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Effects of Methyltestosterone on Insulin Secretion and Sensitivity In Women¹

Department Obstetrics and Gynecology (M.P.D., M.C.D.), Division of Reproductive Endocrinology and Infertility, Hutzel Hospital/Wayne State University School of Medicine, Detroit, Michigan 48201; Center for Reproductive Medicine (D.G.), Wichita, Kansas 67214; Department of Internal Medicine (R.S.S.), Yale New Haven Hospital, New Haven, Connecticut 06520; Diabetes Division, Department of Medicine R.A.D.), University of Texas Health Science Center, San Antonio, Texas 78284-7870 ,

Address correspondence and requests for reprints to: Michael P. Diamond, MD, Professor of Obstetrics and Gynecology, Hutzel Hospital/Wayne State University, 4707 St Antoine Boulevard, Detroit, Michigan 48201.

The frequent coexistence of hyperandrogenism and insulin resistance is well established; however, whether a cause and effect relationship exists remains to be established. In this study we tested the hypothesis that short-term androgen administered to women would induce insulin resistance. To test this hypothesis, regularly menstruating, nonobese women were studied before and during methyltestosterone administration (5 mg tid for 10–12 days) by the hyperglycemic (n = 8) and euglycemic, hyperinsulinemic (n = 7) clamp techniques.

Short-term methyltestosterone administration had no significant effects on the fasting levels of glucose, insulin, c-peptide, glucagon, or glucose turnover. During the hyperglycemic clamp studies, the mean glucose level during the final hour was 203 ± 2 and 201 ± 1 mg/dL in the methyltestosterone and control studies, respectively. The insulin response to this hyperglycemic challenge was slightly but not significantly greater during methyltestosterone treatment (first phase 59 ± 8 vs. 50 ± 8 µU/mL in controls; second phase 74 ± 9 vs. 67 ± 9 µU/mL in controls; total insulin response 133 ± 16 vs. 117 ± 15 µU/mL in controls). In spite of this, glucose uptake was reduced from the control study value of 10.96 ± 1.11 to 7.3 ± 0.70 mg/kg/min by methyltestosterone (P < 0.05). The ratio of glucose uptake per unit of insulin was also significantly reduced from a control study value of 14.3 ± 1.4 to 9.4 ± 1.3 mg/kg/min per µU/mL x 100 during methyltestosterone administration. In the euglycemic hyperinsulinemic clamp studies, insulin was infused at rates of 0.25 and 1.0 mU/kg/min to achieve insulin levels of approximately 25 and 68 µU/mL, respectively. During low-dose insulin infusion, rates of endogenous hepatic glucose production were equivalently suppressed from basal values of 2.37 ± 0.29 and 2.40 ± 0.27 mg/kg/min to 0.88 ± 0.25 and 0.77 ± 0.26 mg/kg/min in the methyltestesterone and control studies respectively. Whole body glucose uptake during low-dose insulin infusion was minimally affected. During the high-dose insulin infusion, endogenous hepatic glucose production was nearly totally suppressed in both groups. However, whole body glucose uptake was reduced from the control value of 6.11 ± 0.49 mg/kg/min to 4.93 ± 0.44 mg/kg/min during methyltestosterone administration (P < 0.05).

Our data demonstrate that androgen excess leads to the development of insulin resistance during both hyperglycemic and euglycemic hyperinsulinemia. These findings provide direct evidence for a relationship between hyperandrogenemia and insulin resistance, and its associated risk factors for cardiovascular disease.

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