Induction of insulin resistance by androgens and estrogens.

Abstract

Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral contraceptives. To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals. Utilization and production of glucose and levels of sex steroids were measured during a three-step hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone (0.1 mg/day, orally) or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp, with insulin levels in the physiological range, glucose utilization decreased from 3.5 +/- 1.2 to 2.6 +/- 0.9 mmol/kg lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 +/- 0.7 to 2.5 +/- 0.5 mmol/kg lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.

Estrogen Receptor .ALPHA. Regulates Insulin Sensitivity through IRS-1 Tyrosine Phosphorylation in Mature 3T3-L1 Adipocytes

“…These results are consistent with clinical and experimental observations that estrogen excesses, as in pregnancy [2,3], trans-sexuality [4], and during menstrual cycles [5], or estrogen deficiencies as in aromatase deficient [6] and OVX animals [7], cause insulin resistance. Moreover, a selective ER-α antagonist, MPP, diminished the beneficial effect of E2 at 10 -8 M on glucose uptake.…”

“…In clinical studies, high concentrations of estrogens, as in pregnancy [2,3], trans-sexuality [4] and during menstrual cycles [5], appear to contribute to the development of insulin resistance. On the other hand, there is considerable evidence against adverse effects of estrogens on glucose metabolism and some for beneficial actions of estrogen.…”

Testosterone, SHBG and cardiovascular health in postmenopausal women

“…Androgen administration reduces insulin sensitivity in young, regularly menstruating women 93 and peripheral glucose uptake in FM transsexuals. 94 Similarly, antiandrogen therapy partially improves insulin sensitivity in hyperandrogenic women. 95,96 In addition, rat experimental data show that testosterone impairs insulinmediated glucose uptake at the skeletal muscle by reducing the expression of glycogen synthase.…”

Diagnosis of Polycystic Ovary Syndrome

“…(62) This is further confirmed by a study on female to male transsexuals that administration of testosterone induces insulin resistance in healthy female subjects. (63) Clinically, a number of antiandrogens including cyproterone acetate, flutamide, spironolacton, and finasteride have been used to treat hyperan-drogenism in women with or without PCOS. (64)(65)(66)(67)(68)(69) Despite slight worsening of glucose tolerance, a combination of estrogen and cyproterone acetate is an efficient treatment for women with hyperandrogenism and hirsutism.…”