Suppression of Serum Dehydroepiandrosterone Sulfate Levels by Insulin: An Evaluation of Possible Mechanisms *

Abstract

We previously demonstrated a progressive decline in serum dehydroepiandrosterone sulfate (DHEA-S) levels in women during a hyperinsulinemic-euglycemic clamp. To determine whether this fall in serum DHEA-S levels might have been due to insulin-stimulated 1) hydrolysis of DHEA-S to dehydroepiandrosterone (DHEA), 2) conversion of DHEA-S/DHEA to androstenedione, and/or 3) urinary excretion of these steroids, 10 additional men were studied by the hyperinsulinemic-euglycemic clamp technique. Each man received a 0.1 U/kg (0.72 nmol/kg) insulin bolus dose, followed by a 10 mU/kg.min (72 pmol/kg.min) insulin infusion for 4 h. An average insulin level of 12,390 +/- 259 (+/- SE) pmol/L (1,726.8 +/- 36 microU/mL) was achieved; serum glucose was maintained at 5.0 +/- 0.1 mmol/L (90.5 +/- 2.3 mg/dL). During the hyperinsulinemia, serum DHEA-S levels fell progressively and were significantly lower than baseline at 4 and 6 h of study (85.5 +/- 5.9% and 79.1 +/- 3.2% of baseline values, respectively; P less than 0.05). Serum DHEA levels fell concurrently and were significantly lower than baseline at 2, 4, and 6 h of study (66.2 +/- 12.3%, 61.6 +/- 11.2%, and 52.9 +/- 10.2% of baseline values, respectively; P less than 0.05). The percent fall in serum DHEA levels correlated positively with the percent fall in serum DHEA-S levels (r = 0.44; P less than 0.02). Serum androstenedione levels also fell progressively during hyperinsulinemia and were significantly lower than baseline at 2, 4, and 6 h of study (71.5 +/- 4.1%, 71.0 +/- 7.2%, and 48.1 +/- 3.3% of baseline values, respectively; P less than 0.05). No change in serum DHEA-S, DHEA, or androstenedione levels occurred in paired control studies, during which 0.45% saline was infused at rates matched exactly to the rates of the dextrose and insulin infusions during the hyperinsulinemic clamp studies. Despite decreasing serum DHEA-S and DHEA levels during hyperinsulinemia, urinary DHEA-S and DHEA glucuronide excretions were increased by 50% (P less than 0.05) and 86% (P = 0.05), respectively, compared to urinary excretion of these steroids during control studies. In contrast, urinary excretion of unconjugated DHEA was unchanged. Quantitatively, however, increased urinary excretion of conjugated DHEA during hyperinsulinemia accounted for only about 5% of the concomitant fall in serum DHEA-S concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche

“…As discussed above, DHEAS levels, in relation to enhanced insulin secretion, may even be reduced as a result of increased metabolic turnover of this hormone (22)(23)(24)(25)(26). In fact, there are yet other factors in addition to IGF-I or leptin, which increase with body size or obesity and stimulate adrenal steroids, but their investigation could not be carried out in this study.…”

“…In obese women, DHEAS levels are slightly increased and independent of insulin secretion, but positively correlated with IGF-I (21). In contrast, in adult men with obesity (22) and hyperinsulinaemia (23,24) DHEA(S) is decreased. Levels of dehydroepiandrosterone or DHEAS are similarly reduced in women with severe obesity or type 2 diabetes (25,26).…”

Human granulosa cells are a site of sulphatase activity and are able to utilize dehydroepiandrosterone sulphate as a precursor for oestradiol production

“…In contrast, Nestler and colleagues (1987) studied the effects of insulin on serum DHEAS levels in women during a hyperinsulinaemiceuglycaemic clamp and found that insulin had a suppressive effect. When these findings were further investigated by repeating the study in men, both DHEAS and DHEA levels fell progressively and proportionally (Nestler et al 1989). Interestingly, androstenedione levels also fell in Figure 1 Sulphatase activity measured by production of DHEA from DHEAS substrate (31 nM) in granulosa cells cultured in the presence or absence (control) of (a) LH at 0·25-5 ng/ml, (b) insulin at 0·25-10 ng/ml or (c) the specific sulphatase inhibitor EMATE at 1-5000 nM.…”

Plasma lipids, dehydroepiandosterone sulphate and insulin concentrations in elderly overweight angina patients, and effect of weight loss

“…6,7 In women, however, a prospective study failed to ®nd any relationship between DHEAS concentrations and ischaemic heart disease (IHD). 8 Experimentally induced hyperinsulinaemia lowers DHEAS concentrations 5 and weight loss decreases plasma insulin concentrations. 9 A reduction in weight may result in a decrease in insulin and therefore an increase in DHEAS, so contributing the ultimate reduction in IHD risk.…”