Increased Plasma Testosterone in Streptozotocin-Diabetic Female Rats*

We have examined the effect of experimental diabetes on plasma testosterone levels in adult female Sprague-Dawley rats. Within 24 h after the injection of streptozotocin (SZ), plasma testosterone concentrations increased from 46.5 ± 3.16 (mean ± SE) to 270 ± 43.5 ng/dl (P < 0.001), levels observed in normal, reproductively competent male rats. This elevation persisted for the entire 4-week period studied and appeared to be closely correlated with plasma ketone levels (r = 0.895). Animals made diabetic with alloxan had less severe diabetes with minimal ketosis, but still had testosterone levels more than 3 times those of controls. Prevention of diabetes by injection of 3-O-methylglucose before SZ administration abolished the increase in testosterone. Insulin therapy, initiated 16 h after SZ and continued every 4 h for an additional 32 h to maintain normoglycemia, maintained plasma testosterone at normal female levels. The plasma precursor steroids 17-hydroxyprogesterone and androstenedione were elevated (P < 0.001) in diabetic rats; dehydroepiandrosterone (DHEA) was not. Studies were performed to determine the origin of these steroids. When adult rats were ovariectomized 8 days before SZ injection, testosterone was elevated to 180 ± 9 ng/dl 48 h after the onset of diabetes, but to a lesser degree than in intact diabetics. Adrenalectomy 2 days after SZ administration not only prevented the increase in plasma testosterone, but decreased these values compared to those in both unoperated and adrenalectomized controls. When incubated with [3H]DHEA, hepatic cytosol preparations from 5-day-diabetic rats showed a marked increase in the conversion of DHEA to androstenedione and testosterone (P < 0.001) compared to controls. These results indicate that experimental diabetes resulting in ketosis leads to increased plasma testosterone levels in adult female rats. The large elevation in plasma testosterone appears to be mainly of adrenal origin. Increased precursor steroids are present in plasma, and increased peripheral conversion of DHEA to testoserone can be demonstrated in vitro. This elevation of plasma testosterone may account for some of the previously observed abnormalities of reproductive function in the female diabetic rat.