs (16, 17, 18), but there are no studies verifying measurements of truncal soft tissue mass by DEXA with either CT or magnetic resonance imaging (MRI) even though almost half of the lean mass in the body is found in the trunk (19). Verification of the changes seen in truncal lean mass in our study by CT or MRI is needed.

The increase in lean mass with T administration seen in our study could be explained by an increase in the water content of this tissue, as one of the side-effects of T administration is fluid retention (4). However, it is likely that the observed changes in lean mass reflect increases in muscle mass, not fluid shifts. In a study similar to ours, Bhasin et al. (10) administered T to healthy young men at doses ranging from 25–600 mg. Total lean mass increased 2.9 ± 0.8% after the administration of 125 mg T, im, for 20 wk, as measured by DEXA and underwater weighing. To determine whether the increase in lean mass was secondary to water retention, total body water was measured by nuclear magnetic spectroscopy after the men ingested deuterium hydroxide. The ratio of total body water to fat-free mass by underwater weighing did not significantly change for any treatment group.

Measurement of abdominal fat mass by DEXA has been demonstrated to correlate highly with abdominal fat measured by MRI and CT (20, 21). In 17 eugonadal men, the average central abdominal fat between L1 and L3 was 1.13 ± 0.34 kg by DEXA and 0.89 ± 0.2 kg by MRI, with a correlation of r² = 0.87 (P < 0.001) (20). There was also a strong relationship between abdominal fat percentage and volumes of fat measured between L1 and L4 by DEXA and CT (r² = 0.92; P < 0.001). We measured a window of fat from L1 to just above the pelvic sacrum. This region of measurement is slightly larger than that in the previous studies and includes the suprapubic area of fat to ensure that the complete abdomen was included in the window of measurement.

Total and abdominal fat mass in our study decreased significantly in the T alone group in 8 wk. Interestingly, although T decreased abdominal fat mass, abdominal fat mass increased in the group administered LNG alone. T+LNG did not affect abdominal fat mass, consistent with the opposite effect of LNG on fat mass than T. The individual effects of the hormones on fat mass are therefore cancelled when both hormones are administered together, suggesting that LNG differentially affects lean and fat mass.

Another explanation for the increase in fat mass in the LNG alone group could be that gonadotropin and T levels were significantly suppressed by LNG. However, if LNG also bound to and suppressed sex hormone-binding globulin similar to androgens (22, 23), increasing free T levels, fat mass would be expected to decrease similar to levels in the T alone group. Free T levels were not measured in this study.

The increase in lean mass and decrease in fat mass by T in this study are consistent with reports in hypogonadal men (7, 8, 9), eugonadal young (10), and older men (24). Muscle strength has been demonstrated to increase after im T administration to men in as little as 1 month of treatment (4, 25, 26). It is interesting that the rapid increase in lean mass was offset by a similar rapid decrease in fat mass, so that weight and BMI did not change. There was an increase in absolute lean mass by DEXA in the T+LNG group, suggesting that a longer study would have demonstrated the increase in weight as changes in lean mass accrued, as weight gain is clearly associated with T administration to eugonadal and hypogonadal men at these doses (8, 27, 28).

As T is metabolized to E₂ by aromatase, and E₂ levels were increased by approximately 39% in the groups administered T, the question arises as to what role E₂ has in determining body composition in men administered T. Estrogen receptors are found in adipocytes in male rats (29) and male estrogen receptor- knockout mice have increased white adipose tissue as well as adipocyte size and amount (30), suggesting that the elevated E₂ levels in men administered T might play a role in decreasing fat mass. Analysis of body composition when T is administered with and without an aromatase inhibitor would help decipher the role E₂ plays in body composition in men given T.

Exogenous T plus a progestin such as LNG is a promising combination for a male contraceptive regimen. One of the major side-effects of exogenous T and progestin is decreased serum high density lipoproteins and possibly increased low density lipoprotein particle concentrations (11, 31, 32, 33). These lipid alterations associated with a T plus progestin combination might confer a higher cardiovascular risk (33). The favorable changes on lean and fat mass after an androgen-based contraceptive such as T+LNG might offset the effects of the unfavorable effects on lipid parameters.

Further investigations must be performed of the effects of androgens and progestins on fat mass and lean body mass to fully understand the risks and benefits of androgen-based contraceptives.

	Acknowledgments

 
We acknowledge the generous gift of levonorgestrel from Wyeth Ayerst, technical assistance from Dorothy McGuinness and Arlen Sarkissian, and administrative assistance from Connie Nosbisch, Kathy Winters, Elaine Rost, and Connie Pete.

	Footnotes

 
This work was supported by V.A. Merit Review Research Funds, the NICHHD, NIH through Cooperative Agreement U54-HD-12629 as part of the Specialized Cooperative Centers Program in Reproduction Research, and NIDDK Metabolism Training Grant T32-DK-O7247 (to K.L.H.).

Abbreviations: BMI, Body mass index; CT, computed tomography; DEXA, dual energy x-ray absorptiometry; E₂, estradiol; LNG, levonorgestrel; MRI, magnetic resonance imaging; T, testosterone.

Received June 12, 2002.

Accepted November 20, 2002.

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