Physiological Doses Of Testosterone Research Articles

Kisspeptins centrally modulate food intake and locomotor activity in mice independently of gonadal steroids in a sexually dimorphic manner.

Kisspeptins are essential regulators of the reproductive axis, with capacity to potently activate gonadotropin-releasing hormoneneurons, acting also as central conduits for the metabolic regulation of fertility. Recent evidence suggests that kisspeptins per se may also modulate several metabolic parameters, including body weight, food intake or energy expenditure, but their actual roles and site(s) of action remain unclear. We present herein a series of studies addressing the metabolic effects of central and peripheral administration of kisspeptin-10 (Kp-10; 1 nmol and 3 nmol daily, respectively) for 11 days in mice of both sexes. To assess direct metabolic actions of Kp-10 versus those derived indirectly from its capacity to modulate gonadal hormone secretion, kisspeptin effects were tested in adult male and female mice gonadectomized and supplemented with fixed, physiological doses of testosterone or 17β-estradiol, respectively. Central administration of Kp-10 decreased food intake in male mice, especially during the dark phase (~50%), which was accompanied by a reduction in total and nocturnal energy expenditure (~16%) and locomotor activity (~70%). In contrast, opposite patterns were detected in female mice, with an increase in total and nocturnal locomotor activity (>65%), despite no changes in food intake or energy expenditure. These changes were independent of body weight, as no differences were detected in mice of both sexes at the end of Kp-10 treatments. Peripheral administration of Kp-10 failed to alter any of the metabolic parameters analyzed, except for a decrease in locomotor activity in male mice and a subtle increase in 24 h food intake in female mice, denoting a predominant central role of kisspeptins in the control of energy metabolism. Finally, glucose tolerance and insulin sensitivity were not significantly affected by central or peripheral treatment with Kp-10. In conclusion, our data reveal a potential role of kisspeptins in the control of key metabolic parameters, including food intake, energy expenditure and locomotor activity, with a preferential action at central level, which is sex steroid-independent but sexually dimorphic.

Suppression of myofilament cross-bridge kinetic in the heart of orchidectomized rats

AimsThe increased incidence of heart failure with reduced ejection fraction in men compared with women suggests that male sex hormones significantly impact myocardial contractile activation. This study aims to examine associations among molecular alterations, cellular modulations and in vivo cardiac contractile function upon deprivation of testicular hormones. Main methodsMyocardial structure and functions were compared among sham-operated control and twelve-week orchidectomized (ORX) male rats with and without testosterone supplementation. Key findingsEchocardiography and pressure-volume relationships demonstrated a decreased left ventricular ejection fraction compared with sham-operated controls. The percentage of contractility reduction was generally similar to the decrease in tension development detected in both right ventricular trabeculae and skinned isolated left ventricular cardiomyocytes of ORX rats. Reductions in tension cost and the rate constant of tension redevelopment (ktr) in ORX samples suggested a decrease in the rate of cross-bridge formation, reflecting a reduced number of cross-bridges. Slow cross-bridge detachment in ORX rat hearts could result from a shift of myosin heavy chain isoforms towards a slower ATPase activity β-isoform and reductions in the phosphorylation levels of cardiac troponin I and myosin binding protein-C. All the changes in the ORX rat heart, including ejection fractions and myofilament protein expression and phosphorylation, were completed attenuated by a physiological dose of testosterone. SignificanceTestosterone plays a critical role in regulating the mechanical and contractile dynamics of the heart. Deprivation of male sex hormones cause the loss of normal preserved cardiac contractile function leading to a high risk of severe cardiomyopathy progression.

Effect of Sex Steroids on expression of genes regulating adipose tissue

Obesity represents an important health issue, since it is a risk factor for the development of a number of medical conditions, including type 2 diabetes, hypertension and cardiovascular disease. In men, visceral adipose tissue has been related to low plasma testosterone levels and low levels of oestrogens are associated with increased adipose tissue. In female, testosterone and estradiol plasma levels are related to fat cell morphology and expression of genes regulating adipocyte differentiation and adipocytokines secretion. In this present study we have analysed the effect of testosterone and estradiol on gene expression of adipose tissue regulating genes in adipocytes. The human preadipocyte cell line (SGBS) was differentiated into adipocytes and exposed to different concentrations (range 0.25–3nM) of testosterone and estradiol. The gene expression was analysed using quantitative real time PCR (qRT‐PCR). Our results indicate that physiological doses of testosterone and estradiol at do not alter expression of PPARγ, CEBPα, and adiponectin in differentiated adipocytes. Moreover, expression of cytokines (resistin, IL‐6, and TNFα) was very low in SGBS and not altered by sex steroids.Support or Funding InformationKing Saud University

Side-specific effect of yolk testosterone elevation on second-to-fourth digit ratio in a wild passerine.

Second-to-fourth digit ratio is a widely investigated sexually dimorphic morphological trait in human studies and could reliably indicate the prenatal steroid environment. Conducting manipulative experiments to test this hypothesis comes up against ethical limits in humans. However, oviparous tetrapods may be excellent models to experimentally investigate the effects of prenatal steroids on offspring second-to-fourth digit ratio. In this field study, we injected collared flycatcher (Ficedula albicollis) eggs with physiological doses of testosterone. Fledglings from eggs with elevated yolk testosterone, regardless of their sex, had longer second digits on their left feet than controls, while the fourth digit did not differ between groups. Therefore, second-to-fourth digit ratio was higher in the testosterone-injected group, but only on the left foot. This is the first study which shows experimentally that early testosterone exposure can affect second-to-fourth digit ratio in a wild population of a passerine bird.

AB0221 Estrogen modulation of endosome-associated toll-like receptors and ZAS3: An underlying mechanism of gender-BIAS in systemic lupus erythematosus?

BackgroundSystemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by significant gender bias. Previous studies have demonstrated the contributions of hormones, particularly estrogen (E2), to SLE pathogenesis. E2 has...

Profiling of Androgen Response in Rainbow Trout Pubertal Testis: Relevance to Male Gonad Development and Spermatogenesis

The capacity of testicular somatic cells to promote and sustain germ cell differentiation is largely regulated by sexual steroids and notably androgens. In fish species the importance of androgens is emphasized by their ability to induce sex reversal of the developing fries and to trigger spermatogenesis. Here we studied the influence of androgens on testicular gene expression in trout testis using microarrays. Following treatment of immature males with physiological doses of testosterone or 11-ketotestosterone, 418 genes that exhibit changes in expression were identified. Interestingly, the activity of testosterone appeared stronger than that of 11-ketotestosterone. Expression profiles of responsive genes throughout testis development and in isolated germ cells confirmed androgens to mainly affect gene expression in somatic cells. Furthermore, specific clusters of genes that exhibit regulation coincidently with changes in the natural circulating levels of androgens during the reproductive cycle were highlighted, reinforcing the physiological significance of these data. Among somatic genes, a phylogenetic footprinting study identified putative androgen response elements within the proximal promoter regions of 42 potential direct androgen target genes. Finally, androgens were also found to alter the germ line towards meiotic expression profiles, supporting the hypothesis of a role for the somatic responsive genes in driving germ cell fate. This study significantly increases our understanding of molecular pathways regulated by androgens in vertebrates. The highly cyclic testicular development in trout together with functions associated with regulated genes reveal potential mechanisms for androgen actions in tubule formation, steroid production, germ cell development and sperm secretion.

Testosterone, Hemostasis, and Cardiovascular Diseases in Men

Men have a higher incidence of cardiovascular disease (CVD) than women, and adverse thrombotic events increase with age. Recent experimental cross-sectional, and case-control studies have shown that testosterone may affect the hemostatic/fibrinolytic system in men in several ways. It has been hypothesized that physiological doses of testosterone would have a beneficial effect on tissue factor-induced thrombin generation and the development of CVD. The search for eternal youth has created a market for testosterone treatment in aging men during the last few years. However, whether testosterone supplementation could be useful in the treatment of testosterone-deficient elderly men is still controversial. The present review focuses on the coagulation system and CVD from the perspective of testosterone.

Regulation of atherosclerotic plaque growth and stability by testosterone and its receptor via influence of inflammatory reaction

Background Platelets play crucial roles in the development of arterial thrombosis and other pathophysiologies leading to clinical ischemic events. Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis. The purposes of the study are to determine whether atherosclerotic plaque growth or stability is regulated by physiological doses of testosterone via its receptor, and to further investigate the possible mechanisms of inflammatory reaction. Methods and results We prepared models of castrated male rabbits. Pathological sections of aorta were performed hematoxylin–eosin (HE) staining and Masson's trichrome staining. Total plasma testosterone was measured using ADVIA Centaur® Immunoassay System (Bayer, Germany). Serum TNF α and IL 6 were assayed using radio-immunoassay kit and serum sICAM-1 and MMP 2 were measured using ELISA kit. Our results showed that castration significantly lowered plasma testosterone levels, whereas testosterone replacement at a dose of 6 mg/kg/two-week restored circulating testosterone to physiological levels, without being altered by treatment with flutamide (a testosterone receptor inhibitor). Testosterone undecanoate replacement reduced the plaque area and the aortic intimal thickness, whereas the fibrous cap thickness and collagen contents increased in castrated rabbits. However, the presence of flutamide increased the plaque area and the aortic intimal thickness, whereas the fibrous cap thickness and collagen contents decreased in castrated rabbits again. Moreover, the levels of serum TNF α, IL 6, sICAM and MMP 2 increased in cholesterol-rich diet rabbits as compared with standard diet rabbits. Castration caused increases in the levels of serum TNF α, IL 6, sICAM and MMP 2 in castrated rabbits as compared with sham-operated rabbits. Treatment of testosterone undecanoate reduced the levels of serum TNF α, IL 6, sICAM and MMP 2 in castrated rabbits, while the presence of flutamide increased the levels of serum TNF α, IL 6, sICAM and MMP 2 again. Conclusion Replacement of physiological testosterone regulates atherosclerotic plaque growth and stability via its receptor in castrated rabbits, which is probably related to their influence on inflammatory reaction.

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Dehydroepiandrosterone (DHEA) is one of our body's most abundant sex steroids. The abundance declines slowly with age, however, and replacing it has become a fashionable way of maintaining eternal youth....

Yolk Testosterone Stimulates Growth and Immunity in House Finch Chicks

Female birds deposit variable amounts of androgens, such as testosterone, into the yolks of their eggs. Evidence suggests that yolk androgens play an important role in the determination of offspring phenotype. While androgens are generally regarded as anabolic and immunosuppressive, studies of the behavioral and physiological effects of yolk androgens on offspring of several avian species have been conflicting, leaving the adaptive significance associated with deposition patterns of yolk androgens unclear. We injected either a physiological dose of testosterone or a control vehicle into house finch (Carpodacus mexicanus) eggs and examined the effects of these injections on offspring growth and immunity. Two days after hatching, nestlings from eggs treated with testosterone were significantly larger than nestlings from eggs treated with a control injection, suggesting a stimulatory effect of yolk androgens in early development. By 8 d after hatching, however, this effect disappeared, and chicks from the two treatment groups were similar in size. Nestlings in the testosterone treatment group showed a significantly larger swelling response to phytohemagglutinin than control nestlings 15 d after hatching, which is close to fledging. Overall, our observations show that when food resources are abundant, testosterone stimulates both early growth and immunity in developing house finches.

Testosterone and estradiol up-regulate androgen and estrogen receptors in immature and adult rat thyroid glands in vivo

Thyroid gland is one of the non-classical target organs for sex steroids. Presence of androgen and estrogen receptors in the neoplastic and non-neoplastic thyroid glands of mammalian species is well documented. The aim of the present study is to elucidate the changes in serum and thyroidal sex steroids, and their receptors in the thyroid gland of rats from immature to adult age under gonadectomized (GDX) and sex steroids replaced conditions. Normal Wistar male and female rats from immature to adult age (day 21, 30, 45, 60 and 160 post-partum (pp)) were used in the present study. One group (I) of rats was GDX at an early age (day 10 pp) and the other group (II) at the adult age (day 120 pp). Group I rats were sacrificed at different experimental periods such as 21, 30, 45 and 60 days pp, and group II rats were sacrificed at day 160 pp. Another group of GDX rats from group I and II were replaced with physiological doses of testosterone or estradiol. Serum and thyroidal concentrations of sex steroids were estimated by RIA method and the concentrations of receptors by radioreceptor assay. Gonadectomy significantly decreased serum and thyroidal testosterone and estradiol and concentrations of androgen receptor (AR) and estrogen receptor (ER) in the thyroid. Replacement of sex steroids to GDX rats restored the normal level of sex steroids, AR and ER. Therefore, it is suggested from the present study that (i) sex steroids up-regulate their own receptors in the thyroid, (ii) sex steroids may influence thyroid growth and the proliferation of thyrocytes by modulating their receptor concentrations in the thyroid.

Responsiveness to testosterone of male gerbils from known intrauterine positions

Following either a) castration or b) both castration and implantation with capsules releasing a constant, physiological dose of testosterone, adult male Mongolian gerbils that had matured in intrauterine positions between two male fetuses still scent marked with greater frequency than did male gerbils that had matured in intrauterine positions between two female fetuses. We also found significant positive correlations between the relative frequency of scent marking exhibited by individual male gerbils when intact, after castration and after both castration and implantation with capsules releasing testosterone. Each of these findings is consistent with the view that differential exposure to testosterone, as a consequence of fetal intrauterine position, has lasting effects on the organization of scent-marking by male gerbils.

Testosterone Regulates Pro-Opiomelanocortin Gene Expression in the Primate Brain*

Endogenous opioid peptides such as beta-endorphin, derived from proopiomelanocortin (POMC), have been widely implicated as serving an important role in the neuroendocrine regulation of the primate reproductive axis. In both human and nonhuman primates, POMC neurons are thought to mediate, at least in part, the negative feedback action of sex steroids on GnRH. Sex steroids, such as testosterone, are thought to inhibit GnRH secretion by enhancing the inhibitory activity of beta-endorphin; however, the cellular mechanisms by which steroid hormones regulate the activity of POMC neurons in the primate brain are unknown. In this study, we tested the hypothesis that testosterone stimulates POMC gene expression within the primate brain and that this regulation occurs within a specific subset of POMC neurons residing in the arcuate nucleus of the hypothalamus. We used in situ hybridization to compare cellular levels of POMC messenger RNA in intact (n = 4), castrated (n = 4), and castrated/testosterone-treated (n = 4) monkeys. We report that after castration of the male macaque (Macaca fascicularis), cellular POMC messenger RNA levels decline significantly (P less than 0.05) in neurons within the arcuate nucleus and that this decline is prevented by replacement with physiological doses of testosterone. Moreover, we found that this testosterone-dependent modulation of POMC gene expression is restricted to a small fraction of the numerous POMC neurons located within the most anterior region of the arcuate nucleus in the brain of this primate species. These observations provide evidence that sex steroids regulate expression of the POMC gene in the primate brain.

The musk shrew,Suncus murinus, a unique animal model for the study of female behavioral endocrinology

Insectivora is the third largest mammalian order, composed of a number of unusual species considered to be the most primitive of the modern eutherian mammals. Yet, little is known about the members of this evolutionarily unique and important group. The musk shrew (Suncus murinus) is a convenient and practical laboratory animal. The study of the reproductive biology of this species will yield needed comparative data. Moreover, the little information that we have collected on this species suggests that several unusual characteristics make this animal a worthwhile and novel model for endocrine research. Most of the current and past research on this species has focused on the endocrinology of the female musk shrew. Unlike conventional small mammal models, the female musk shrew has no spontaneous ovarian cycle. The ovaries of the adult, unmated female do not undergo spontaneous follicular development. At the time of mating only small, relatively immature follicles are present. As a consequence, ovarian hormone production is not cyclic. Thus, traditional hormone target tissues such as the vaginal epithelium and the uterus do not exhibit cycles in cell proliferation. Sexual behavior is likewise demonstrated in an acyclic manner. Virgin females become sexually receptive within minutes after their first exposure to a male, and nonpregnant females are virtually always sexually receptive. Sexual receptivity in the virgin female musk shrew occurs in the face of relatively low plasma estradiol levels and higher androgen levels, and does not appear to be mediated via ovarian estradiol. Instead, recent work suggests that close to physiological doses of testosterone can restore sexual behavior in ovariectomized musk shrews.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of defolliculation and 17 alpha-hydroxy, 20 beta-dihydroprogesterone on cyclic AMP level in full-grown oocytes of the rainbow trout, Salmo gairdneri.

The changes in cAMP were followed in trout oocytes incubated in vitro after defolliculation performed by either enzymatic or manual dissection. Both defolliculation methods induced a highly significant rise in oocyte cAMP level (4.5 times the basal level of control [follicle-enclosed oocytes], after 6 h). Treatment of defolliculated oocytes with 17 alpha-hydroxy, 20 beta-dihydroprogesterone (17 alpha, 20 beta-OH-P) (10(-6) M), which induced oocyte maturation (germinal vesicle breakdown [GVBD]) was able, first, to interrupt the increase of oocyte cAMP level promoted by defolliculation and then to lower this level significantly down to values that still remained higher than folliculated controls. Very low concentrations of 17 alpha, 20 beta-OH-P (1.38-55.6 10(-9) M), or physiological doses of testosterone (0.35 10(-6) M, in the range found in vivo before ovulation) were able to induce a similar decrease of oocyte cAMP level without inducing GVBD. Under the same experimental conditions estradiol (0.35 10(-6) M) exhibited no action. These results suggest that some factor(s) originating in the follicle (FIF), inhibit the oocytes' tendency to accumulate cAMP before the final surge of 17 alpha, 20 beta-OH-P. This factor might be a follicular steroid such as testosterone or nonmaturing concentrations of 17 alpha, 20 beta-OH-P. Moreover our data favour the hypothesis that the final surge of 17 alpha, 20 beta-OH-P could induce distinct intraoocyte mechanisms: the first induces an irreversible blockage of cAMP level before the inhibitory action of the FIF is suppressed by ovulation, and the second mechanism leads to GVBD.

Opioid modulation of LHRH release in vitro depends upon levels of testosterone in vivo.

The in vitro release of LHRH from hypothalami of adult male rats (intact, 5-day castrates, 5-day castrates replaced with various doses of testosterone) was measured under basal conditions and after the addition of KCl, the opiate antagonist naloxone or the opiate agonist DAGO to the perifusion medium. Hypothalami from all treatment groups responded to 56 mM KCl with an increased output of LHRH. LHRH release was also induced by naloxone (10(-6)M), but only from tissues derived from intacts and castrates given physiological doses of testosterone. The opiate agonist DAGO (10(-6)M) did not alter the basal release of LHRH; it, however, caused a significant decrease in the K+-induced release of LHRH from hypothalami derived from intact rats and rats replaced with physiological levels of testosterone but not from those derived from castrate rats or castrate rats replaced with small amounts of testosterone. The specificity of this latter response was shown by its reversibility with naloxone. The lack of DAGO effects upon tissues from rats with low levels of steroid implied steroid dependency of the response to opioidergic influences and indeed, the response to DAGO was restored when testosterone was replaced at physiological doses. Measurement of hypothalamic LHRH content showed no significant differences between tissues obtained from intact, castrate and testosterone-replaced castrate rats. These in vitro data support the view that the inhibitory influence of opioids upon LHRH release depends on the presence of gonadal steroids in vivo.

Effects of oestradiol 17B, progesterone and testosterone upon proceptivity and receptivity in ovariectomized common marmosets (Callithrix jacchus)

The sexual behaviour of eight pairs of marmosets was observed during blocks of 30 minute tests after the ovariectomized female partners were treated with physiological doses of testosterone, oestradiol and progesterone. The effects of an intra-vaginal progesterone treatment were also investigated. Pre-ovulatory levels of oestradiol significantly increased the females' proceptive and receptive tongue-flicking displays and reduced the percentage of mounts refused. Mid-luteal levels of progesterone, by comparison, virtually abolished proceptive and receptive tongue-flicking and significantly increased mount refusals. Testosterone treatment was without effect. Vaginal application of progesterone unlike subcutaneous implantation of the hormone did not significantly alter the females' sexual behaviour. These results indicate that central actions of oestradiol and progesterone upon proceptivity and receptivity may occur in this primate, although further research using intra-cranial implants of these steroids is required to test this hypothesis.

Gonadal hormones induce dendritic growth in the adult avian brain.

Ovariectomized adult female canaries were treated with physiological doses of testosterone, dihydrotestosterone, or estradiol. Singing, which is typical of males, occurred in the testosterone-treated birds but not in any of the other birds. The effect of these hormones was assessed on dendrites from a class of neurons in the nucleus robustus archistriatalis (RA), a forebrain nucleus for song control. The RA neurons of the testosterone-treated birds had dendritic trees resembling those of intact males. The RA neurons of the estradiol- and dihydrotesterone-treated birds resembled those of intact females. All hormone-treated groups had dendrites that were significantly longer than those of untreated ovariectomized females. Thus gonadal hormones induce dendritic growth in the adult avian brain.

An effect of castration and testosterone replacement on a circadian pacemaker in mice (Mus musculus).

Castration of mice in freerunning conditions (total darkness, DD) causes a reduction of running wheel activity in the beginning of the active period (alpha) and stimulates activity at the end of alpha. Simultaneously, the period (tau) of the freerunning rhythm is increased. Both effects are abolished by implantation of a Silastic capsule from which a physiological dose of testosterone is released at a constant rate. The results are tentatively explained by differential endocrine influences on two oscillating components in the pacemaker of the circadian activity rhythm.