Search

Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/ peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20-73 yr, BMI 21-32 kg/[m.sup.2], participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion (P = 0.003), 2) potentiated the agerelated abbreviation of LH secretory bursts (P = 0.025), 3) suppressed incremental GnRH-induced LH release (P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release (P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH (P = 0.002) and T (P = 0.017) concentrations, 2) accelerating LH pulse frequency (P = 0.013), 3) amplifying total (basal plus pulsatile) LH (P = 0.002) and T (P < 0.001) secretion, 4) shortening LH secretory bursts (P = 0.032), and 5) reducing LH secretory regularity (P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion (P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men. leuteinizing hormone; testosterone; pulsatile; secretion; human; approximate entropy doi: 10.1152/ajpendo.00300.2010.

The marked sexual dimorphism that exists in human cardiovascular diseases has led to the dogmatic concept that testosterone (Tes) has deleterious effects and exacerbates the development of cardiovascular disease in males. While some animal studies suggest that Tes does exert deleterious effects by enhancing vascular tone through acute or chronic mechanisms, accumulating evidence suggests that Tes and other androgens exert beneficial effects by inducing rapid vasorelaxation of vascular smooth muscle through nongenomic mechanisms. While this effect frequently has been observed in large arteries at micromolar concentrations, more recent studies have reported vasorelaxation of smaller resistance arteries at nanomolar (physiological) concentrations. The key mechanism underlying Tes-induced vasorelaxation appears to be the modulation of vascular smooth muscle ion channel function, particularly the inactivation of L-type voltage-operated [Ca.sup.2+] channels and/or the activation of voltage-operated and [Ca.sup.2+]-activated [K.sup.+] channels. Studies employing Tes analogs and metabolites reveal that androgen-induced vasodilation is a structurally specific nongenomic effect that is fundamentally different than the genomic effects on reproductive targets. For example, 5[alpha]-dihydrotestosterone exhibits potent genomic-androgenic effects but only moderate vasorelaxing activity, whereas its isomer 5[beta]-dihydrotestosterone is devoid of androgenic effects but is a highly efficacious vasodilator. These findings suggest that the dihydro-metabolites of Tes or other androgen analogs devoid of androgenic or estrogenic effects could have useful therapeutic roles in hypertension, erectile dysfunction, prostatic ischemia, or other vascular dysfunctions. 5[alpha]-dihydrotestosterone; 5[beta]-dihydrotestosterone; hypertension: vascular relaxation; vasodilation doi: 10.1152/ajpheart.00753.2009.

Woods LL, Morgan TK, Resko JA. Castration fails to prevent prenatally programmed hypertension in male rats. Am J Physiol Regul Integr Comp Physiol 298: Rl111-Rl116, 2010. First published January 27, 2010; doi:10.1152/ajpregu.00803.2009.--Male offspring of rats that were modestly protein restricted during pregnancy become hypertensive as adults, whereas their female littermates remain normotensive. The purpose of this study was to determine the role of testosterone in promoting this sexual dimorphism of prenatally programmed hypertension. Rats were fed either a normal (19% protein, NP) or modestly protein-restricted (8.5% protein, LP) diet throughout pregnancy. Male offspring either remained intact or were castrated (CAS) at 30 days of age. Female offspring remained intact. At ~22 wk of age, the offspring were chronically instrumented for measurement of mean arterial pressure and renal function. Intact male LP offspring were hypertensive compared with male NP offspring (138 [+ or -] 2 vs. 130 [+ or -] 2 mmhg, P < 0.007), whereas female LP offspring were normotensive (123 [+ or -] 1 vs. 122 [+ or -] 2 mmHg in NP females). In CAS males, blood pressure in both diet groups was not different from that in intact males of the same group (138 [+ or -] 3 mmHg in LP CAS males, and 131 [+ or -] 2 mmHg in NP CAS males). Glomerular filtration rate and effective renal plasma flow were also not significantly affected by castration. However, castration significantly reduced protein excretion in LP males to levels not different from those in NP CAS and intact males. Renal histopathology scores showed a similar pattern. Thus removal of androgens by castration failed to provide any protective effect against the hypertension programmed by maternal protein restriction. Castration also failed to abolish the sex difference in blood pressure in both diet groups. These findings suggest that the lifelong presence of normal levels of testicular hormones does not play a major role either in maintaining baseline blood pressure higher in males than in females, or in promoting further elevations in blood pressure in males due to prenatal undernutrition. However, androgens such as testosterone may promote renal injury in LP males. dietary protein restriction; sexual dimorphism; glomerular filtration rate doi: 10.1152/ajpregu.00803.2009.

The mechanisms by which aging progressively depletes testosterone (Te) availability in the male are unknown. Accordingly, the objective was to estimate brain gonadotropin-releasing hormone (GnRH) outflow (release and action), which cannot be observed directly, on the basis of downstream effects on pituitary luteinizing hormone (LH) secretion. LH, in turn, feeds forward on (stimulates) gonadal Te secretion, which then feeds back on (inhibits) GnRH-driven LH secretion. LH and Te concentrations were measured repetitively (every 10 min) over 18 h during graded pharmacological blockade of endogenous GnRH outflow in 24 healthy 20- to 72-yr-old men. Data were analyzed using a new age-dependent regression model of GnRH-LH-Te interactions to estimate pulsatile LH secretion and elimination, GnRH outflow, LH feedforward, and Te feedback. By incorporating regression on age within the dose-response model, we show that aging erodes all three primary forward and reverse pathways linking the brain, pituitary gland, and testes. Aging is associated with concomitant deficits in GnRH [right arrow] LH feedforward, LH [right arrow] Te feedforward, and Te [right arrow] GnRH/LH feedback. The analytical formalism should be generalizable to other ensemble regulatory systems, such as those that control growth, reproduction, stress adaptations, and glucose metabolism. gonadotropin; men; human; testosterone; testis; model doi: 10.1152/ajpregu.90800.2008.

Soluble epoxide hydrolase (Ephx2, sEH) is a bifunctional enzyme with COOH-terminal hydrolase and [NH.sub.2]-terminal phosphatase activities. sEH converts epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), and the phosphatase activity is suggested to be involved in cholesterol metabolism. EETs participate in a wide range of biological functions, including regulation of vascular tone, renal tubular transport, cardiac contractility, and inflammation. Inhibition of sEH is a potential approach for enhancing the biological activity of EETs. Therefore, disruption of sEH activity is becoming an attractive therapeutic target for both cardiovascular and inflammatory diseases. To define the physiological role of sEH, we characterized a knockout mouse colony lacking expression of the Ephx2 gene. Lack of sEH enzyme is characterized by elevation of EET to DHET ratios in both the linoleate and arachidonate series in plasma and tissues of both female and male mice. In male mice, this lack of expression was also associated with decreased plasma testosterone levels, sperm count, and testicular size. However, this genotype was still able to sire litters. Plasma cholesterol levels also declined in this genotype. Behavior tests such as anxiety-like behavior and hedonic response were also examined in Ephx2-null and WT mice, as all can be related to hormonal changes. Null mice showed a level of anxiety with a decreased hedonic response. In conclusion, this study provides a broad biochemical, physiological, and behavioral characterization of the Ephx2-null mouse colony and suggests a mechanism by which sEH and its substrates may regulate circulating levels of testosterone through cholesterol biosynthesis and metabolism. cholesterol; fertility

Chronically decerebrate (CD) rats, in which the forebrain and its descending projections are completely neurally isolated from hindbrain and rostral projections, gain substantial amounts of body fat, lose lean tissue, and have low circulating testosterone concentrations. We tested whether testosterone replacement would normalize body composition of male CD rats. Five groups of rats were used: CD placebo, CD testosterone, control placebo, castrate placebo, and castrate testosterone. Testosterone replacement was initiated at the first stage of CD surgery in both CDs and castrate controls. The second stage of CD surgery occurred 8 days later, and the study ended 15 days later. Testosterone implants produced 10-fold normal circulating concentrations. Food intake was fixed for all rats by tube feeding. CD rats had substantially more body fat and less lean tissue than neurally intact rats. Testosterone replacement did not affect adiposity of CD rats but did increase carcass water content. Energy expenditure of CD rats was significantly lower than that of control placebo and castrated rats. Testosterone lowered respiratory equivalency ratio and ameliorated a fall in energy expenditure late in the intermeal interval in CD rats. Castration increased, and testosterone decreased luteinizing hormone (LH) and follicle stimulating hormone (FSH) in neurally intact controls. LH was undetectable, and FSH was equivalent to neurally intact controls in CD rats, and neither was affected by testosterone. Collectively, low testosterone did not explain obesity or decreased lean body mass of CD rats, although CD rats exhibited abnormal levels of circulating reproductive hormones and disrupted testosterone negative feedback. caudal brainstem; white adipose tissue; energy expenditure; body composition

Chronic mountain sickness (CMS) is characterized by excessive erythrocytosis (EE) secondary to hypoventilation. Erythropoietin (Epo) and testosterone regulate erythrocyte production. Low thyroid hormone levels are also associated to hypoventilation. Hence, these hormones can play a role in etiopathogeny of EE. The purpose of this study was to elucidate the effect of sexual and thyroid hormones and Epo in residents from Lima (150 m) and Cerro de Pasco (4,340 m), Peru, and the response to human chorionic gonadotrophin stimulation (hCG). Three groups, one at low altitude and two at high altitude [1 with hemoglobin values >16-21 g/dl and the second with Hb [greater than or equal to]21 g/dl (EE)], were studied. hCG was administered intramuscularly in a single dose (1,000 IU), and blood samples were obtained at 0, 6, 12, 24, 48, and 72 h after injection. High-altitude natives present similar levels of gonadotropins and thyroid hormones but lower dehydroepiandrosterone sulphate (DHEAS) levels (P < 0.01) and greater Epo (P < 0.01), 17[alpha]-hydroxyprogesterone (P < 0.01), and testosterone levels (P < 0.01) than those at 150 m. Serum testosterone levels (524.13 [+ or -] 55.91 [micro]g/dl vs. 328.14 [+ or -] 53.23 ng/dl, means [+ or -] SE; P < 0.05) and testosterone/ DHEAS ratios are higher (7.98 [+ or -] 1.1 vs. 3.65 [+ or -] 1.1; P < 0.01) and DHEAS levels lower in the EE group (83.85 [+ or -] 14.60 [micro]g/dl vs. 148.95 [+ or -] 19.11 ug/dl; P < 0.05), whereas Epo was not further affected. Testosterone levels were highest and DHEAS levels lowest in the EE group at all times after hCG stimulation. In conclusion, high androgen activity could be involved in the etiopathogeny of CMS. This evidence provides an opportunity to develop new therapeutic strategies. sex hormones; altitude; estradiol; dehydroepiandrosterone sulfate

Blood pressure (BP) is more salt sensitive in men than in premenopausal women. In Dahl salt-sensitive rats (DS), high-salt (HS) diet increases BP more in males than females. In contrast to the systemic renin-angiotensin system, which is suppressed in response to HS in male DS, intrarenal angiotensinogen expression is increased, and intrarenal levels of ANG II are not suppressed. In this study, the hypothesis was tested that there is a sexual dimorphism in HS-induced upregulation of intrarenal angiotensinogen mediated by testosterone that also causes increases in BP and renal injury. On a low-salt (LS) diet, male DS had higher levels of intrarenal angiotensinogen mRNA than females. HS diet for 4 wk increased renal cortical angiotensinogen mRNA and protein only in male DS, which was prevented by castration. Ovariectomy of female DS had no effect on intrarenal angiotensinogen expression on either diet. Radiotelemetric BP was similar between males and castrated rats on LS diet. HS diet for 4 wk caused a progressive increase in BP, protein and albumin excretion, and glomerular sclerosis in male DS rats, which were attenuated by castration. Testosterone replacement in castrated DS rats increased BP, renal injury, and upregulation of renal angiotensinogen associated with HS diet. Testosterone contributes to the development of hypertension and renal injury in male DS rats on HS diet possibly through upregulation of the intrarenal renin-angiotensin system. androgens; hypertension; renal injury; glomerular sclerosis; angiotensinogen

Circulating testosterone (T) and GH/IGF-I are diminished in healthy aging men. Short-term administration of high doses of T augments GH secretion in older men. However, effects of long-term, low-dose T supplementation on GH secretion are unknown. Our objective was to evaluate effects of long-term, low-dose T administration on nocturnal GH secretory dynamics and AM concentrations of IGF-I and IGFBP-3 in healthy older men (65-88 yr, n = 34) with low-normal T and IGF-I. In a double-masked, placebo-controlled, randomized study we assessed effects of low-dose T supplementation (100 mg im every 2 wk) for 26 wk on nocturnal GH secretory dynamics [8 PM to 8 AM, Q2o min sampling, analyzed by multiparameter deconvolution and approximate entropy (ApEn) algorithms]. The results were that T administration increased serum total T by 33% (P = 0.004) and E2 by 31% (P = 0.009) and decreased SHBG by 17% (P = 0.002) vs. placebo. T supplementation increased nocturnal integrated GH concentrations by 60% (P = 0.02) and pulsatile GH secretion by 79% (P = 0.05), primarily due to a twofold increase in GH secretory burst mass (P = 0.02) and a 1.9-fold increase in basal GH secretion rate (P = 0.05) vs. placebo. There were no significant changes in GH burst frequency or orderliness of GH release (ApEn). IGF-I levels increased by 22% (P = 0.02), with no significant change in IGFBP-3 levels after T vs. placebo. We conclude that low-dose T supplementation for 26 wk increases spontaneous nocturnal GH secretion and morning serum IGF-I concentrations in healthy older men. pulsatility; testosterone replacement; aging

Polycystic ovary syndrome (PCOS), a leading cause of infertility, affects ~10% of women of reproductive age. The etiology and pathophysiology of PCOS are poorly understood. PCOS is multifaceted and includes reproductive abnormalities and components of the metabolic syndrome such as insulin resistance, obesity, dyslipidemia, and hypertension. Exposure to excess testosterone (T) during the prenatal period may predispose individuals to PCOS phenotype. The goal of this study was to determine whether hypertension and dyslipidemia occur in a well-characterized model of PCOS produced by prenatal treatment of sheep with T. Radiotelemetry was used to measure blood pressure over a 24-h period in conscious, undisturbed animals. To normalize circulating estradiol levels across treatment, control (n = 4) and prenatal T-treated (100 mg T propionate im twice weekly from days 30 to 90 of fetal life, n = 4) 2-yr-old females were ovariectomized, instrumented with a radiotelemetry transmitter, and clamped with early follicular phase levels of estrogen using an implant. Six days later, a 24-h recording period commenced. Prenatal T-treated sheep were hypertensive compared with control sheep, and heart rate tended to be higher. T-treated sheep had hyperglycemia, insulin resistance, hypernatremia, and hyperchloremia, and both total and LDL cholesterol tended to be higher. Plasma aldosterone and epinephrine were significantly lower in T-treated sheep, whereas norepinephrine was unchanged. This first-ever use of radiotelemetric blood pressure recordings in sheep demonstrates that mild hypertension, a risk factor reported in some women with PCOS, is also a feature of the sheep model of PCOS produced by prenatal T treatment. intrauterine programming; polycystic ovary syndrome; dyslipidemia; hyperglycemia; hypernatremia doi:10.1152/ajpendo.00668.2006

Hypoxia has been shown to stimulate the expression of vascular endothelial growth factor (VEGF), which is a major mediator for angiogenesis and vasculogenesis. During hypoxia, VEGF promotes angiogenesis in the testis. However, the effect of VEGF on the steroidogenesis of testosterone and the cell proliferation in Leydig cells is unclear. To assess the effects and the action mechanisms of hypoxia, a mouse TM3 Leydig cell line was employed in the present study. The Leydig cells were incubated in an incubator chamber (95% N2-5% CO2) for 1-24 h. The cultured media were collected and assayed by testosterone RIA and VEGF enzyme immunoassay. 3-(4,50-Dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide assay was used to detect the proliferation of Leydig cells. The present results showed that the proliferation of Leydig cells was enhanced significantly by hypoxia. The basal VEGF release was increased, and the response of VEGF production to human chorionic gonadotropin (hCG) was also enhanced in hypoxic condition. During hypoxia, administration of hCG or VEGF stimulated proliferation of Leydig cells, but the stimulatory effect was abolished by the administration of anti-VEGF antibody. Higher doses of VEGF stimulated testosterone release in a dose-dependent manner. Administration of anti-VEGF antibody abolished the stimulatory effect of VEGF on testosterone release. These data suggest that hypoxia stimulates cell proliferation and testosterone release in Leydig cells via an increase of VEGF production. hypoxia; mouse TM3 Leydig cells; testosterone doi:10.1152/ajpendo.00611.2006.

The mouse kidney expresses the gene of ornithine aminotransferase (Oat). Previous works suggest that Oat is differentially expressed in female and male mouse kidney (Alonso E, Rubio V. Biochem J 259: 131-138, 1989; Levillain O, Diaz JJ, Blanchard O, Dechaud H. Endocrinology 146: 950-959, 2005; Manteuffel-Cymborowska M, Chmurzynska W, Peska M, Grzelakowska-Sztabert B. Int J Biochem Cell Biol 27: 287-295, 1995; Natesan S, Reddy SR. Comp Biochem Physiol B Biochem Mol Biol 130: 585-595, 2001; Yu H, Yoo PK, Aguirre CC, Tsoa RW, Kern RM, Grody WW, Cederbaum SD, Iyer RK. J Histochem Cytochem 51: 1151-1160, 2003). This study was designed to provide a detailed description of the sexual dimorphism of Oat expression in the mouse kidney and to test the influence of sex hormones on its regulation. Experiments were performed on male and female Swiss OF1 mice during their postnatal development, at adulthood, and in orchidectomized and ovariectomized mice. Kidneys, dissected renal zones, and mitochondria were used to analyze OAT mRNA and protein levels and measure OAT activity. The results revealed that before puberty, Oat expression was similar between female and male kidneys whereas from puberty until adulthood Oat expression increased in the female kidney, becoming [approximately equal to] 2.5-fold higher than in the male kidney. This sex-differential expression of Oat was associated with a sex-specific distribution of Oat along the corticopapillary axis and within the nephron. OAT was three- to fourfold more expressed in the female than the male cortex. In males, Oat was highly expressed in the medulla, mainly in the thick ascending limbs. Renal Oat distribution in orchidectomized mice resembled that in the females. Ovariectomy did not influence Oat expression. Sex differences are explained by the physiological increase in plasma testosterone in males. Expression of medium-chain acyl-CoA synthetase protein confirmed this finding. We report sexual dimorphism of Oat expression in the mouse kidney and show that Oat is naturally downregulated in the presence of testosterone. gene expression; testosterone; postnatal development; renal zones; Ascm; castration; male; female

Our laboratory uses a model of intrauterine growth restriction (IUGR) induced by placental insufficiency in the rat to examine the developmental origins of adult disease. In this model only male IUGR offspring remain hypertensive in adulthood, revealing sex-specific differences. The purpose of this study was to determine whether testosterone with participation of the rehin-angiotensin system (RAS) contributes to hypertension in adult male IUGR offspring. At 16 wk of age a significant increase in testosterone (346 [+ or -] 34 vs. 189 [+ or -] 12 ng/dl, P < 0.05) was associated with a significant increase in mean arterial pressure (MAP) measured by telemetry in IUGR offspring (147 [+ or -] 1 vs. 125 [+ or -] 1 mmHg, P < 0.05, IUGR vs. control, respectively). Gonadectomy (CTX) at 10 wk of age significantly reduced MAP by 16 wk of age in IUGR offspring (124 [+ or -] 2 mmHg, P < 0.05 vs. intact IUGR) but had no effect in control (125 [+ or -] 2 mmHg). A significant decrease in MAP in intact IUGR (111 [+ or -] 3 mmHg, P < 0.05 vs. untreated intact IUGR) and castrated IUGR (110 [+ or -] 4 mmHg, P < 0.05 vs. untreated CTX IUGR) after treatment with enalapril for 2 wk suggests a role for RAS involvement. However, the decrease in blood pressure in response to enalapril was greater in intact IUGR ([DELTA]36 [+ or -] 1 mmHg, P < 0.05) compared with CTX IUGR ([DELTA]15 [+ or -] 2 mmHg), indicating an enhanced response to RAS blockade in the presence of testosterone. Thus these results suggest that testosterone plays a role in modulating hypertension in adult male 1UGR offspring with participation of the RAS. hypertension; rat; gonadectomy; renin; angiotensin

Although the mechanisms are not understood, evidence suggests that 17[beta]-estradiol ([E.sub.2]) confers protection from cardiovascular and renal complications in many diseases. We have reported that [E.sub.2] decreases angiotensin type 1 receptors (A[T.sub.1]Rs) in different tissues and hypothesize that [E.sub.2] exerts tonic inhibition on A[T.sub.1]Rs, reducing effects of ANG II. This study determined the effects of [E.sub.2] and dihydrotestosterone (DHT) on cortical estrogen receptors (ERs) and glomerular A[T.sub.1]R binding in rats. Animals underwent sham operation, ovariectomy (Ovx) or orchidectomy (Cas) and were treated (Ovx [+ or -] [E.sub.2]; Cas [+ or -] DHT) for 3 wk. Cortical ER[alpha] protein was 2.5 times greater, and ER[beta] was 80% less in females vs. males (P < 0.01). Glomerular A[T.sub.1]R binding was lower in females than males [4,657 [+ or -] 838 vs. 7,457 [+ or -] 467 counts per minute (cpm), P < 0.01]. Ovx reduced ER[alpha] protein by 50%, whereas [E.sub.2] increased ER[alpha] expression after Ovx. The decrease in cortical ER[alpha] in Ovx rats was associated with a significant increase in A[T.sub.1]R binding (6,908 [+ or -] 609 cpm), and [E.sub.2] prevented this increase. There was no change in ER[alpha] or A[T.sub.1]R binding following Cas [+ or -] DHT (25 mg) treatment, although Cas did elevate cortical ER[beta] (P < 0.01). Interestingly, the high dose DHT (200 mg) elevated ER[alpha] 150% above intact levels and profoundly decreased A[T.sub.1]R binding (1,824 [+ or -] 705 cpm, P < 0.001 vs. intact male). This indicates that under normal conditions, glomerular A[T.sub.1]R binding is significantly greater in male than female animals, which may be important in development of cardiovascular and renal disease in males. Furthermore, [E.sub.2] regulates ER[alpha] and is inversely associated with glomerular A[T.sub.1]R binding, supporting our hypothesis that [E.sub.2] tonically suppresses A[T.sub.1]Rs and suggesting a potential mechanism for the protective effects of estrogen. kidney; 17[beta]-estradiol; dihydrotestosterone; testosterone; ovariectomy; castration; angiotensin II

Insulin resistance has been shown to be associated with increased blood pressure (BP). The sex hormones estrogen and testosterone have opposing effects in the development of increased BP. Since testosterone has been implicated in increased BP following insulin resistance, we have tried to dissect out the effects of insulin resistance on endothelium-dependent vasorelaxation in the presence and absence of testosterone. Both gonadectomized and sham-operated male Wistar rats fed with a high-fructose diet developed insulin resistance, but BP increased only in the sham-operated rats. Reintroduction of testosterone in vivo restored the increase in BP, thereby abolishing the protective effects of gonadectomy. Fructose feeding did not affect plasma testosterone levels. Insulin resistance induced endothelial dysfunction in the mesenteric arteries of sham-operated rats, which was prevented by gonadectomy, thus suggesting a key role for testosterone in the pathogenesis of secondary vascular complications. Subsequent to blocking the actions of endothelium-dependent hyperpolarizing factor (EDHF), relaxation to acetylcholine (ACh) was lower in sham-operated fructose-fed rats compared with other groups, suggesting the involvement of nitric oxide (NO) in vasorelaxation. Inhibition of NO synthesis nearly abolished the ACh-evoked relaxation in both fructose-fed groups, thus suggesting a testosteroneindependent impairment of EDHF-mediated relaxation. The improvement in endothelial function following gonadectomy could be ascribed to a NO component, although plasma nitrite and nitrate levels were unchanged. In summary, testosterone is essential in vivo for the development of endothelial dysfunction and hypertension secondary to insulin resistance, suggesting a facilitatory role for testosterone in increasing BP in fructose-fed male rats. insulin resistance; fructose-fed rat; blood pressure; testosterone; nitric oxide; endothelium-derived hyperpolarizing factor

We hypothesized that suppression of endogenous testosterone would inhibit the adaptations to strength training in otherwise healthy men. Twenty-two young men with minor experience with strength training participated in this randomized, placebo-controlled, double-blinded intervention study. The subjects were randomized to treatment with the GnRH analog goserelin (3.6 mg) or placebo (saline) subcutaneously every 4 wk for 12 wk. The strength training period of 8 wk, starting at week 4, included exercises for all major muscles [3-4 sets per exercise x 6-10 repetitions with corresponding 6- to 10-repetition maximum (RM) loads, 3/wk]. A strength test, blood sampling, and whole body DEXA scan were performed at weeks 4 and 12. Endogenous testosterone decreased significantly (P < 0.01) in the goserelin group from 22.6 [+ or -] 5.5 (mean [+ or -] SD) nmol/1 to 2.0 [+ or -] 0.5 (week 4) and 1.1 [+ or -] 0.6 nmol/1 (week 12), whereas it remained constant in the placebo group. The goserelin group showed no changes in isometric knee extension strength after training, whereas the placebo group increased from 240.2 [+ or -] 41.3 to 264.1 [+ or -] 35.3 Nm (P < 0.05 within and P = 0.05 between groups). Lean mass of the legs increased 0.37 [+ or -] 0.13 and 0.57 [+ or -] 0.30 kg in the goserelin and placebo groups, respectively (P < 0.05 within and P = 0.05 between groups). Body fat mass increased 1.4 [+ or -] 1.0 kg and decreased 0.6 [+ or -] 1.2 kg in the goserelin and placebo groups, respectively (P < 0.05 within and between groups). We conclude that endogenous testosterone is of paramount importance to the adaptation to strength training. gonadotropin-releasing hormone analog; exercise; isometric strength; lean body mass; fat mass

The plasma levels of dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) decline ~80% between the ages of 25 and 75 yr. Muscle mass and strength also decrease with aging. Published data on the effects of DHEA replacement on muscle mass and strength are conflicting. The goals of this study were to determine whether DHEA replacement increases muscle mass and strength and/or enhances the effects of heavy resistance exercise in elderly women and men. We conducted a randomized, double-blind, placebo-controlled study of the effects of 10 mo of DHEA replacement therapy with the addition of weightlifting exercise training during the last 4 mo of the study (DHEA + exercise group, n = 29; placebo + exercise group, n = 27). DHEA alone for 6 mo did not significantly increase strength or thigh muscle volume. However, DHEA therapy potentiated the effect of 4 mo of weightlifting training on muscle strength, evaluated by means of one-repetition maximum measurement and Cybex dynamometry, and on thigh muscle volume, measured by magnetic resonance imaging. Serum insulin-like growth factor concentration increased in response to DHEA replacement. This study provides evidence that DHEA replacement has the beneficial effect of enhancing the increases in muscle mass and strength induced by heavy resistance exercise in elderly individuals. estradiol; insulin-like growth factor I; magnetic resonance imaging; testosterone; dehydroepiandrosterone

Although serum testosterone levels decrease acutely in critically ill patients, estrogen levels rise. We hypothesized that increased rates of aromatization of androgens to estrogens underlie the increase in serum estrogen levels. Eleven men and three women (age 42-69 yr) were prospectively studied before and again after elective coronary artery bypass graft surgery (CABG). Each patient received priming doses of [[sup.14]C]androgen and [[sup.3]H]estrogen that were immediately followed by peripheral infusions for 210 min. Eight men and three women received androstenedione ([A.sub.4])/estrone ([E.sub.1]) and three men received testosterone (T)/estradiol ([E.sub.2]). Adipose tissue biopsies were obtained in another six men before and after CABG to evaluate levels of P450 aromatase mRNA. Serum T levels decreased postoperatively in all 17 men (P < 0.001), whereas [E.sub.1] levels rose (P = 0.004), with a trend toward a rise in [E.sub.2] (P = 0.23). Peripheral aromatization rates of androgens to estrogens rose markedly in all 14 patients (P < 0.0001). Estrogen clearance rates rose (P < 0.002). Mean serum [A.sub.4] levels increased slightly postoperatively (P = 0.04), although no increase in [A.sub.4] production rates (PRs) was observed. T PRs decreased in two of three men, whereas clearance rates increased in all three. Adipose tissue P450 aromatase mRNA content increased postoperatively (P < 0.001). We conclude that the primary cause of increased estrogen levels in acute illness is increased aromatase P450 gene expression, resulting in enhanced aromatization of androgens to estrogens, a previously undescribed endocrine response to acute illness. Both increased T clearance and decreased T production contribute to decreased serum T levels. Animal studies suggest that these opposing changes in circulating estrogen and androgen levels may be important to reduce morbidity and mortality in critical illness. aromatase; cardiac surgery; estradiol; testosterone doi:10.1152/ajpendo.00467.2005

Androgens promote anabolism in skeletal muscle; however, effects on subsequent muscle function are less well defined because of a lack of reliable experimental models. We established a rigorous model of androgen withdrawal and administration in male mice and assessed androgen regulation of muscle mass, structure, and function. Adult C57B1/6J male mice were orchidectomized (Orx) or sham-operated (Sham) and received 10 wk of continuous testosterone (T) or control treatment (C) via intraperitoneal implants. Mass, fiber cross-sectional area (CSA), and in vitro contractile function were assessed for fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles. After 10 wk, Orx+C mice had reduced body weight gain (P < 0.05), seminal vesicle mass (P < 0.01), and levator ani muscle mass (P < 0.001) compared with Sham+C mice, and these effects were prevented with testosterone treatment. Orx+T mice had greater EDL (P < 0.0t) and SOL (P < 0.01) muscle mass compared with Orx+C mice; however, median fiber CSA was not significantly altered in these muscles. EDL and SOL muscle force was greater in Sham+T compared with Orx+C mice (P < 0.05) in proportion to muscle mass. Unexpectedly, Orx+T mice had increased fatigue resistance of SOL muscle compared with Orx+C mice (P < 0.001). We used a rigorous model of androgen withdrawal and administration in male mice to demonstrate an essential role of androgens in the maintenance of muscle mass and force. In addition, we showed that testosterone treatment increases resistance to fatigue of slow- but not fast-twitch muscle. contractile function; force; androgen receptor doi: 10.1152/ajpendo.00058.2006

Chronic endogenous testosterone exposure adversely affects proinflammatory and proapoptotic signaling after ischemia/reperfusion; however, it remains unknown whether a single acute testosterone exposure is equally detrimental. We hypothesized that acute exogenous testosterone infusion before ischemia would worsen myocardial functional recovery, increase the activation of MAPKs and caspase-3, and increase myocardial proinflammatory cytokine production. To study this, isolated-perfused rat hearts (Langendorff) from adult females and castrated males were subjected to 25-min ischemia and 40-min reperfusion with and without acute testosterone infusion (17[beta]-hydroxy-4-androstenone, 10 ng*[ml.sup.-1]*[min.sup.-1]) before ischemia. Myocardial contractile function was continuously recorded. After ischemia/reperfusion, hearts were assessed for levels of testosterone (ELISA), expression of proinflammatory cytokines (ELISA), and activation of MAPKs and caspase-3 (Western blot analysis). Data were analyzed with two-way ANOVA or Student's t-test; P < 0.05 was statistically significant. All indices of postischemic functional recovery were decreased with acute exogenous testosterone compared with the untreated groups. Acute testosterone infusion increased activation of MAPKs and caspase-3 following ischemia/reperfusion. However, there were no significant differences in the myocardial proinflammatory cytokine production after brief testosterone infusion. A single acute exposure to exogenous testosterone before ischemia worsens myocardial functional recovery and increases activation of MAPKs and caspase-3. These findings confirm the deleterious effects of testosterone on myocardium, elucidate the nongenomic mechanistic pathways of testosterone, and may have important clinical implications for patients who have acute exposure to exogenous testosterone. myocardial infarction; sex hormones; inflammation

Cardiac rupture can be fatal after myocardial infarction (MI). Experiments in animals revealed gender differences in rupture rate; however, patient data are controversial. We found a significantly higher rupture rate in testosterone-treated female mice within 1 wk after MI, whereas castration in males significantly reduced rupture. We hypothesized that testosterone may adversely affect remodeling after MI, exaggerating the inflammatory response and increasing cardiac rupture, whereas estrogen may be cardioprotective, attenuating early remodeling and reducing rupture rate. We studied the effect of gender and hormone manipulation on morphological and histological changes during early remodeling after MI in 4-wk-old male and female C57BL/6J mice and how these events could affect cardiac function. Females were randomly divided into 1) sham ovariectomy + placebo (s-ovx + P), 2) s-ovx + testosterone (T), 3) ovx + P, and 4) ovx + T; males were divided into 1) sham castration + P (s-cas + P), 2) s-cas + 17[beta]-estradiol (E), 3) cas + P, and 4) cas + E. At 6 wk after gonadectomy and hormone manipulation, MI was induced. Mice were randomly killed 1, 2, 4, 7, and 14 days after MI. The left ventricle was weighed and sectioned for evaluation of MI size, infarct expansion index (IEI), and neutrophil infiltration. Transthoracic echocardiography was performed in conscious mice in the 14-day group before organ harvest. Cardiac rupture rate and IEI were significantly higher in testosterone-treated females and noncastrated males than in controls; these effects were accompanied by enhanced neutrophil infiltration and pronounced deterioration of cardiac function and left ventricular dilatation. Ovariectomy in females and estrogen supplementation in males did not confer significant protection from cardiac rupture, IEI, or neutrophil infiltration. We concluded that, in mice, high testosterone levels enhance acute myocardial inflammation, adversely affecting myocardial healing and early remodeling, as indicated by increased cardiac rupture, and possibly causing deterioration of cardiac function after MI, and, conversely, estrogen seems to have no significant protective effect in the acute phase after MI. left ventricle; infarct expansion index; neutrophil infiltration; hormone manipulation

Although testosterone (T) has striking effects on mature skeletal size and structure, it is not clear whether this depends exclusively on adult circulating levels of T or whether additional early-life factors also play a role. We have compared the androgen-deficient hypogonadal (hpg) mutant mouse with intact, orchidectomized, and T-treated non-hpg mice to determine relative contributions of adult and perinatal T to bone growth and development. At 3 wk of age, although trabecular and cortical bone structure was normal, bone turnover was significantly altered in hpg male mice; osteoid volume (OV/BV) and osteoblast surface (ObS/BS) were significantly lower and osteoclast surface (OcS/BS) significantly higher in hpg mice compared with age-matched non-hpg mice, pointing to a role for the perinatal T surge in determining bone turnover levels befbre sexual maturity. At 9 wk of age, the hpg bone phenotype mimicked closely that of age-matched non-hpg mice that had been orchidectomized at 3 wk of age, including low trabecular bone mass and high bone turnover. These bone phenotypes of hpg and orcfiidectomized non-hpg mice were all prevented by replacement doses of T or dihydrotestosterone (DHT), suggesting that these are determined by adult sex steroid hormones. In contrast, a short bone phenotype that could not be prevented by T or DHT treatment was observed in 9-wk-old hpg mice yet not in intact or castrated non-hpg mice. These data suggest a role for the perinatal T surge in determining adult bone length and confirms that adult circulating T determines adult bone density. hypogonadism; skeleton; androgens

Testosterone (T) secretion declines in the aging male, albeit for unknown reasons. From an ensemble perspective, repeated incremental signaling among gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and T is required to maintain physiological androgen availability. Pattern-regularity statistics, such as univariate approximate entropy (ApEn) and bivariate cross-ApEn, provide specific and sensitive model-free measurement of altered multipathway control. The present study exploits partial muting of one pathway (GnRH drive) to appraise adaptive regulation of LH and T secretion in young and aging individuals. Analyses comprised 100 paired 18-h LH and T concentration time series obtained in 25 healthy men ages 20-72 yr each administered placebo and three graded doses of a specific GnRH-receptor antagonist. Graded blockade of GnRH drive increased the individual regularity of LH and T secretion and the synchrony of LH-T feedforward and T-LH feedback in the cohort as a whole (P < 0.001 for each). However, age markedly attenuated ganirelix-induced enhancement of univariate T orderliness and bivariate LH-T feedback and T-LH feedback synchrony (P [less than or equal to] 0.0025). In summary, the present analyses support the thesis that aging disrupts coordinate control of T secretion, LH-T feedforward, and T-LH feedback in healthy men. Thus the experimental strategy of stepwise silencing of an agonistic pathway may have utility in dissecting the bases of altered neurohormonal linkages in other systems. gonadotropin-releasing hormone; gonadotropin; aging; male; androgen; secretion; luteinizing hormone

Activation of inflammatory mechanisms contributes to cerebrovascular pathophysiology. Male gender is associated with increased stroke risk, yet little is known about the effects of testosterone in the cerebral circulation. Therefore, we explored the impact of testosterone treatment on cerebrovascular inflammation with both in vivo and in vitro models of inflammation. We hypothesized that testosterone would augment the expression of two vascular markers of cellular inflammation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Using four groups of male rats [intact, orchiectomized (ORX), and ORX treated with either testosterone (ORXT) or the testosterone metabolite 17[beta]-estradiol (ORXE)], we determined effects of the sex hormones on cerebrovascular inflammation after intraperitoneal LPS injection. Western blot analysis showed that induction of inflammatory markers was increased in cerebral blood vessels from ORXT rats compared with intact or ORX rats. In contrast, in cerebral blood vessels from ORXE rats, there was a significant decrease in endotoxin-induced COX-2 and iNOS protein levels. Confocal microscopy of cerebral blood vessels from ORXT rats showed increased COX-2 and iNOS immunoreactivity in both endothelial and smooth muscle cells after LPS treatment. In vitro incubation with LPS also induced COX-2 in pial vessels isolated from the four animal treatment groups, with the greatest induction observed in ORXT vessels compared with the ORX and ORXE groups. Production of PG[E.sub.2], a principal COX-2-derived prostaglandin end product, was also greatest in cerebral vessels isolated from ORXT rats. In conclusion, testosterone increases cerebrovascular inflammation; this effect may contribute to stroke differences between men and women. estrogen; lipopolysaccharide; cyclooxygenase-2; inducible nitric oxide synthase

Pulsatile and thus total testosterone (Te) secretion declines in older men, albeit for unknown reasons. Analytical models forecast that aging may reduce the capability of endogenous luteinizing hormone (LH) pulses to stimulate Leydig cell steroidogenesis. This notion has been difficult to test experimentally. The present study used graded doses of a selective gonadotropin releasing hormone (GnRH)-receptor antagonist to yield four distinct strata of pulsatile LH release in each of 18 healthy men ages 23-72 yr. Deconvolution analysis was applied to frequently sampled LH and Te concentration time series to quantitate pulsatile Te secretion over a 16-h interval. Log-linear regression was used to relate pulsatile LH secretion to attendant pulsatile Te secretion (LH-Te drive) across the four stepwise interventions in each subject. Linear regression of the 18 individual estimates of LH-Te feedforward dose-response slopes on age disclosed a strongly negative relationship (r = -0.721, P < 0.001). Accordingly, the present data support the thesis that aging in healthy men attenuates amplitude-dependent LH drive of burst-like Te secretion. The experimental strategy of graded suppression of neuroglandular outflow may have utility in estimating dose-response adaptations in other endocrine systems. gonadotropin releasing hormone; luteinizing hormone; aging; male; androgen; secretion

We investigated the impact of growth hormone (GH) alone, testosterone (T) alone, and combined GH and T on whole body protein metabolism. Twelve hypopituitary men participated in two studies. Study 1 compared the effects of GH alone with GH plus T, and study 2 compared the effects of T alone with GH plus T. IGF-I, resting energy expenditure (REE), and fat oxidation ([F.sub.ox]) and rates of whole body leucine appearance ([R.sub.a]), oxidation ([L.sub.ox]), and nonoxidative leucine disposal (NOLD) were measured. In study 1, GH treatment increased mean plasma IGF-I (P < 0.001). GH did not change leucine [R.sub.a] but reduced [L.sub.ox] (P < 0.02) and increased NOLD (P < 0.02). Addition ofT resulted in an additional increase in IGF-I (P < 0.05), reduction in Lox (P < 0.002), and increase in NOLD (P < 0.002). In study 2, T alone did not alter IGF-I levels. T alone did not change leucine [R.sub.a], but reduced [L.sub.ox] (P < 0.01) and increased NOLD (P < 0.01). Addition of GH further reduced [L.sub.ox] (P < 0.05) and increased NOLD (P < 0.05). In both studies, combined treatments on REE and [F.sub.ox] were greater than either alone. In summary, GH-induced increase of circulating IGF-I is augmented by T, which does not increase IGF-I in the absence of GH. T and GH exerted independent and additive effects on protein metabolism, [F.sub.ox] and REE. The anabolic effects of T are independent of circulating IGF-I. insulin-like growth factor I; protein turnover

Testosterone (Te) concentrations fall gradually in healthy aging men. Postulated mechanisms include relative failure of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and/or gonadal Te secretion. Available methods to test Leydig cell Te production include pharmacological stimulation with human chorionic gonadotropin (hCG). We reasoned that physiological lutropic signaling could be mimicked by pulsatile infusion of recombinant human (rh) LH during acute suppression of LH secretion. To this end, we studied eight young (ages 19-30 yr) and seven older (ages 61-73 yr) men in an experimental paradigm comprising 1) inhibition of overnight LH secretion with a potent selective GnRH-receptor antagonist (ganirelix, 2 mg sc), 2) intravenous infusion of consecutive pulses of rh LH (50 IU every 2 h), and 3) chemiluminometric assay of LH and Te concentrations sampled every 10 min for 26 h. Statistical analyses revealed that 1) ganirelix suppressed LH and Te equally (> 75% median inhibition) in young and older men, 2) infused LH pulse profiles did not differ by age, and 3) successive intravenous pulses of rh LH increased concentrations of free Te (ng/dl) to 4.6 [+ or -] 0.38 (young) and 2.1 [+ or -] 0.14 (older; P luteinizing hormone; Leydig cell; aging; male; human

Endogenous testosterone increases L-type [Ca.sup.2+] channel expression in porcine coronary smooth muscle. Am J Physiol Heart Circ Physiol 287: H2091-H2098, 2004. First published July 8, 2004: doi: 10.1152/ajpheart.00258.2004.--Evidence indicates that gender and sex hormonal status influence cardiovascular physiology and pathophysiology. We recently demonstrated increased L-type voltage-gated [Ca.sup.2+] current ([I.sub.Ca,L]) in coronary arterial smooth muscle (CASM) of male compared with female swine. The promoter region of the L-type voltage-gated [Ca.sup.2+] channel (VGCC) ([Ca.sub.v] 1.2) gene contains a hormone response element that is activated by testosterone. Thus the purpose of the present study was to determine whether endogenous testosterone regulates CASM [I.sub.Ca, L] through regulation of VGCC expression and activity. Sexually mature male and female Yucatan swine (7-8 mo; 35-45 kg) were obtained from the breeder. Males were left intact (IM, n = 8), castrated (CM, n = 8), or castrated with testosterone replacement (CMT, n = 8; 10 mg/day Androgel). Females remained gonad intact (n = 8). In right coronary arteries, both [Ca.sub.v] 1.2 mRNA and protein were greater in IM compared with intact females. [Ca.sub.v] 1.2 mRNA and protein were reduced in CM compared with IM and restored in CMT. In isolated CASM, both peak and steady-state [I.sub.Ca] were reduced in CM compared with IM and restored in CMT. In males, a linear relationship was found between serum testosterone levels and [I.sub.Ca]. In vitro, both testosterone and the nonaromatizable androgen, dihydrotestosterone, increased [Ca.sub.v] 1.2 expression. Furthermore, this effect was blocked by the androgen receptor antagonist cyproterone. We conclude that endogenous testosterone is a primary regulator of [Ca.sub.v] 1.2 expression and activity in coronary arteries of males. voltage clamp; vascular; voltage-gated calcium channels

Little is known about vascular effects of testosterone. We previously reported chronic testosterone treatment increases vascular tone in middle cerebral arteries (MCA; 300 [micro]m diameter) of male rats. In the present study, we investigated the hypothesis that physiological levels of circulating testosterone affect endothelial factors that modulate cerebrovascular reactivity. Small branches of MCA (150 [micro]m diameter) were isolated from orchiectomized (ORX) and testosterone-treated (ORX+T) rats. Intraluminal diameters were recorded after step changes in intralumiual pressure (20-100 Torr) in the absence or presence of [N.sup.G]-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor; indomethacin, a cyclooxygeuase (COX) inhibitor: and/or apamin and charybdotoxin (CTX); and [K.sub.Ca] channel blockers used to inhibit endothelium-derived hyperpolarizing factors (EDHF). At intraluminal pressures [greater than or equal to] 60 Torr, arteries from ORX+T developed greater tone compared with ORX arteries. This difference was abolished by removal of the endothelium but remained after treatment of intact arteries with indomethacin or L-NAME. In addition, testosterone treatment had no effect on cerebrovascular production of endothelin-1 or prostacyclin nor did it alter protein levels of endothelial NOS or COX-1. Endothelium removal after L-NAME/ indomethacin exposure caused an additional increase in tone. Interestingly, the latter effect was smaller in arteries from ORX+T, suggesting testosterone affects endothelial vasodilators that are independent of NOS and COX. Apamin/CTX, in the presence of L-NAME/indomethacin, abolished the difference in tone between ORX and ORX+T and resulted in vessel diameters similar to those of endothelium-denuded preparations. In conclusion, testosterone may modulate vascular tone in cerebral arteries by suppressing EDHF. endothelium; vascular tone; endothelium-derived hyperpolarizing factor

Testosterone-induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab 283: E154-E164, 2002. First published March 12, 2002; 10.1152/ajpendo.00502.2001.--Administration of replacement doses of testosterone to healthy hypogonadal men and supraphysiological doses to eugonadal men increases muscle size. To determine whether testosterone-induced increase in muscle size is due to muscle fiber hypertrophy, 61 healthy men, 18-35 yr of age, received monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion and weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate (TE) for 20 wk. Thigh muscle volume was measured by magnetic resonance imaging (MRI) scan, and muscle biopsies were obtained from vastus lateralis muscle in 39 men before and after 20 wk of combined treatment with GnRH agonist and testosterone. Administration of GnRH agonist plus TE resulted in mean nadir testosterone concentrations of 234, 289, 695, 1,344, and 2,435 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Graded doses of testosterone administration were associated with testosterone dose and concentration-dependent increase in muscle volume measured by MRI (changes in vastus lateralis volume, -4, +7, +15, +32, and +48 ml at 25-, 50-, 125-, 300-, and 600-mg doses, respectively). Changes in cross-sectional areas of both type I and II fibers were dependent on testosterone dose and significantly correlated with total (r = 0.35, and 0.44, P < 0.0001 for type I and II fibers, respectively) and free (r = 0.34 and 0.35, P < 0.005) testosterone concentrations during treatment. The men receiving 300 and 600 mg of TE weekly experienced significant increases from baseline in areas of type I (baseline vs. 20 wk, 3,176 [+ or -] 186 vs. 4,201 [+ or -] 252 [micro][m.sup.2], P < 0.05 at 300-mg dose, and 3,347 [+ or -] 253 vs. 4,984 [+ or -] 374 [micro][m.sup.2], P = 0.006 at 600-mg dose) muscle fibers; the men in the 600-mg group also had significant increments in cross-sectional area of type II (4,060 [+ or -] 401 vs. 5,526 [+ or -] 544 [micro][m.sup2], P = 0.03) fibers. The relative proportions of type I and type II fibers did not change significantly after treatment in any group. The myonuclear number per fiber increased significantly in men receiving the 300- and 600-mg doses of TE and was significantly correlated with testosterone concentration and muscle fiber cross-sectional area. In conclusion, the increases in muscle volume in healthy eugonadal men treated with graded doses of testosterone are associated with concentration-dependent increases in cross-sectional areas of both type I and type II muscle fibers and myonuclear number. We conclude that the testosterone induced increase in muscle volume is due to muscle fiber hypertrophy. androgen; muscle hypertrophy; satellite cells; mechanism of action

Research was conducted to examine whether the administration of testosterone to female mice could mimic the splenocyte immune depression occurring in male mice after trauma hemorrhage. For pretreatment purposes, the testosterone derivative 5-alpha-dihydrotestosterone was selected since it is considered as a primary androgenic hormone in males. Results indicate that male sex hormones contribute to the different immune responses in males compared with females.

A study was conducted on how aging influence testosterone and luteinizing hormone secretion. Feed-forward stimulation and feedback inhibition were examined using deconvolution analysis. Both young and older men sampled exhibited statistically similar mean serum luteinizing hormone and testosterone levels. Older men, however, exhibited delayed feedback inhibition and lower feed-forward stimulation.

Androgen concentrations exceeding a critical threshold in spring result in terminal arousal of male squirrels. This steroid-independent mechanism is similar to the one operating in the earlier parts of the hibernation season. Findings show that 64% of the squirrels, castrated 1 wk after terminal arousal, resume hibernation. They also show that torpor resumption latency is 9 (plus or minus 2 days) from castration time, and that squirrels have 4.3 (plus or minus 0.9) bouts before permanent euthermia. After castration, hibernated squirrels have shorter bout duration and shallower torpor.

Ba, Zheng F., Ping Wang, Douglas J. Koo, Mian Zhou, William G. Cioffi, Kirby I. Bland, and Irshad H. Chaudry. Testosterone receptor blockade after trauma and hemorrhage attenuates depressed adrenal function. Am J Physiol Regulatory Integrative Comp Physiol 279: R1841-R1848, 2000.--Although the testosterone receptor antagonist flutamide restores the depressed immune function in males after trauma and hemorrhage, it remains unknown whether this agent has any salutary effects on adrenal function. To study this, male rats underwent laparotomy and were bled to and maintained at a blood pressure of 40 mmHg until 40% of the shed blood volume was returned in the form of Ringer lactate. Animals were then resuscitated and fiutamide (25 mg/kg body wt) was administered subcutaneously. Plasma adrenocorticotropic hormone (ACTH) and corticosterone, as well as adrenal corticosterone and cAMP were measured 20 h after resuscitation. In additional animals, ACTH was administered and ACTH-induced corticosterone release and adrenal cAMP were determined. The results indicate that adrenal contents of corticosterone and cAMP were significantly decreased and morphology was altered after hemorrhage. Administration of flutamide improved corticosterone content, restored cAMP content, and attenuated adrenal morphological alterations. Flutamide also improved the diminished ACTH-induced corticosterone release and adrenal cAMP response at 20 h after hemorrhage and resuscitation. Furthermore, the diminished corticosterone response to ACTH stimulation in the isolated adrenal preparation was improved with flutamide. These results suggest that flutamide is a useful adjunct for improving adrenal function in males following trauma and hemorrhage. adrenal function; isolated perfused adrenal preparation; corticosterone; adenosine 3',5'-cycle monophosphate; adrenocorticotropic hormone

Single exposure to testosterone in adulthood rapidly induces regularity in the growth hormone release process. Am J Physiol Endocrinol Metab 278: E933-E940, 2000.--The neonatal gonadal steroid milieu is known to be important in imprinting the striking sexual dimorphism of growth hormone (GH) secretion; however, the influence of the sex steroids on GH control in adult life and their mechanism/site of action are largely unknown. In the present study, we tested the hypothesis that testosterone (T) subserves the gender-specific regularity of the GH release process in adulthood. The approximate entropy statistic (ApEn) was used to quantify the degree of regularity of GH release patterns over time. Eighteen hours after a single subcutaneous injection of 1 mg T, both sham-operated and ovariectomized (OVX) female adult rats displayed plasma GH profiles that were strikingly similar to the regular male-like ultradian rhythm of GH secretion. The highest ApEn values, denoting greater disorderliness of GH secretion, were observed in the ovary-intact group, and T injection significantly (P [is less than] 0.001) reduced this irregularity whether or not the ovaries were present. Serial intravenous injections of GH-releasing hormone (GHRH) caused a similar increase in plasma GH levels in sham-operated females independently of time of administration. In contrast, female rats administered T exhibited a male-like intermittent pattern of GH responsiveness to GHRH, the latter known to be due to the cyclic release of endogenous somatostatin. These results demonstrate that acute exposure to T during adult life can rapidly and profoundly 'masculinize' GH pulse-generating circuits in the female rat. Our findings suggest that the enhanced orderliness characteristic of the GH release process in males, compared with females, is regulated by T. We postulate that this T-induced regularity is mediated at the level of the hypothalamus by inducing regularity in somatostatin secretion, which in turn governs overall GH periodicity. sexual dimorphism; growth hormone pulsatility; somatostatin; growth hormone-releasing hormone; approximate entropy