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Journal of Chmcal Endocrinology and Metabolism
Copyright 0 1996 by The Endocrine Society
Vol. 81, No. 4
Printed in U.S.A.
Nandrolone, a 19=Nortestosterone, Enhances Insulin-
Independent Glucose Uptake in Normal Men*
CURTIS J. HOBBS, ROBERT E. JONES, AND STEPHEN R. PLYMATE
Department of Clinical Investigation, Madigan Army Medical Center (C.J.H, R.E.J.), Tacoma,
Washington 98431; Geriatric Research, Education, and Clinical Center, American Lake VAMC (182B),
Tacoma, Washington 98493; and Department of Medicine, University of Washington (S.R.P.), Seattle,
Washington 98195
ABSTRACT
The effect of exogenous androgens on glucose metabolism is controversial.
This study was designed to clarify the impact of testosterone
enanthate (TE), an aromatizable androgen, and nandrolone
decanoate (ND), a nonaromatizable androgen, on glucose disposal.
Eleven healthy men were enrolled in a randomized, double-blind
cross-over study. All subjects completed two treatment cycles consisting
of two weekly injections of placebo followed by six weekly
injections of either TE (300 mg/week) or ND (300 mg/week). Treatment
periods were separated by a 4-week washout. A tolbutamidemodified,
frequently sampled, iv glucose tolerance test was used to
assess insulin-dependent and insulin-independent glucose disposal.
Data were analyzed using Bergman’s minimal model. Parameters
examined included acute insulin response to glucose, fasting insulin
level, glucose disappearance constant, insulin sensitivity index, glucose
effectiveness at basal insulin (So), and glucose effectiveness at
zero insulin (GEZI). Neither androgen adversely affected glucose disposal.
To the contrary, treatment with ND actually improved noninsulin-
mediated glucose disposal as expressed by So and GEZI. In
ND-treated men, So (X 10-z mini) rose from 2.4 ? 0.2 at the end of
the placebo period to 3.7 i 0.6 after treatment (P < 0.051, whereas
GEZI (X lo-’ min-I) increased from 1.8 2 0.2 to 3.1 2 0.6 (P < 0.01).
We conclude that the treatment of normal men with supraphysiological
doses of either TE or ND does not adversely affect glucose metabolism.
Treatment with a nonaromatizable androgen, such as ND,
actually improves glucose metabolism by enhancing noninsulin-mediated
glucose disposal. (J Clin Endocrinol Metab 81: 1582-1585,
1996)
T ESTOSTERONE and its cogeners have been proposed
for use as male contraceptives and as agents that will
favorably redistribute fat mass in abdominally obese middleaged
men (l-3). Proposals for contraception include the administration
of 300 mg of a testosterone ester weekly. Such
a dose of testosterone will significantly (3-fold) increase the
serum testosterone level in normal men (4). Because androgen
treatment would be given over several years, problematical
adverse effects should be well defined. The literature
pertaining to one such adverse effect, the impact of exogenous
hyperandrogenism on glucose metabolism, is somewhat
ambiguous. The oral administration of 17-alkylated
androgens has been reported to induce insulin resistance
(5-7); however, the parenteral administration of either testosterone
or 19-nortestosterone does not adversely affect glucose
metabolism (4).
modified, iv, glucose tolerance test (mIVGTT) before and
after androgen treatment (8-10). Bergman’s minimal model
was chosen because it permits assessment of both insulin
sensitivity and glucose effectiveness in a single assay.
Subjects
Materials and Methods
In an effort to better characterize the effect of exogenous
androgens on glucose metabolism, we enrolled 11 normal
men in a randomized, double-blind cross-over study comparing
the administration of testosterone enanthate (TE) to
19-nortestosterone decanoate (nandrolone; ND). ND was
chosen because it is not aromatized to estradiol. We employed
Bergman’s minimal model of glucose kinetics to establish
glucose-insulin interactions during a tolbutamide-
Eleven healthy men volunteered for participation in the study. The
study was reviewed and approved by the Human Use Committee at
Mad&an Army Medical Center, and all subjects gave written informed
consent before enrollment. The subjects were in good health, with no
major illness, history of psychiatric disease, or substance abuse. None
had a personal or family history of diabetes mellitus or glucose intolerance.
They were not taking any medications and had not received
anabolic steroids in the 6 months before study. Each subject was instructed
not to change his total caloric intake, dietary composition, or
level of physical activity during the study. Baseline clinical characteristics
and serum hormone concentrations for the two groups are shown
in Table 1.
Anthropometrical measurements
Subjects were weighed weekly throughout the study. Body mass
index (BMI) was calculated by dividing the weight in kilograms by the
square of the height in meters. Percent body fat was estimated by a
circumference method using waist, neck, and height measurements (11).
Both BMI and fat mass were recorded at the start and end of each
treatment cycle.
Received June 27, 1995. Revision received September 29, 1995.
Accepted October 3, 1995.
Experimental protocol
Address all correspondence and requests for reprints to: Curtis A. General overview. This was a randomized, double-blind cross-over
Hobbs, Department of Clinical Investigation, Madigan Army Medical
Center, MAJMC, Tacoma, Washington 98431.
study. As described in Fig. 1, the study involved five phases (I, II, III, IV,
* Supported in part by Veteran’s Administration Merit Review Grant
and V) and lasted 20 weeks. Phase I was a placebo period lasting 2 weeks.
(to S.R.P.).
During this phase the subjects believed themselves to be receiving an
anabolic steroid. They actually received weekly injections of vehicle
1582
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NANDROLONE ENHANCES GLUCOSE UPTAKE 1583
TABLE 1. Clinical characteristics and baseline hormonal
determinations of the two groups before any therapy
Variable TE group ND group
(n = 5) (n = 6)
Age (yr)
BMI (kg/m21
Body fat (%)
Fasting insulin (pmol/L)
Testosterone (nmoVL)
Calculated free testosterone (pmol/L)
Percent free testosterone (%I
E&radio1 (pmol/L)
Sex hormone binding globulin
(nmoliL)
Mean values ? SE are shown.
27.2 + 2.4
26.1 5 1.0
12.8 2 2.1
51.6 ? 10.0
20.8 2 3.1
397.9 -c 65.5
1.9 ? 0.1
112.1 ? 13.9
33.2 -c 3.0
24.0 2 1.3
25.2 + 0.9
15.2 r 0.8
60.3 k 6.5
15.3 2 2.4
300.1 2 45.7
2.0 2 0.1
118.0 ? 34.0
25.7 -c 1.9
(sesame oil). This placebo period was used to validate the fact that
subjects did not change their diets or activity levels based on the knowledge
that they were receiving an anabolic steroid.
Beginning at week 3 (Fig. l), the subjects were randomly assigned in
a double-blind fashion to receive either TE or ND. Nandrolone was
chosen as an androgen comparable to testosterone because the relative
binding affinity of TE for the androgen receptor is 0.1-0.2, whereas that
for ND is 0.3-0.4 with a reference value of 1.0 for dihydrotestosterone
(12). On the other hand, ND is not readily aromatized to estradiol. As
described in Fig. 1, subjects received weekly injections of the assigned
steroid for 6 weeks (phase II). At the end of this 6-week treatment period,
all subjects entered a 4-week washout period (phase III). At the end of
this washout period, subjects again entered a 2-week placebo period
(phase IV). After this second placebo period, subjects who were initially
randomized to TE were crossed over to receive ND for a 6-week period,
while those who had been initially assigned to receive ND were now
given TE for 6 weeks (phase V).
B. Androgen administration. Five subjects were initially randomized to
receive TE (Steris, Phoenix, AZ); six subjects initially received ND
(Organon, Oak Forest, IL). Each androgen (300 mg) was given by deep
im injection into the buttock. Injection sites were alternated weekly.
C. Minimal model analysis. Bergman’s minimal model of glucose kinetics was
used to establish glucose-insulin interactions during a tolbutamide-modified,
iv mIVGTT. Details of this analysis have been described previously
(13). All subjects were studied after an overnight fast of at least 10 h. In brief,
an iv Teflon catheter (5 cm, 16 gauge) was inserted into each of the antecubital
veins, one to permit the administration of glucose and tolbutamide,
and the other to allow frequent sampling of venous blood arterialized by
wrapping the forearm in a heated pad 04). Baseline samples for insulin and
glucose levels, as well as estradiol (Ez), total testosterone (T), and sex
hormone-binding globulin, were drawn 5, 10, and 15 min after iv placement.
Glucose as a 25% solution (0.3 g/kg) was injected over 30 set after
the last baseline sample was drawn. Beginning 20 min after glucose administration,
tolbutamide (as a bolus of 150 mg/m’) was injected over 30
set (Orinase Diagnostic, UpJohn, Kalamazoo, MI). Blood samples (3 mLj,
for measurement of glucose and insulin, were drawn 2,3,4,5,6,8,10,12,
14, 16, 19, 22, 23, 24, 25, 27, 30, 35,40, 50, 60, 70, 80, 90, 100, 120, 140, 160,
and 180 min after starting the glucose injection.
Minimal model analysis permits identification of the two components
that account for glucose disappearance during a mIVGTT. These components
are the disappearance of glucose because of the dynamic plasma
insulin response [the insulin sensitivity index (S,)] and the disappear-
FIG. 1. Study flow chart
ante of glucose independent of the dynamic insulin response [glucose
effectiveness at basal insulin (S,)J.
Both S, and So were determined using the MINMOD computer program
(15) (R. N. Bergman) run on an IBM PC. The contribution to glucose
disappearance of noninsulin-dependent glucose uptake [glucose effectiveness
at zero insulin (GEZI)] was calculated as described by Kahn et
al. (16). A mIVGTT was performed on each individual at the beginning
and end of phases II and V.
Analytical methods
All samples from the same subject were measured in duplicate in a
single assay. Serum glucose concentrations were determined by the
glucose oxidase method (Beckman Glucose Analyzer, Fullerton, CA).
Serum levels of insulin, SHBG, total and free testosterone, and estradiol
were determined as previously described (4, 17).
Statistical analysis
All statistics were performed with the Statview program (Abacus
Concepts, Berkeley, CA) on a Macintosh computer (Apple Computer,
Cupertino, CA). All data are expressed as the mean + SE. Tests were
done to determine whether the order in which the treatments were given
affected the outcome (sequence effect) or whether the response seen in
the first treatment period differed from that seen in the second treatment
period (period effect). Data for which no sequence or period effect could
be detected was analyzed to establish: 1) if the effect of androgen therapy
on any measured variable differed depending upon whether TE or ND
was used (a between-treatment analysis); and 2) if a given variable
changed over time because of androgen therapy (a within-treatment
analysis). If no sequence or period effects were noted, the study was
analyzed as a cross-over design. Paired data was analyzed using Student’s
t test. An unpaired t test was used for differences between the
groups. The significance level was set at P 5 0.05.
Results
All subjects completed the entire study. There were no
adverse reactions to either TE or ND. A single subject developed
a localized phlebitis after a mIVGTT; he responded
rapidly to conservative therapy. Minimal model analysis
could not be performed on the data derived from one subject’s
post-TE treatment mIVGTT caused by an inability to
administer glucose in bolus fashion. Therefore, S,, So, and
GEZI are not reported for this individual.
Analysis for sequence and period effects
There were no significant sequence or period effects on any
measured variable. Consequently, data from treatment period
1 and treatment period 2 were pooled for further analysis.
Within-treatment analysis
A. Anthropometrics. Neither androgen affected percent body
fat. It should be noted that our subjects were quite lean, with
an average fat mass of less than 16%. Weight and BMI increased
in both TE- and ND-treated subjects, although the
change was only significant in TE-treated subjects. In this
latter group, mean weight rose from 82.4 2 2.4 kg at the start
of TE administration to 84.7 -C 2.0 kg at the end of treatment
(P = 0.04). In the ND-treated group, mean weight increased
from 81.4 t 2.1 kg to 85.2 ? 2.0 kg (not significant).
l3. Minimal model analysis. As shown in Table 2, there were no
significant changes in PI, acute insulin response to glucose
(AIJ&mse)~ KS, or S, caused by androgen therapy in either TEor
ND-treated men. In contrast, both parameters of insulinon
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HOBBS ET AL. JCE & M . 1996
Vol81. No 4
TABLE 2. Postplacebo and postandrogen glucose tolerance parameters for TE- (n = 11) and ND-treated (n = 11) men
Variable Postplacebo Post-TE Postplacebo Post-ND
FI (pmol/L) 48.5 + 5.0 47.9 t 4.4 57.4 2 4.5 58.7 + 11.4
orgy,,,, (PmoW 348.5 + 88.5 310.2 + 56.2 355.7 t 43.0 382.1 k 92.5
Kg (min-l) 2.2 2 0.2 2.6 + 0.4 2.5 2 0.3 2.3 t 0.4
S, (X low4 . min-‘/pU * ml) 8.8 I! 1.4 8.9 + 2.8 7.9 -c 1.1 8.1 5 1.6
S, ( X lo-’ * min- I) 2.3 2 0.2 3.0 k 0.4 2.4 ? 0.2 3.7 + 0.6”
GEZI (X lo-’ * min- I) 1.9 k 0.2 2.5 t 0.4 1.8 2 0.2 3.1 2 0.6&
Mean values ? SE are shown.
a P = 0.02; b P = 0.01.
independent glucose disposal (SG and GEZI) increased significantly
in men receiving ND. Specifically, S, increased from 2.4
2 0.2 X lo-’ min-’ before ND treatment to 3.7 ? 0.6 X lo-’
min-’ after ND treatment (P = 0.02). Similarly, GEZI increased
from 1.8 2 0.2 X lo-’ min-’ before ND treatment to 3.1 + 0.6
X lo-* min-’ after ND treatment (P = 0.01).
C. Sex steroids. See Table 3. Although E2 levels fell with ND
treatment from 139.1 2 27.5 pmol/L to 89.2 +- 20.2 pmol/L,
the decline was not significant (P 5 0.17). This was due to one
individual who had an increase of estradiol on ND although
his T level decreased, indicating he was getting ND. Removing
this individual from the analysis, the E, levels were 143
2 29 pmol/L and 75 t 14 pmol/L, pre-ND VS. post-ND (P
5 0.04). The reason for the increase in E, in this individual
after ND administration could not be determined.
Between-treatment analysis
A. Anthropometrical measurements. There were no differential
treatment effects for either androgen on weight, BMI, or
percent body fat.
B. Minimal model analysis. There were no differential treatment
effects for either androgen on fasting insulin (FI),
AIRglucose, glucose disappearance constant (K,), S, glucose
effectiveness at basal insulin (S,), or GEZI.
C. Sex steroids. The two groups (TE vs. ND) differed significantly
with regard to the effect of androgen therapy on E,, T, fT, and
percent free testosterone (% fT) levels. Specifically, E, levels rose
by 193.04 2 19.82 pmol/L in the T&treated men, while falling
by 50.65 2 34.50 pmol/L in the ND-treated men (P = 0.0002).
Total testosterone levels increased 0.32 t 0.05 nmol/L in the
TE-treated men, but fell by 0.07 ? 0.02 nmol/L in the NDtreated
men (P = 0.0001). Free testosterone increased 915.6 ?
139.5 pmol/L in the TE-treated group; the ND-treated group
had a decline of 119.4 2 52.2 pmol/L (P = 0.0001). The %fT
increased in both groups but rose higher in the TE-treated men
than in the ND-treated men (0.63 + 0.09% and 0.20 + 0.05%, TE
vs. ND, respectively, P = 0.003).
Discussion
Confirming previous work from our laboratory (4), we
found no adverse effect of either TE or ND on glucose tolerance
or insulin secretion in normal men given these androgens
for a 6-week period. To the contrary, the present
study documents a significant improvement in noninsulinmediated
glucose disposal in men receiving ND.
Studies addressing the effect of anabolic steroids on glucose
metabolism are contradictory. Early literature contended
that anabolic steroids lowered fasting blood sugar
and reduced glycosuria and insulin requirements in diabetes
(18-26). Most of these studies failed to identify a mechanism
through which these agents could improve glucose tolerance,
though methandienone (Al-17-a methyltestosterone) was
reported to enhance insulin secretion (6, 27, 28).
Later work indicated that anabolic steroids adversely affected
glucose metabolism. Woodard et al. (29) reported that
oxymethalone (2-carboxylated methyltestosterone) led to
impaired glucose tolerance and hyperinsulinemia, as measured
in an oral glucose tolerance test in children with idiopathic
acquired aplastic anemia or Fanconi’s anemia. However,
these authors compared the study population (N = 7)
with a group of normal children, not to untreated children
with these anemias. Landon et al. (27) demonstrated that
methandienone induced a 3-fold increase in the insulin response
to iv tolbutamide without a change in plasma glucose.
However, the methodology employed in their study could
not identify which factors were responsible for apparent
insulin resistance, i.e. changes in P-cell sensitivity to glucose,
insulin-independent glucose uptake, or sensitivity of glucose
TABLE 3. Within treatment analysis: Postplacebo and postandrogen sex steroids for TE- (n = 11) and ND-treated (n = 11) men
Variable Postplacebo Post-TE Postplacebo Post-ND
SHBG (nmol/L) 30.1 + 3.2 22.1 + 2.9 25.6 k 2.2 20.2 + 1.8
(P = 0.02) (P = 0.003)
E, (pmol/L) 77.4 + 15.0 270.5 + 22.4 139.1 2 27.5 89.2 2 20.2
(P = 0.003)
T (nmol/L) 11.6 t 3.1 43.2 + 5.4 16.5 -c 2.4 10.0 ? 1.3
(P = 0.001) (P = 0.02)
f T (pmol/L) 226.6 2 59.3 1142.2 k 150.6 352.4 2 60.4 233.0 k 31.6
(P = 0.001) (P = 0.05)
%fT 1.99 2 0.09 2.62 ” 0.10 2.10 ? 0.80 2.33 + 0.08
(P = 0.0001) (P = 0.0006)
Mean values t SE are shown.
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NANDROLONE ENHANCES GLUCOSE UPTAKE
uptake to insulin. Cohen et al. (5) concluded that powerlifters
who ingested anabolic steroids had insulin resistance IIS.
nonsteroid-using powerlifters, obese sedentary men, or
nonobese sedentary men. However, treated subjects were
lo-15 kg heavier than controls; this difference may have
affected the outcome.
In the present study, treatment with an anabolic steroid
did not adversely affect glucose tolerance. To the contrary,
ND actually improved insulin-independent glucose disposal.
This finding is echoed in a recent report using a canine
model system to study the effect of 19-nortestosterone administration
at doses designed to approximate those used by
athletes (30). The authors of this report found that although
the insulin responsiveness of insulin-dependent glucose utilization
decreased by 40%, insulin-independent glucose disposal
was increased 3-fold. Hence, overall glucose tolerance
was not impaired.
The effect of an anabolic steroid on glucose disposal may
be dose dependent. Marin et al. have shown that a single im
injection of 250 mg testosterone undecanoate given to obese
middle-aged men improves insulin sensitivity, whereas a
single dose of 500 mg has no effect (31). Animal studies by
this same group demonstrate that the castrate rat has a decreased
S, that improves with physiological T replacement
but declines with supraphysiological doses of T (32). Although
the dose of androgen administered in our study (300
mg) approximated that used by Marin, we saw no effect on
S,. Two methodological differences may account for these
disparate results. First, the subjects in M&in’s study were
mildly obese middle-aged men with subnormal serum T
levels, whereas our men were lean and had normal T levels.
Second, the frequency with which our androgens were administered
may have increased serum androgen levels beyond
the window of efficacy for improvement in Si as described
by Marin.
It is uncertain why ND improved noninsulin-mediated
glucose disposal, whereas T did not. The difference may
reflect the metabolic fate of the agent, i.e. ND is not effectively
aromatized to estradiol. This conclusion is supported in work
by Polderman et al., who used 3-step hyperinsulinemiceuglycemic
clamp studies to identify cross-gender hormone
therapy-induced insulin resistance in transsexuals (33).
Polderman reported that insulin sensitivity declined in transsexual
men given ethyl estradiol. Hence, it may be that any
improvement in glucose disposal owing to an androgen is
offset by aromatization of the androgen.
In conclusion, 6 weeks’ treatment of normal men with
either TE or ND does not impair glucose tolerance. In constrast,
treatment with ND, an nonaromatizable androgen,
actually improves noninsulin-mediated glucose disposal.
Acknowledgments
The authors wish to extend thanks to Mr. Troy Patience, Mr. Louis
Matej, and Dr. Brenda K. Bell for their guidance anh technical assistance.
Injectable tolbutamide (Orinase) used in the mIVGTT studies was kindly
donated by Upjohn.
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Journal of Chmcal Endocrinology and Metabolism
Copyright 0 1996 by The Endocrine Society
Vol. 81, No. 4
Printed in U.S.A.
Nandrolone, a 19=Nortestosterone, Enhances Insulin-
Independent Glucose Uptake in Normal Men*
CURTIS J. HOBBS, ROBERT E. JONES, AND STEPHEN R. PLYMATE
Department of Clinical Investigation, Madigan Army Medical Center (C.J.H, R.E.J.), Tacoma,
Washington 98431; Geriatric Research, Education, and Clinical Center, American Lake VAMC (182B),
Tacoma, Washington 98493; and Department of Medicine, University of Washington (S.R.P.), Seattle,
Washington 98195
ABSTRACT
The effect of exogenous androgens on glucose metabolism is controversial.
This study was designed to clarify the impact of testosterone
enanthate (TE), an aromatizable androgen, and nandrolone
decanoate (ND), a nonaromatizable androgen, on glucose disposal.
Eleven healthy men were enrolled in a randomized, double-blind
cross-over study. All subjects completed two treatment cycles consisting
of two weekly injections of placebo followed by six weekly
injections of either TE (300 mg/week) or ND (300 mg/week). Treatment
periods were separated by a 4-week washout. A tolbutamidemodified,
frequently sampled, iv glucose tolerance test was used to
assess insulin-dependent and insulin-independent glucose disposal.
Data were analyzed using Bergman’s minimal model. Parameters
examined included acute insulin response to glucose, fasting insulin
level, glucose disappearance constant, insulin sensitivity index, glucose
effectiveness at basal insulin (So), and glucose effectiveness at
zero insulin (GEZI). Neither androgen adversely affected glucose disposal.
To the contrary, treatment with ND actually improved noninsulin-
mediated glucose disposal as expressed by So and GEZI. In
ND-treated men, So (X 10-z mini) rose from 2.4 ? 0.2 at the end of
the placebo period to 3.7 i 0.6 after treatment (P < 0.051, whereas
GEZI (X lo-’ min-I) increased from 1.8 2 0.2 to 3.1 2 0.6 (P < 0.01).
We conclude that the treatment of normal men with supraphysiological
doses of either TE or ND does not adversely affect glucose metabolism.
Treatment with a nonaromatizable androgen, such as ND,
actually improves glucose metabolism by enhancing noninsulin-mediated
glucose disposal. (J Clin Endocrinol Metab 81: 1582-1585,
1996)
T ESTOSTERONE and its cogeners have been proposed
for use as male contraceptives and as agents that will
favorably redistribute fat mass in abdominally obese middleaged
men (l-3). Proposals for contraception include the administration
of 300 mg of a testosterone ester weekly. Such
a dose of testosterone will significantly (3-fold) increase the
serum testosterone level in normal men (4). Because androgen
treatment would be given over several years, problematical
adverse effects should be well defined. The literature
pertaining to one such adverse effect, the impact of exogenous
hyperandrogenism on glucose metabolism, is somewhat
ambiguous. The oral administration of 17-alkylated
androgens has been reported to induce insulin resistance
(5-7); however, the parenteral administration of either testosterone
or 19-nortestosterone does not adversely affect glucose
metabolism (4).
modified, iv, glucose tolerance test (mIVGTT) before and
after androgen treatment (8-10). Bergman’s minimal model
was chosen because it permits assessment of both insulin
sensitivity and glucose effectiveness in a single assay.
Subjects
Materials and Methods
In an effort to better characterize the effect of exogenous
androgens on glucose metabolism, we enrolled 11 normal
men in a randomized, double-blind cross-over study comparing
the administration of testosterone enanthate (TE) to
19-nortestosterone decanoate (nandrolone; ND). ND was
chosen because it is not aromatized to estradiol. We employed
Bergman’s minimal model of glucose kinetics to establish
glucose-insulin interactions during a tolbutamide-
Eleven healthy men volunteered for participation in the study. The
study was reviewed and approved by the Human Use Committee at
Mad&an Army Medical Center, and all subjects gave written informed
consent before enrollment. The subjects were in good health, with no
major illness, history of psychiatric disease, or substance abuse. None
had a personal or family history of diabetes mellitus or glucose intolerance.
They were not taking any medications and had not received
anabolic steroids in the 6 months before study. Each subject was instructed
not to change his total caloric intake, dietary composition, or
level of physical activity during the study. Baseline clinical characteristics
and serum hormone concentrations for the two groups are shown
in Table 1.
Anthropometrical measurements
Subjects were weighed weekly throughout the study. Body mass
index (BMI) was calculated by dividing the weight in kilograms by the
square of the height in meters. Percent body fat was estimated by a
circumference method using waist, neck, and height measurements (11).
Both BMI and fat mass were recorded at the start and end of each
treatment cycle.
Received June 27, 1995. Revision received September 29, 1995.
Accepted October 3, 1995.
Experimental protocol
Address all correspondence and requests for reprints to: Curtis A. General overview. This was a randomized, double-blind cross-over
Hobbs, Department of Clinical Investigation, Madigan Army Medical
Center, MAJMC, Tacoma, Washington 98431.
study. As described in Fig. 1, the study involved five phases (I, II, III, IV,
* Supported in part by Veteran’s Administration Merit Review Grant
and V) and lasted 20 weeks. Phase I was a placebo period lasting 2 weeks.
(to S.R.P.).
During this phase the subjects believed themselves to be receiving an
anabolic steroid. They actually received weekly injections of vehicle
1582
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NANDROLONE ENHANCES GLUCOSE UPTAKE 1583
TABLE 1. Clinical characteristics and baseline hormonal
determinations of the two groups before any therapy
Variable TE group ND group
(n = 5) (n = 6)
Age (yr)
BMI (kg/m21
Body fat (%)
Fasting insulin (pmol/L)
Testosterone (nmoVL)
Calculated free testosterone (pmol/L)
Percent free testosterone (%I
E&radio1 (pmol/L)
Sex hormone binding globulin
(nmoliL)
Mean values ? SE are shown.
27.2 + 2.4
26.1 5 1.0
12.8 2 2.1
51.6 ? 10.0
20.8 2 3.1
397.9 -c 65.5
1.9 ? 0.1
112.1 ? 13.9
33.2 -c 3.0
24.0 2 1.3
25.2 + 0.9
15.2 r 0.8
60.3 k 6.5
15.3 2 2.4
300.1 2 45.7
2.0 2 0.1
118.0 ? 34.0
25.7 -c 1.9
(sesame oil). This placebo period was used to validate the fact that
subjects did not change their diets or activity levels based on the knowledge
that they were receiving an anabolic steroid.
Beginning at week 3 (Fig. l), the subjects were randomly assigned in
a double-blind fashion to receive either TE or ND. Nandrolone was
chosen as an androgen comparable to testosterone because the relative
binding affinity of TE for the androgen receptor is 0.1-0.2, whereas that
for ND is 0.3-0.4 with a reference value of 1.0 for dihydrotestosterone
(12). On the other hand, ND is not readily aromatized to estradiol. As
described in Fig. 1, subjects received weekly injections of the assigned
steroid for 6 weeks (phase II). At the end of this 6-week treatment period,
all subjects entered a 4-week washout period (phase III). At the end of
this washout period, subjects again entered a 2-week placebo period
(phase IV). After this second placebo period, subjects who were initially
randomized to TE were crossed over to receive ND for a 6-week period,
while those who had been initially assigned to receive ND were now
given TE for 6 weeks (phase V).
B. Androgen administration. Five subjects were initially randomized to
receive TE (Steris, Phoenix, AZ); six subjects initially received ND
(Organon, Oak Forest, IL). Each androgen (300 mg) was given by deep
im injection into the buttock. Injection sites were alternated weekly.
C. Minimal model analysis. Bergman’s minimal model of glucose kinetics was
used to establish glucose-insulin interactions during a tolbutamide-modified,
iv mIVGTT. Details of this analysis have been described previously
(13). All subjects were studied after an overnight fast of at least 10 h. In brief,
an iv Teflon catheter (5 cm, 16 gauge) was inserted into each of the antecubital
veins, one to permit the administration of glucose and tolbutamide,
and the other to allow frequent sampling of venous blood arterialized by
wrapping the forearm in a heated pad 04). Baseline samples for insulin and
glucose levels, as well as estradiol (Ez), total testosterone (T), and sex
hormone-binding globulin, were drawn 5, 10, and 15 min after iv placement.
Glucose as a 25% solution (0.3 g/kg) was injected over 30 set after
the last baseline sample was drawn. Beginning 20 min after glucose administration,
tolbutamide (as a bolus of 150 mg/m’) was injected over 30
set (Orinase Diagnostic, UpJohn, Kalamazoo, MI). Blood samples (3 mLj,
for measurement of glucose and insulin, were drawn 2,3,4,5,6,8,10,12,
14, 16, 19, 22, 23, 24, 25, 27, 30, 35,40, 50, 60, 70, 80, 90, 100, 120, 140, 160,
and 180 min after starting the glucose injection.
Minimal model analysis permits identification of the two components
that account for glucose disappearance during a mIVGTT. These components
are the disappearance of glucose because of the dynamic plasma
insulin response [the insulin sensitivity index (S,)] and the disappear-
FIG. 1. Study flow chart
ante of glucose independent of the dynamic insulin response [glucose
effectiveness at basal insulin (S,)J.
Both S, and So were determined using the MINMOD computer program
(15) (R. N. Bergman) run on an IBM PC. The contribution to glucose
disappearance of noninsulin-dependent glucose uptake [glucose effectiveness
at zero insulin (GEZI)] was calculated as described by Kahn et
al. (16). A mIVGTT was performed on each individual at the beginning
and end of phases II and V.
Analytical methods
All samples from the same subject were measured in duplicate in a
single assay. Serum glucose concentrations were determined by the
glucose oxidase method (Beckman Glucose Analyzer, Fullerton, CA).
Serum levels of insulin, SHBG, total and free testosterone, and estradiol
were determined as previously described (4, 17).
Statistical analysis
All statistics were performed with the Statview program (Abacus
Concepts, Berkeley, CA) on a Macintosh computer (Apple Computer,
Cupertino, CA). All data are expressed as the mean + SE. Tests were
done to determine whether the order in which the treatments were given
affected the outcome (sequence effect) or whether the response seen in
the first treatment period differed from that seen in the second treatment
period (period effect). Data for which no sequence or period effect could
be detected was analyzed to establish: 1) if the effect of androgen therapy
on any measured variable differed depending upon whether TE or ND
was used (a between-treatment analysis); and 2) if a given variable
changed over time because of androgen therapy (a within-treatment
analysis). If no sequence or period effects were noted, the study was
analyzed as a cross-over design. Paired data was analyzed using Student’s
t test. An unpaired t test was used for differences between the
groups. The significance level was set at P 5 0.05.
Results
All subjects completed the entire study. There were no
adverse reactions to either TE or ND. A single subject developed
a localized phlebitis after a mIVGTT; he responded
rapidly to conservative therapy. Minimal model analysis
could not be performed on the data derived from one subject’s
post-TE treatment mIVGTT caused by an inability to
administer glucose in bolus fashion. Therefore, S,, So, and
GEZI are not reported for this individual.
Analysis for sequence and period effects
There were no significant sequence or period effects on any
measured variable. Consequently, data from treatment period
1 and treatment period 2 were pooled for further analysis.
Within-treatment analysis
A. Anthropometrics. Neither androgen affected percent body
fat. It should be noted that our subjects were quite lean, with
an average fat mass of less than 16%. Weight and BMI increased
in both TE- and ND-treated subjects, although the
change was only significant in TE-treated subjects. In this
latter group, mean weight rose from 82.4 2 2.4 kg at the start
of TE administration to 84.7 -C 2.0 kg at the end of treatment
(P = 0.04). In the ND-treated group, mean weight increased
from 81.4 t 2.1 kg to 85.2 ? 2.0 kg (not significant).
l3. Minimal model analysis. As shown in Table 2, there were no
significant changes in PI, acute insulin response to glucose
(AIJ&mse)~ KS, or S, caused by androgen therapy in either TEor
ND-treated men. In contrast, both parameters of insulinon
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HOBBS ET AL. JCE & M . 1996
Vol81. No 4
TABLE 2. Postplacebo and postandrogen glucose tolerance parameters for TE- (n = 11) and ND-treated (n = 11) men
Variable Postplacebo Post-TE Postplacebo Post-ND
FI (pmol/L) 48.5 + 5.0 47.9 t 4.4 57.4 2 4.5 58.7 + 11.4
orgy,,,, (PmoW 348.5 + 88.5 310.2 + 56.2 355.7 t 43.0 382.1 k 92.5
Kg (min-l) 2.2 2 0.2 2.6 + 0.4 2.5 2 0.3 2.3 t 0.4
S, (X low4 . min-‘/pU * ml) 8.8 I! 1.4 8.9 + 2.8 7.9 -c 1.1 8.1 5 1.6
S, ( X lo-’ * min- I) 2.3 2 0.2 3.0 k 0.4 2.4 ? 0.2 3.7 + 0.6”
GEZI (X lo-’ * min- I) 1.9 k 0.2 2.5 t 0.4 1.8 2 0.2 3.1 2 0.6&
Mean values ? SE are shown.
a P = 0.02; b P = 0.01.
independent glucose disposal (SG and GEZI) increased significantly
in men receiving ND. Specifically, S, increased from 2.4
2 0.2 X lo-’ min-’ before ND treatment to 3.7 ? 0.6 X lo-’
min-’ after ND treatment (P = 0.02). Similarly, GEZI increased
from 1.8 2 0.2 X lo-’ min-’ before ND treatment to 3.1 + 0.6
X lo-* min-’ after ND treatment (P = 0.01).
C. Sex steroids. See Table 3. Although E2 levels fell with ND
treatment from 139.1 2 27.5 pmol/L to 89.2 +- 20.2 pmol/L,
the decline was not significant (P 5 0.17). This was due to one
individual who had an increase of estradiol on ND although
his T level decreased, indicating he was getting ND. Removing
this individual from the analysis, the E, levels were 143
2 29 pmol/L and 75 t 14 pmol/L, pre-ND VS. post-ND (P
5 0.04). The reason for the increase in E, in this individual
after ND administration could not be determined.
Between-treatment analysis
A. Anthropometrical measurements. There were no differential
treatment effects for either androgen on weight, BMI, or
percent body fat.
B. Minimal model analysis. There were no differential treatment
effects for either androgen on fasting insulin (FI),
AIRglucose, glucose disappearance constant (K,), S, glucose
effectiveness at basal insulin (S,), or GEZI.
C. Sex steroids. The two groups (TE vs. ND) differed significantly
with regard to the effect of androgen therapy on E,, T, fT, and
percent free testosterone (% fT) levels. Specifically, E, levels rose
by 193.04 2 19.82 pmol/L in the T&treated men, while falling
by 50.65 2 34.50 pmol/L in the ND-treated men (P = 0.0002).
Total testosterone levels increased 0.32 t 0.05 nmol/L in the
TE-treated men, but fell by 0.07 ? 0.02 nmol/L in the NDtreated
men (P = 0.0001). Free testosterone increased 915.6 ?
139.5 pmol/L in the TE-treated group; the ND-treated group
had a decline of 119.4 2 52.2 pmol/L (P = 0.0001). The %fT
increased in both groups but rose higher in the TE-treated men
than in the ND-treated men (0.63 + 0.09% and 0.20 + 0.05%, TE
vs. ND, respectively, P = 0.003).
Discussion
Confirming previous work from our laboratory (4), we
found no adverse effect of either TE or ND on glucose tolerance
or insulin secretion in normal men given these androgens
for a 6-week period. To the contrary, the present
study documents a significant improvement in noninsulinmediated
glucose disposal in men receiving ND.
Studies addressing the effect of anabolic steroids on glucose
metabolism are contradictory. Early literature contended
that anabolic steroids lowered fasting blood sugar
and reduced glycosuria and insulin requirements in diabetes
(18-26). Most of these studies failed to identify a mechanism
through which these agents could improve glucose tolerance,
though methandienone (Al-17-a methyltestosterone) was
reported to enhance insulin secretion (6, 27, 28).
Later work indicated that anabolic steroids adversely affected
glucose metabolism. Woodard et al. (29) reported that
oxymethalone (2-carboxylated methyltestosterone) led to
impaired glucose tolerance and hyperinsulinemia, as measured
in an oral glucose tolerance test in children with idiopathic
acquired aplastic anemia or Fanconi’s anemia. However,
these authors compared the study population (N = 7)
with a group of normal children, not to untreated children
with these anemias. Landon et al. (27) demonstrated that
methandienone induced a 3-fold increase in the insulin response
to iv tolbutamide without a change in plasma glucose.
However, the methodology employed in their study could
not identify which factors were responsible for apparent
insulin resistance, i.e. changes in P-cell sensitivity to glucose,
insulin-independent glucose uptake, or sensitivity of glucose
TABLE 3. Within treatment analysis: Postplacebo and postandrogen sex steroids for TE- (n = 11) and ND-treated (n = 11) men
Variable Postplacebo Post-TE Postplacebo Post-ND
SHBG (nmol/L) 30.1 + 3.2 22.1 + 2.9 25.6 k 2.2 20.2 + 1.8
(P = 0.02) (P = 0.003)
E, (pmol/L) 77.4 + 15.0 270.5 + 22.4 139.1 2 27.5 89.2 2 20.2
(P = 0.003)
T (nmol/L) 11.6 t 3.1 43.2 + 5.4 16.5 -c 2.4 10.0 ? 1.3
(P = 0.001) (P = 0.02)
f T (pmol/L) 226.6 2 59.3 1142.2 k 150.6 352.4 2 60.4 233.0 k 31.6
(P = 0.001) (P = 0.05)
%fT 1.99 2 0.09 2.62 ” 0.10 2.10 ? 0.80 2.33 + 0.08
(P = 0.0001) (P = 0.0006)
Mean values t SE are shown.
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NANDROLONE ENHANCES GLUCOSE UPTAKE
uptake to insulin. Cohen et al. (5) concluded that powerlifters
who ingested anabolic steroids had insulin resistance IIS.
nonsteroid-using powerlifters, obese sedentary men, or
nonobese sedentary men. However, treated subjects were
lo-15 kg heavier than controls; this difference may have
affected the outcome.
In the present study, treatment with an anabolic steroid
did not adversely affect glucose tolerance. To the contrary,
ND actually improved insulin-independent glucose disposal.
This finding is echoed in a recent report using a canine
model system to study the effect of 19-nortestosterone administration
at doses designed to approximate those used by
athletes (30). The authors of this report found that although
the insulin responsiveness of insulin-dependent glucose utilization
decreased by 40%, insulin-independent glucose disposal
was increased 3-fold. Hence, overall glucose tolerance
was not impaired.
The effect of an anabolic steroid on glucose disposal may
be dose dependent. Marin et al. have shown that a single im
injection of 250 mg testosterone undecanoate given to obese
middle-aged men improves insulin sensitivity, whereas a
single dose of 500 mg has no effect (31). Animal studies by
this same group demonstrate that the castrate rat has a decreased
S, that improves with physiological T replacement
but declines with supraphysiological doses of T (32). Although
the dose of androgen administered in our study (300
mg) approximated that used by Marin, we saw no effect on
S,. Two methodological differences may account for these
disparate results. First, the subjects in M&in’s study were
mildly obese middle-aged men with subnormal serum T
levels, whereas our men were lean and had normal T levels.
Second, the frequency with which our androgens were administered
may have increased serum androgen levels beyond
the window of efficacy for improvement in Si as described
by Marin.
It is uncertain why ND improved noninsulin-mediated
glucose disposal, whereas T did not. The difference may
reflect the metabolic fate of the agent, i.e. ND is not effectively
aromatized to estradiol. This conclusion is supported in work
by Polderman et al., who used 3-step hyperinsulinemiceuglycemic
clamp studies to identify cross-gender hormone
therapy-induced insulin resistance in transsexuals (33).
Polderman reported that insulin sensitivity declined in transsexual
men given ethyl estradiol. Hence, it may be that any
improvement in glucose disposal owing to an androgen is
offset by aromatization of the androgen.
In conclusion, 6 weeks’ treatment of normal men with
either TE or ND does not impair glucose tolerance. In constrast,
treatment with ND, an nonaromatizable androgen,
actually improves noninsulin-mediated glucose disposal.
Acknowledgments
The authors wish to extend thanks to Mr. Troy Patience, Mr. Louis
Matej, and Dr. Brenda K. Bell for their guidance anh technical assistance.
Injectable tolbutamide (Orinase) used in the mIVGTT studies was kindly
donated by Upjohn.
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