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Ovarian Hyperandrogenism Is Associated with Insulin Resistance to Both Peripheral Carbohydrate and Whole-Body Protein Metabolism in Postpubertal Young Females: A Metabolic Study¹

Nemours Children’s Clinic, Jacksonville, Florida 32207

Address all correspondence and requests for reprints to: Nelly Mauras, Nemours Children’s Clinic, 807 Nira Street, Jacksonville, Florida 32207. E-mail: nmauras{at}nemours.org

	Abstract

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The role of endogenous androgens in enhancing the body’s protein anabolic capacity has been controversial. To examine this question we chose to study whole-body protein and glucose kinetics in a group of 21 young, postpubertal females (16.3 ± 0.6 yr), 8 of whom had clinical and laboratory evidence of ovarian hyperandrogenism (OH) (BMI = 37.8 ± 1.3 kg/m²). We used L-[1-¹³C]leucine and [6,6,²H₂]glucose tracer infusions before and after suppression of their endogenous androgens with estrogen/progesterone supplementation in the form of Triphasil for 4 weeks. Their baseline data were also compared with those of similar aged girls, 7 obese (OB) (BMI = 36.4 ± 1.5) and 6 lean (LN) (BMI = 20.9 ± 0.7) who were normally menstruating and had no evidence of androgen excess. Despite comparable glucose concentrations, both OH and OB groups had significant hyperinsulinemia (OH > OB), both basally and after iv glucose stimulation, as compared to LN controls (basal insulin: OH, 252 ± 52 pmol/L; OB, 145 ± 41; LN, 60 ± 9, P = 0.009 OH vs. LN; peak insulin: OH, 2052 ± 417; OB, 1109 ± 127, LN, 480 ± 120, P = 0.0009 OH vs. LN). The rate of appearance (Ra) of glucose, a measure of glucose production, was greater in the LN controls than in the OH or OB groups (OH, 2.0 ± 0.1 mg/kg·fat free mass·min; OB, 1.9 ± 0.1; LN, 3.3 ± 0.1, P < 0.004 vs. LN). Calculated total rates of whole-body protein breakdown (leucine Ra), oxidation, and protein synthesis (nonoxidative leucine disposal) were substantially higher in the OH and OB groups as compared with LN controls (P < 0.04 vs. LN); however, when data are expressed on a per kilogram of fat free mass basis, the OH group had higher rates of proteolysis than the OB and LN, with indistinguishable rates between the latter two groups. None of the above-mentioned parameters changed after 1 month of administration of Triphasil, despite marked improvement in circulating testosterone and free testosterone concentrations after treatment (testosterone, -50%, P = 0.003; free testosterone, -70%, P = 0.02).

We conclude that obesity in young postpubertal females is associated with insulin resistance for both peripheral carbohydrate and protein metabolism, and that patients with the OH syndrome have even greater insulin resistance as compared with simple obesity, regardless of treatment for the androgen excess. Carefully designed studies targeting interventions to improve both the hyperandrogenic and hyperinsulinemic state may prove useful even in the early juvenile stages of this disease.

	Introduction

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OVARIAN hyperandrogenism (OH) is a complex disorder characterized by hirsutism, menstrual irregularities, and many times, significant obesity. The metabolic derangements of these patients are thought to be caused, at least in part, by excessive production of ovarian androgens (1). Recent evidence suggests that stimulation of intraovarian cytochrome P450c17 may play a pivotal role in the overproduction of those androgens (2). In addition, the role of insulin in the stimulation of ovarian androgenesis has been extensively studied, and peripheral insulin resistance eventually leading to impaired carbohydrate tolerance is a well characterized feature of this condition (3, 4, 5, 6, 7). Reported data have shown that in obesity per se, women in their mid to late 30s have greater estimates of the rate of whole-body proteolysis [leucine rate of appearance (Ra)] than lean, age-matched controls (8, 9). Whether this difference is caused by the larger body size or the hyperinsulinemic status in the obese women is yet to be clearly characterized (8, 10).

In the OH subjects, both obesity, with and without insulin resistance, and androgens participate in the metabolic derangements of these women. The role of androgens enhancing the protein anabolic capacity in humans is still controversial (11), and in the female specifically, designing well-controlled ethical experiments to examine the in vivo effects of androgens has proven difficult. Under specific experimental conditions, androgens have a protein-anabolic effect in immature castrated (12) and eugonadal animals (13), as well as in hypogonadal and GH-deficient individuals (14, 15), and in patients with myotonic dystrophy (16). Both in young boys (17), and in elderly men (18), testosterone (T) treatment has been shown to have significant whole-body (17) and muscle protein-anabolic effects (18). Estrogen treatment, on the other hand, has not been shown to affect whole-body protein kinetics in the hypogonadal female (19). It is teleologically possible, that both insulin and androgens, alone and in combination, may enhance the protein anabolic capacity of these women.

We designed the following studies with two specific aims. First, to investigate whether the hyperandrogenic state is associated with a greater whole-body protein-anabolic capacity (i.e. net increase in protein synthesis with decreased oxidation rates) in young girls with OH compared with either age-matched nonandrogenized controls or to themselves after suppression of the ovarian androgens with estrogen/progesterone supplementation. Second, to investigate the potential impact of hyperinsulinemia in the metabolic changes of these youngsters. We chose to study a young group of subjects (mean age 16 ± 1 yr), who were only a few years postmenarche, to assess the early metabolic derangements in this disease.

	Methods

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Subjects

These studies were approved by the Nemours Children’s Clinic Clinical Research Review Committee and Baptist Medical Center/Wolfson Children’s Hospital Institutional Review Committee. Sixteen postpubertal females were recruited for these studies after informed written consent from their parents and them.

Eight of the subjects had clinical and biochemical evidence of OH, defined as moderate to severe hirsutism, elevated androgens [T, free testosterone (FT), and/or 17 ketosteroids], no evidence of adrenal dysfunction (normal adrenal steroid responses to ACTH), lack of suppression of circulating androgens to overnight dexamethasone administration, and/or irregular menstrual periods. All of the subjects were obese. Seven healthy, obese, nonhyperandrogenic females of comparable age were also studied as controls (OB group), as well as a group of six healthy, nonhyperandrogenic females that were lean (LN group). They were studied, on the average, 4 yr from the onset of menarche. Their clinical characteristics are summarized in Table 1.

All subjects consumed a weight maintenance diet for at least 3 days before admission consisting of approximately 1 gm/kg of protein per day. Either the evening before the metabolic study or early the morning of the study, subjects were admitted to the Clinical Investigation Unit at Wolfson Children’s Hospital. The morning of the study, after an overnight fast of approximately 12 h, two iv heparin locks were placed, one in an antecubital vein for the administration of isotopes, another in a contralateral forearm vein that was kept heated for arterialized blood sampling (20). Subjects were kept NPO except for H₂O until the completion of the study. At 0800 h (time 0), a primed dose constant infusion of L-[1-¹³C]leucine (4.5 µmol/kg; 0.07 µmol/kg·min) and [6,6, ²H₂]glucose 33 µmol/kg; 0.33 µmol/kg·min) were initiated and continued for 240 min. Frequent blood and breath samples were obtained as detailed below. At time 240 min (time 0) the tracer infusions were discontinued and an iv bolus dose of glucose was given as a 25% dextrose solution (0.5 gm/kg) over 3 sec. Blood sampling was continued over the next 30 min (see below).

Measurement of percent body fat was performed using the sum of the thickness of four skinfolds using calipers (ßTechnology, Cambridge, MA). Indirect calorimetry was performed three times during the first 240 min using a CPX-MAX calorimeter (Medical Graphics, St. Paul, MN) using a mouthpiece.

After the baseline study was completed, the OH subjects were started on oral replacement of estrogen/progesterone in the form of Triphasil (Wyeth, Philadelphia, PA). The contents of the pills changes every 7 days [0.05 mg levonorgestrel (levo)/0.03 mg ethinyl estradiol (EE); 0.075 mg levo/0.04 mg EE; 0.125 mg levo/0.03 mg EE]. Subjects took the 21 tablets of medication and started a new package, skipping all placebo tablets. They were studied while taking the 0.05 mg levo/0.03 mg EE combination within 4 weeks of the initiation of treatment (D2).

Blood and breath samples

Blood was withdrawn at 10-min intervals for the determination of serum GH concentrations. At times -5, 30, 90, 150, 180, and 240 min blood was also withdrawn for the determination of [1-¹³C]ketoisocaproic acid ([¹³C]KIC) and [²H₂]glucose enrichments. Breath samples were obtained at -20, -5, 120, 160, 200, and 220 min for measurement of the enrichment expired ¹³CO₂. Plasma insulin, glucose, and insulin growth factor-I (IGF-I) concentrations were measured at times 0, 120, and 240 min. After the iv glucose load (time 0 min), blood was withdrawn at times -30, -10, -3, 0, 1, 3, 5, 7, 10, 20, and 30 min for determination of glucose and insulin concentrations.

Assays

The analysis for plasma enrichments of [1-¹³C] KIC and [²H₂]glucose were determined by gas chromatography/mass spectrometry as previously described (21, 22), using a 5970 gas chromatographer/mass spectrometer (Hewlett-Packard, Palo Alto, CA) with an intraassay coefficient of variation (CV) of 1.1% for the mole percent enrichments of both KIC and glucose correspondingly. ¹³CO₂ enrichment was measured using an automated dual-inlet isotope ratio mass spectrometer (23, 24) with an intraassay CV of 0.22%. Plasma glucose was measured by a glucose oxidase method using a Beckman glucose analyzer (Beckman Instruments, Palo Alto, CA). Plasma insulin, T, and FT concentrations were measured by RIA at Endocrine Sciences Laboratories (Calabasas Hills, CA), with intraassay CVs of 7.6% for insulin, 5.4% for IGF-I, 8.4% for T, and 10.5% for FT. Serum GH concentrations were measured by a chemiluminescence assay at the University of Virginia Core Laboratory, with an intraassay CV of 4.6%.

Calculations

Calculations of glucose and leucine kinetics were performed at isotopic steady state. Leucine kinetics were performed using the reciprocal pool model (21, 25). Calculations for leucine Ra, oxidation, and nonoxidative leucine disposal (NOLD) have been previously described (21). Glucose Ra was calculated as: Ra = [(Ei/Ep) - 1]F where F is the infusion rate of the glucose tracer, Ei is the enrichment of the infusate, and Ep is the enrichment of plasma glucose at steady state.

Substrate oxidation rates for protein, glucose, lipid, and resting energy expenditure were calculated using the gaseous exchange equations previously described (26). The substrate oxidation rates were calculated as: Lipid oxidation = 1.67 (CO₂ - O₂) + 1.92N Glucose oxidation = 4.55 CO₂ - 3.21 O₂ - 2.87 Protein oxidation = x 6.25 where CO₂ and O₂ are the liters per minute gaseous exchange obtained from calorimetry; represents total nitrogen excretion (grams per minute) estimated from the leucine oxidation rates as described previously (27).

Body composition [fat free mass (FFM) and percent fat mass (%FM)] were calculated using the sum of four skinfolds as previously described (28, 29).

Isotopes

L-[1-¹³C]leucine was 99% enriched (Merck, Sharpe & Dohme, St. Louis, MO) and [6,6-²H₂]glucose was 99.7% enriched (MSD Isotopes, St. Louis, MO). They were determined to be sterile and pyrogen free and prepared using 0.9% nonbacteriostatic saline.

Statistical analyses

All results are expressed as mean ± SEM. To estimate the differences between OH subjects before and after treatment, a paired Student’s t test was performed. One-way ANOVA was used to assess the differences in different parameters among the OH, OB, and LN groups. Multiple regression analysis was used to estimate relative correlations between different parameters. Significance was established at P < 0.05.

	Results

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Insulin/glucose metabolism

The OH group had significantly higher circulating insulin concentrations as compared with the OB and LN group, both at baseline and after an iv glucose, yet all groups had comparable fasting and peak glucose concentrations (Table 2, Fig. 1). The Ra of glucose, a measure of glucose production, was higher in the LN group as compared with OH and OB groups (P = 0.005) (Table 2).

View larger version (20K): [in this window] [in a new window]   Figure 1. Insulin concentrations (top), and glucose concentrations (bottom), during an iv glucose tolerance test in girls with OH before (OH-D1) and after treatment with Triphasil (OH-D2) n = 8; normal obese (OB) n = 7, and LN controls n = 6.

There was adequate suppression of ovarian androgens in the OH group with Triphasil (T, 74 ± 11 vs. 36 ± 7 ng/dL, P = 0.02; FT, 14.5 ± 3.6 vs. 4.3 ± 0.8 pg/mL, P = 0.02).

Substrate oxidation rates

Using indirect calorimetry, the calculated rates of glucose, protein, and lipid oxidation were comparable among all three groups, even though there was a trend towards higher lipid oxidation rates and lower glucose oxidation rates in the LN group as compared with the OH group. These rates did not change significantly after normalization of circulating androgens with estrogen/progesterone supplementation [glucose: 12.8 ± 2.0 (OH-D1), 13.1 ± 1.9 Kcal/kg FFM·day (OH-D2), 8.1 ± 2.5 (OB), 6.8 ± 1.8 (LN), P = 0.05 LN vs.. OH-D1, others >0.30; lipid: 14.5 ± 2.2 (OH-D1), 15.7 ± 2.0 (OH-D2), 17.8 ± 3.1 (OB), 20.4 ± 1.5 (LN), P = 0.06 LN vs.. OH-D1, others P > 0.30; protein: 3.3 ± 0.3 (OH-D1), 3.7 ± 0.3 (OH-D2), 2.5 ± 0.3 (OB), 2.5 ± 0.3 (LN), P > 0.30 ANOVA). Resting energy expenditure was also comparable among all groups and did not change with Triphasil treatment in the OH group (30.7 ± 2.3 Kcal/kg FFM·day (OH-D1), 32.6 ± 1.9 (OH-D2), 28.8 ± 2.6 (OB), 30.4 ± 2.3 (LN), P > 0.30).

Leucine kinetics (Table 3)

Calculated total rates of leucine Ra (an estimate of whole-body protein breakdown), leucine oxidation, and NOLD (an estimate of protein synthesis) were substantially higher in the OH and OB groups compared with LN controls and did not change after 1 month of administration of Triphasil. When the data are expressed as micromoles per kilogram FFM per minute, however, the OB and LN groups had virtually identical rates of leucine kinetics, values that were clearly lower than the OH group (Fig. 2). Multiple regression analysis showed that fasting and stimulated insulin concentrations were correlated only with total rates of leucine kinetics (i.e. independent of weight) (R² between 19–32%, P < 0.05, all parameters).

View larger version (25K): [in this window] [in a new window]   Figure 2. Fig. 2. Ra of leucine, a measure of proteolysis (top), oxidation (middle), and NOLD (bottom), a measure of whole-body protein synthesis, in girls with OH (D1 and D2), OB, and LN controls.

Mean and peak GH concentrations were comparable between OH and LN groups, but markedly lower in the OB group as compared with LN controls (Table 4). Circulating IGF-I concentrations were the same in all three groups on D1, but were suppressed in the OH group after the administration of estrogen/progesterone for 1 month (Table 4).

	Discussion

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Using the same leucine tracer techniques as in the present work, previous studies in obese women have reported higher rates of leucine Ra compared with lean controls even when data were expressed per kilogram of FFM (8, 9), whereas our younger OB subjects had comparable leucine turnover rates as the LN group. Collectively, these data suggest that the relative sensitivity to the antiproteolytic effects of insulin may be decreased with age in the obese female. However, we did not study older obese females in these experiments, hence this comparison should be interpreted with caution.

Interestingly, the measure of glucose production (glucose Ra) derived from the glucose tracer kinetic data, was significantly lower in the hyperinsulinemic patients (OH/OB) than in the lean controls. This suggests that these young hyperinsulinemic girls still retain hepatic sensitivity to the higher insulin concentrations to which they are exposed. Both the increase and the apparent normality of whole-body rates of protein turnover in the OH and OB groups, respectively, suggest that the insulin resistance affects both protein and peripheral carbohydrate metabolism in this patient population. It is, however, possible that other mechanisms, intrinsic to the obesity state, may differentially regulate whole-body protein pools.

The effect of androgens on insulin sensitivity has been the subject of intense investigation, yet the results are not consistently unidirectional. Even though insulin sensitivity has been shown to decrease after T treatment in oophorectomized rats (34), human studies in women with polycystic ovarian syndrome have shown either an improvement in insulin sensitivity with antiandrogens (35) or no change (36). In the present studies, short-term administration of estrogen/progesterone combination markedly suppressed circulating androgen concentrations, however, this was not accompanied by any meaningful change in the protein and glucose turnover rates, nor on the relative hyperinsulinemia of the study subjects. It is possible that to detect significant changes in whole-body protein anabolism the messenger RNA gene expression of pertinent proteins affected by the excess androgens would require a more prolonged time of androgen suppression. Interestingly, one subject in the OH group studied a third time after 8 weeks of normalization of her excess androgens with Triphasil, had nearly identical rates of leucine turnover as at baseline (data not shown). The observation of significantly greater rates of whole-body proteolysis in the OH group as compared with OB and LN nonandrogenized, age-matched controls, suggests that in the OH syndrome there is worsening of insulin resistance in the young female, independent of excess androgens, because correction of the hyperandrogenism did not improve any measures of insulin sensitivity. The mechanisms operative for this observation remain to be elucidated.

Even though there was a trend towards higher circulating GH concentrations after treatment of the OH subjects, which did not have statistical significance, plasma IGF-I concentrations were markedly suppressed after therapy. The latter effect, observed despite suppression of ovarian androgens, may be caused by the effect of oral estrogen administration on circulating IGF-I observed previously (37).

We conclude, that in the young postpubertal female, obesity is associated with insulin resistance for both protein and peripheral carbohydrate metabolism, and that in patients with OH syndrome there is even greater insulin resistance in the early stages of this disease. Early recognition of this disease and its associated morbidity will require effective early treatment of both the hyperandrogenic and hyperinsulinemic state. Further studies in the patient population are needed.

	Acknowledgments

 
We are grateful to Brenda Sager and the Nemours Metabolic Core Laboratory for technical support, to Burnese Rutledge and the nursing staff of Wolfson Children’s Hospital for their dedicated care of our patients, to Dr. Valerie Hayes for assistance with graphics, and to Laurie Lee for typing this manuscript.

	Footnotes

 
¹ This work was supported by Nemours Research Programs, Nemours Foundation, Jacksonville, Florida 32207.

Received January 15, 1998.

Revised February 24, 1998.

Accepted March 5, 1998.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mauras, N. Articles by Haymond, M. W. Search for Related Content PubMed PubMed Citation Articles by Mauras, N. Articles by Haymond, M. W.