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Children’s Hospital of Pittsburgh (R.J.S., K.D., V.D.L., S.A.A.), Pittsburgh, Pennsylvania 15213; and Children’s Hospital (B.S.K.), Knoxville, Tennessee 37916
Address all correspondence and requests for reprints to: Silva Arslanian, M.D., Division of Endocrinology, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue at DeSoto Street, Pittsburgh, Pennsylvania 15213. E-mail: arslans{at}chplink.chp.edu
Abstract
Puberty is characterized by temporary insulin resistance, which subsides with the completion of pubertal development. This insulin resistance is manifested by lower rates of insulin-stimulated glucose metabolism and compensatory hyperinsulinemia in pubertal compared with prepubertal children. Whether or not pubertal insulin resistance is the result of sex steroids or GH or a combination of both has been investigated in our laboratory. Previously, we demonstrated that T treatment in adolescents with delayed puberty was not associated with the deterioration of insulin action. The present investigation evaluated the effects of 4 months of dihydrotestosterone administration (50 mg im every 2 wk) on body composition, glucose, fat, and protein metabolism, and insulin sensitivity. Ten adolescents with delayed puberty were evaluated before and after 4 months of DHT administration. Body composition was assessed by dual energy x-ray absorptiometry. Insulin-stimulated glucose metabolism was measured during a 3-h hyperinsulinemic (40 mU/m2·min)-euglycemic clamp procedure. Lipolysis and proteolysis were evaluated by stable isotopes of [2H5]glycerol and [1-13C]leucine. After 4 months of dihydrotestosterone treatment, height, weight, and fat free mass increased and percentage of body fat decreased. IGF-I and nocturnal GH levels did not change. There was no significant change in insulin-stimulated glucose metabolism (57.2 ± 3.9 vs. 58.3 ± 3.9 µmol/kg·min). Total body proteolysis and lipolysis did not change. In summary, based on the present and past studies, we conclude that during puberty insulin resistance/hyperinsulinemia is not attributable to gonadal sex steroids in boys.
PUBERTY IS CHARACTERIZED by a remarkable acceleration in the rate of linear growth and changes in body composition secondary to hormonal and metabolic changes, including doubling of GH secretion and increases in sex steroid levels (1, 2). In addition, multiple studies have shown that puberty is characterized by temporary insulin resistance, which reverses with the completion of pubertal development (3, 4, 5, 6, 7). This insulin resistance is manifested by lower rates of insulin-stimulated glucose metabolism and compensatory hyperinsulinemia in pubertal compared with prepubertal and adult subjects (3, 5, 8).
Whether or not pubertal insulin resistance is the result of sex steroids or GH or a combination of both has been investigated in our laboratory. In a previous study, T treatment in adolescent boys with delayed puberty was not associated with the deterioration of insulin action (9). The aim of the present investigation was to assess longitudinally the effect of dihydrotestosterone (DHT) supplementation in adolescent boys with delayed puberty on body composition, protein, fat, and glucose metabolism, and insulin sensitivity. Unlike T, DHT is a nonaromatizable androgen that accelerates the height velocity without an increase in plasma GH (10, 11, 12). Thus, one can evaluate the effect of sex steroids on insulin sensitivity independent of changes in GH.
Materials and Methods
Subjects
Ten healthy male adolescents, age range 13–16 yr, with
constitutional delay in growth and puberty who were seen at the
Endocrinology Clinic at Children’s Hospital of Pittsburgh participated
in this research (Table 1
).
Constitutional delay in growth and puberty was defined as in our
previous study with T supplementation and according to accepted
criteria in pediatric endocrinology (9, 13, 14). Some of
the participants were already being followed for constitutional delay
in growth and puberty for long periods by our colleagues at our
institution. Some had had complete laboratory evaluations to establish
the diagnosis and others had not. It is well accepted in the pediatric
endocrine scientific community that "the history, physical
examination, and a knowledge of the growth velocity will enable the
diagnosis to be made in the majority of cases without recourse to
biochemical investigations" (13). The study protocol was
approved by the Institutional Human Rights Committee. Parents and
participants gave written informed consent after a thorough explanation
of the proposed studies. Apart from the diagnosis of constitutional
delay in growth and puberty, all subjects were healthy as assessed by
medical history, physical examination, and routine hematological and
biochemical tests. Pubertal development was assessed by Tanner staging
and confirmed by measurement of plasma T. All subjects were prepubertal
in Tanner stage I (Table 1).
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Each subject was studied before and after DHT treatment. DHT heptanoate was administered under an investigational new drug from the Food and Drug Administration (IND 29,139). Each participant received 50 mg of DHT im every 2 wk for a total of 4 months. The DHT dose was similar to the T dose used in our previous study (9) and comparable to the monthly DHT dose used previously in delayed puberty (11, 12). All participants were admitted to the General Clinical Research Center at Children’s Hospital of Pittsburgh on the evening before the day of testing. Studies were performed after 10–12 h of overnight fasting. Posttreatment evaluation was done 1 wk after the last injection of DHT. Pre- and post-DHT evaluations were identical. Overnight blood was obtained every 20 min from 2400 to 0700 h for the determination of GH concentrations. Fasting blood was obtained for the measurement of T, DHT, E2, IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), and triglyceride levels at 0730 h.
Body composition evaluation
Body composition was determined using dual energy x-ray absorptiometry using a Lunar Corp. (Madison, WI) absorptiometer as described by us previously (15). Total body fat, fat free mass, and percent body fat were determined.
Stable isotope infusions for the evaluation of glucose, protein, and fat turnover
From 0730–0930 h, stable isotope infusions of
[6,6-2H2]glucose,
[1-13C]leucine, and
[2H5]glycerol were given
to evaluate baseline substrate turnover (Fig. 1). After this baseline period, a 3-h
hyperinsulinemic-euglycemic clamp procedure was performed between 0930
and 1230 h, during which stable isotope infusions of glycerol and
leucine were continued to assess insulin action in suppressing
lipolysis and proteolysis (Fig. 1). Total body lipolysis was measured
at baseline and during the 3-h hyperinsulinemic euglycemic clamp
procedure with a primed (1.2 µmol/kg) constant rate (0.08
µmol/kg·min) infusion of
[2H5]glycerol as
described by us previously (9, 15). Whole body protein
turnover was evaluated by a primed (5 µmol/kg) constant rate (6
µmol/kg/h) infusion of [1-13C]leucine
according to our published protocols (9, 16). Unlike our
previous studies, however, we could not collect breath samples to
measure protein oxidation because the collaborating laboratory that
used to perform the analysis of 13C enrichment in
expired CO2 was closed (16).
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Indirect calorimetry
Continuous indirect calorimetry by a ventilated hood (Deltratrac
Metabolic Monitor, Sensormedics, Anaheim, CA) was used to measure
CO2 production, O2
consumption, and respiratory quotient (9). Measurements
were made for 30 min at baseline before insulin infusion and for 30 min
at the end of the clamp procedure (Fig. 1
).
Analytical methods
Laboratory analyses were performed as described by us previously (9). Plasma glucose was measured at the bedside by the glucose oxidase method using a YSI, Inc. glucose analyzer (Yellow Springs, OH). Plasma insulin was measured by RIA, GH was measured by double antibody RIA, IGF-I was measured by RIA after acid ethanol extraction, and E2 was measured by double antibody RIA. The sensitivity of the GH assay was 0.1 µg/liter. Cholesterol, HDL, and triglyceride measurements were performed using U.S. Centers for Disease Control and Prevention protocols (9). DHT and T were analyzed by double antibody RIA, IGFBP-3 was analyzed by Immuno Chemimetric Lucent assay, and IGFBP-1 was analyzed by RIA, all in the Endocrine Sciences, Inc. laboratory (Calabasas Hills, CA).
The isotopic enrichments of plasma ketoisocaproate (KIC), glycerol, and glucose were determined as described by us previously (9, 15). Standard curves of known enrichments of KIC, glycerol, and glucose were performed with each assay. Pre- and post-DHT treatment samples were analyzed simultaneously in the same assay. Free fatty acid levels were measured with the commercially available Wako NEFA C kit (Wako Pure Chemical Industries Ltd., Osaka, Japan) that uses the in vitro enzymatic colorimetric method.
Calculations
Calculations were made at baseline during the last 30 min of the
2-h postabsorptive isotope infusion period and during hyperinsulinemia
during the last 30 min of the clamp period. Total body lipolysis was
estimated from the rate of appearance of endogenous glycerol and is
expressed in µmol/kg·min (9). Leucine turnover was
calculated with the reciprocal pool model from the plasma rate of
appearance of KIC (9, 19). Leucine turnover was
extrapolated to whole body proteolysis with the assumption that 1
g of protein contains 590 µmol of leucine (9, 20).
Protein oxidation was estimated from urinary nitrogen excretion using
the following equation: [protein oxidation (g) = 6.25 x
urinary nitrogen (g)], as published previously (21, 22).
Protein synthesis was calculated as the difference between whole body
proteolysis and protein oxidation (9). Fasting hepatic
glucose production was calculated from the rate of appearance of
[6,6-2H2]glucose
(15). A steady state plateau of isotopic enrichment was
achieved for KIC, glycerol, and glucose in the subjects before the
start and during the last 30 min of the hyperinsulinemic clamp
procedure (Fig. 2).
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Statistical analysis
Data are presented as means ± SEM. Paired
t tests were used to compare pretreatment and posttreatment
data. Statistical significance is implied by P 
0.05.
Results
Body composition
After 4 months of DHT treatment, both weight and height increased
(weight, 45.9 ± 3.7 vs. 49.6 ± 3.6 kg,
P < 0.001; height, 149.9 ± 1.6 vs.
152.3 ± 1.5 cm, P < 0.001). Growth velocity
increased from 4.4 ± 0.8 to 5.9 ± 0.9 cm/yr in five
subjects in whom pretreatment growth velocity was available and to
7.1 ± 0.1 cm/yr (n = 10). Fat-free mass (FFM)
increased significantly, and percentage body fat decreased (Table 2). Serum DHT concentrations
increased, whereas IGF-I level and mean nocturnal GH concentrations did
not change (Table 2). Serum E2 levels were less than 18 pmol/liter in
all subjects before and after DHT. In two subjects, T concentration
increased in the Tanner II pubertal range, suggesting that they may
have developed spontaneous puberty. After excluding these two subjects
from the analysis of T data, there was no statistically significant
change in T level after DHT (1.2 ± 0.4 vs. 2.4 ±
0.6 mmol/liter, P = 0.16).
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Fasting glucose, insulin, hepatic glucose production, glucose
oxidation, and resting energy expenditure were not different after 4
months of DHT treatment (Table 3).
During the hyperinsulinemic-euglycemic clamp procedure, steady state
plasma glucose and insulin concentrations were not significantly
different before and after DHT (glucose, 5.6 ± 0.06
vs. 5.5 ± 0.04 mmol/liter; insulin, 635.4 ± 34.8
vs. 691.8 ± 51.6 pmol/liter). Insulin-stimulated
glucose disposal, glucose oxidation, and nonoxidative glucose disposal
were similar before and after DHT treatment (Fig. 3). Insulin sensitivity was
comparable before and after DHT (Fig. 3).
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After 4 months of DHT treatment, there was no significant change
in fasting cholesterol, triglycerides, VLDL, and LDL; however, HDL
level decreased significantly (Table 3). There were no significant
changes in baseline FFA (pre-DHT, 0.33 ± 0.04 mM;
post-DHT, 0.28 ± 0.10 mM, P = 0.13)
and clamp FFA (pre-DHT, 0.09 ± 0.06 mM;
post-DHT, 0.07 ± 0.01 mM, P
= 0.25).
Fat metabolism
Pre-DHT glycerol rate of appearance (lipolysis) (4.03 ± 0.56 µmol/kg·min) was not different from the post-DHT value (3.24 ± 0.35 µmol/kg·min, P = 0.18). Fasting fat oxidation before DHT (3.81 ± 0.67 µmol/kg·min) was similar to the post-DHT value (3.78 ± 0.55 µmol/kg·min). Suppression of lipolysis during hyperinsulinemia was not different before and after DHT therapy (49 ± 6% and 46 ± 6%, respectively, P = 0.6). Rates of fat oxidation during the clamp procedure were comparable before and after DHT (1.70 ± 0.44 and 1.66 ± 0.26 µmol/kg·min, P = 0.9).
Protein metabolism
After 4 months of DHT treatment, whole body proteolysis (pre-DHT, 0.50 ± 0.04 g/h/kg FFM; post-DHT, 0.52 ± 0.04 g/h/kg FFM), protein oxidation (pre-DHT, 0.08 ± 0.01 g/h/kg FFM; post-DHT, 0.07 ± 0.01 g/h/kg FFM), and protein synthesis (pre-DHT, 0.44 ± 0.05 g/h/kg FFM; post-DHT, 0.45 ± 0.05 g/h/kg FFM) did not change significantly. Suppression of proteolysis during hyperinsulinemia was not different before and after DHT therapy (29 ± 3% and 29 ± 2%, respectively).
Discussion
Four months of DHT treatment (50 mg im every 2 wk) in adolescent boys with delayed puberty was associated with: 1) the appearance of secondary sexual characteristics commensurate with Tanner stage II of puberty; 2) body composition changes characterized by increased lean body mass and decreased percent body fat; 3) no change in IGF-I, mean nocturnal GH, and E2 concentrations; 4) no change in rates of lipolysis; 5) no change in rates of proteolysis; 6) decreased HDL level; and 7) no change in glucose metabolism and insulin sensitivity.
During normal puberty, there is a marked acceleration of growth with increasing body size, muscle mass, and changes in body composition. There is a multitude of hormonal changes that occur during puberty, including but not limited to increased sex steroids and increased GH/IGF-I secretion (1, 2, 24). Moreover, several investigators have demonstrated the presence of insulin resistance and compensatory hyperinsulinemia during puberty (3, 5, 6, 7, 8, 25). Whether or not puberty-related decrease in insulin sensitivity is the result of sex steroids vs. GH vs. a combination of both has been investigated in our laboratory. In a previous study, we demonstrated that 4 months of T treatment (50 mg im every 2 wk) in adolescent males with delayed puberty was not associated with the deterioration of insulin action (9). However, because of the concomitant doubling of GH/IGF-I levels, we could not with certainty attribute the observed findings solely to the effect of T. Unlike in our study in adolescents, T treatment in hypogonadal men improved insulin sensitivity (26). Therefore, it is possible that this insulin-enhancing effect of T was counteracted by the insulin-antagonistic effect of increased GH in our study of adolescents.
The role of T in modulating the somatotropic axis and enhancing GH secretion through its aromatization to E is well established (11, 12, 27, 28). On the other hand, DHT, which is a nonaromatizable androgen, has no modulatory action on the somatotropic axis (10, 11, 12, 28). Consistent with this notion, DHT supplementation in the present study was not associated with increased E2 or GH/IGF-I levels. Because of this, changes in insulin action or the lack of changes could be solely attributed to DHT independent of changes in GH. The current results reveal that DHT supplementation in adolescents with delayed puberty does not result in the deterioration of insulin action.
DHT treatment in the present study was not associated with any significant changes in absolute fat mass. This is consistent with the observation that rates of lipolysis did not change with DHT treatment, nor did fat oxidation. However, because of the increase in FFM, percent body fat was proportionally lower after DHT. This is in contrast to the results from the T trial, in which fat oxidation increased after therapy and correlated positively with GH concentrations. This translated to significant decrements in absolute fat mass (9). Thus, it appears that T, through its impact on GH, may modulate lipid metabolism, whereas DHT, independent of GH, has no such effect. In favor of such a proposal is the well defined metabolic action of GH on lipolysis and lipid oxidation both in vitro and in vivo (29, 30, 31). Studies by Yang et al. (32) support the notion that T per se, independent of GH, does not modulate changes in lipid metabolism. T treatment alone of hypophysectomized rats had no effect on in vitro rates of lipolysis of isolated adipocytes, whereas T and GH together restored the lipolytic response. On the other hand, a study in adult men supported the concept that T per se, independent of GH, may affect lipid metabolism (33). In that study, fat oxidation decreased after gonadal steroid suppression with Lupron without associated decreases in GH and IGF-I production. Rates of lipolysis, however, were not measured. The decrease in fat oxidation after gonadal steroid suppression is in agreement with our previous findings of increased fat oxidation after T replacement (9). Besides the present report, there are no published studies investigating the effect of DHT on rates of lipolysis and lipid oxidation. Even though glycerol rate of appearance measured using isotopic tracers is widely used as a quantitative measure of whole body lipolysis, a recent study has challenged this (34). The author demonstrated that, in addition to the major source of glycerol rate of appearance, which is adipose tissue lipolysis, there are two additional sources. One is the hydrolysis of circulating lipoprotein triglycerides via capillary endothelial lipoprotein lipase, and the other is intramuscular triglyceride hydrolysis. Our study was not designed to address this. The present results should be interpreted with caution until additional studies with stimulation of lipolysis and fat mobilization are available to shed further light on the impact of DHT on lipid metabolism and fat mass.
Regarding the anabolic effect of DHT, the results were consistent with T supplementation, although of lesser magnitude. In the present study, after 4 months of DHT supplementation there was an 11% increase in lean body mass compared with an approximately 21% increase with 4 months of T treatment (9). Contrary to the T study, however, DHT treatment did not result in lower rates of proteolysis or protein oxidation (9). This finding is also in contrast to our previous cross-sectional study, in which pubertal adolescents had lower rates of proteolysis and protein oxidation compared with prepubertal children (16). Again, these contrasting findings could be attributed to the combined effect of increasing GH and IGF-I consequent to therapy with T vs. DHT alone. In fact, in our cross-sectional study, we found that puberty-related increases in IGF-I levels were inversely correlated with proteolysis and protein oxidation (16). In the T study, increased GH concentrations were negatively correlated with protein oxidation (9). The major predictor of protein oxidation was mean nocturnal GH, which explained 59% of the variability (9). On the other hand, in a study of healthy men, T suppression was associated with a decrease in protein synthesis without associated changes in circulating GH levels, suggesting that T has direct anabolic effects (33). Based on our findings, it is reasonable to assume that the anabolic action of DHT, as detected by increased growth velocity and increased lean body mass, is most likely mediated through small changes in protein metabolism that are difficult to detect hourly during the short period of the experiment but that would be cumulative in the long term. Thus, it appears that DHT, independent of GH, may have anabolic effects, albeit less than T. Based on our present findings and previous observations, DHT itself can result in the acceleration of height velocity (11, 35). On the other hand, in the absence of a control untreated group, it is difficult to conclude with certainty that the observed changes in body composition are secondary to DHT supplementation and not simply consequent to natural growth. Because these are growing boys, one would expect a natural increase in height and lean body mass whether they were treated with DHT or not. However, the increased growth velocity after DHT supplementation would suggest an effect of DHT rather than spontaneous growth.
Consistent with the T study, DHT supplementation was associated with decreased HDL levels. Limited data in the pediatric age group suggest that the decrease in HDL levels during puberty is related to an increase in T concentrations (36). It could be inferred from the present study and past studies that both T and DHT are associated with decreased HDL levels in boys (36, 37).
Because of the concomitant increase in E2 levels with T therapy, metabolic changes could also be ascribed to Es. However, E suppression in males using an aromataze inhibitor did not lead to changes in body composition, protein turnover, or lipid oxidation (38). Regarding Es and insulin sensitivity, the majority of studies have been in women and show conflicting results. Es alone either had no effect on insulin sensitivity (39, 40, 41) or improved insulin sensitivity (42, 43). Ovariectomy in the rat was associated with insulin resistance, which was restored by the administration of E2 alone (44). Such observations would suggest that puberty-related increase in E level, at least in girls, is not responsible for pubertal insulin resistance. On the other hand, this may not be true for male puberty. Ethinyl estradiol treatment in male-to-female transsexuals was associated with reduction of glucose utilization during low dose insulin clamping but not during high dose insulin clamping (45). In healthy males, suppression of E did not change fasting insulin levels, suggesting no change in insulin sensitivity (38). This observation and our finding of no change in insulin sensitivity with T supplementation (9) would imply that Es during normal puberty in males are unlikely to be responsible for insulin resistance.
Androgens affect insulin sensitivity differently in males and females. In males, the majority of studies show an insulin-enhancing effect, but in females, increased androgens are associated with insulin resistance (9, 26, 46). Even though DHT treatment in boys is not associated with insulin resistance, it is not known how increased DHT per se might affect insulin sensitivity in girls.
In summary, the present study demonstrates that DHT supplementation in adolescents with delayed puberty is associated with increased height and lean body mass accretion but not with insulin resistance. Based on this and our past T study, we conclude that during male puberty, insulin resistance/hyperinsulinemia is not attributable to gonadal sex steroids.
Acknowledgments
We thank Lynnette Orlansky and Kathy Brown for their efforts in coordinating subject participation and the various aspects of the research, the General Clinical Research Center for expert nursing assistance, Resa Brna for laboratory expertise, and Pat Antonio for secretarial assistance. Gratitude is expressed to the research participants and their parents.
Footnotes
This work was supported by United States Public Health Service Grants RO1 HD27503 and MO1-RR00084, General Clinical Research Center, and the Genentech, Inc. Foundation for Growth and Development. This work was presented in part at the 2000 Society for Pediatric Research meeting in Boston, Massachusetts.
Abbreviations: DHT, Dihydrotestosterone; FFM, fat-free mass; HDL, high density lipoprotein; KIC, ketoisocaproate; LDL, low density lipoprotein; VLDL, very low density lipoprotein.
Received November 14, 2000.
Accepted June 4, 2001.
References
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