The functional importance of sex steroid hormones (testosterone and estrogens), derived from extragonadal tissues, has recently gained significant appreciation. Circulating dehydroepiandrosterone (DHEA) is peripherally taken up and converted to testosterone by 3beta-hydroxysteroid dehydrogenase (HSD) and 17beta-HSD, and testosterone in turn is irreversibly converted to estrogens by aromatase cytochrome P-450 (P450arom). Although sex steroid hormones have been implicated in skeletal muscle regulation and adaptation, it is unclear whether skeletal muscles have a local steroidogenic enzymatic machinery capable of metabolizing circulating DHEA. Thus, here, we investigate whether the three key steroidogenic enzymes (3beta-HSD, 17beta-HSD, and P450arom) are present in the skeletal muscle and are capable of generating sex steroid hormones. Consistent with our hypothesis, the present study demonstrates mRNA and protein expression of these enzymes in the skeletal muscle cells of rats both in vivo and in culture (in vitro). Importantly, we also show an intracellular formation of testosterone and estradiol from DHEA or testosterone in cultured muscle cells in a dose-dependent manner. These findings are novel and important in that they provide the first evidence showing that skeletal muscles are capable of locally synthesizing sex steroid hormones from circulating DHEA or testosterone.

The effect of menstrual cycle phase on arterial elasticity is controversial. In 10 healthy women (20.6 ± 1.5 years old, mean ± S.D.), we investigated the variations in central and peripheral arterial elasticity, blood pressure (carotid and brachial), carotid intima-media thickness (IMT), and serum oestradiol and progesterone concentrations at five points in the menstrual cycle

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Sato K, Iemitsu M, Aizawa K, Mesaki N, Fujita S. Increased muscular dehydroepiandrosterone levels are associated with improved hyperglycemia in obese rats. Am J Physiol Endocrinol Metab 301: E274-E280, 2011. First published February 1, 2011 doi:10.1152/ajpendo.00564.2010.-This study was undertaken to assess the effects of dehydroepiandrosterone (DHEA) administration and exercise training on muscular DHEA and 5␣-dihydrotestosterone (DHT) levels and hyperglycemia in dietinduced obese and hyperglycemic rats. After 14 wk of a high-sucrose diet, obese male Wistar rats were assigned randomly to one of three 6-wk regimens: control, DHEA treatment, or exercise training (running at 25 m/min for 1 h, 5 days/wk; n ϭ 10 each group). Results indicate that either 6 wk of DHEA treatment or exercise training significantly attenuated serum insulin and fasting glucose levels compared with the control group. Plasma and muscle concentrations of DHEA and DHT and expression levels of 5␣-reductase were significantly higher in the DHEA-treated and exercise-training groups. Moreover, both DHEA administration and exercise training upregulated GLUT4 translocation with concomitant increases in protein kinase B and protein kinase C/ phosphorylation. Muscle DHEA and DHT concentrations closely correlated with blood glucose levels (DHEA treatment: r ϭ Ϫ0.68, P Ͻ 0.001; exercise training: r ϭ Ϫ0.65, P Ͻ 0.001), serum insulin levels, and activation of the GLUT4-regulated signaling pathway. Thus, increased levels of muscle sex steroids may contribute to improved fasting glucose levels via upregulation of GLUT4-regulated signaling in diet-induced obesity and hyperglycemia. muscle glucose metabolism; exercise; sex steroid hormone EPIDEMIOLOGIC, EXPERIMENTAL, AND CLINICAL EVIDENCE has demonstrated that diet-induced obesity and weight gain are closely associated with increased risk of diabetes morbidity, including cardiovascular diseases, hypertension, and dyslipidemia (9). Obesity triples the diabetes morbidity that results from impaired glucose metabolism, such as decreased uptake and utilization in skeletal muscle (9, 10). These effects are mediated, in part, by impaired regulation of glucose transporter-4 (GLUT4); binding of insulin receptor substrate (IRS) is inhibited in skeletal muscle, which downregulates the activities of protein kinase B (Akt) and/or protein kinase C/ (PKC/) via phosphatidylinositol 3-kinase (PI 3-kinase) (14).Dehydroepiandrosterone (DHEA) and its sulfate derivate (DHEA-S) are precursors of sex steroid hormones. DHEA is converted to testosterone and 5␣-dihydrotestosterone (DHT) by 3␤-hydroxysteroid dehydrogenase (HSD), 17␤-HSD, and 5␣-reductase. DHEA is most abundantly localized in blood before it is used by target tissues. Several reports have shown that short-term DHEA administration (2 wk) induces an acute decrease in blood glucose levels in type 2 diabetic mice (4 -7). Recently, we used cultured muscle cells to demonstrate that DHEA induced local production of testosterone, whereas DHT increased the activation of the G...

Sex steroid hormones, such as testosterone and estradiol, play important roles in developing both strength and mass of skeletal muscle. Recently, we demonstrated that skeletal muscle can synthesize sex steroid hormones. Whether there are sex differences in basal steroidogenesis or acute exercise-induced alterations of steroidogenesis in the skeletal muscle is unknown. We examined sex differences in the levels of testosterone, estradiol, and steroidogenesis-related enzymes, such as 17beta-hydroxysteroid dehydrogenase (HSD), 3beta-HSD, and aromatase cytochrome P-450 (P450arom), in the skeletal muscle at rest and after exercise. We studied the gastrocnemius muscles of resting rats (10 wk old) and exercised rats (10 wk old, treadmill running, 30 m/min, 30 min). Basal muscular testosterone levels were higher in males than females, whereas estradiol did not differ between sexes. Additionally, 17beta-HSD, 3beta-HSD, and P450arom transcript and protein expression were greater in females. After acute exercise, testosterone levels and 17beta-HSD expression increased in muscle in both sexes. By comparison, muscular estradiol levels increased in males following exercise but were unchanged in females. Expression of P450arom, which regulates estrogen synthesis, increased after acute exercise in males but decreased after exercise in females. Thus a single bout of exercise can influence the steroidogenic system in skeletal muscle, and these alterations differ between sexes. The acute exercise-induced alteration of steroidogenic enzymes may enhance the local steroidogenesis in the skeletal muscle in both sexes.