Abstract: Adiponectin, an adipose-specific secretory protein, exhibits antidiabetic and antiatherogenic properties. In the present study, we examined the effects of sex hormones on the regulation of adiponectin production. Plasma adiponectin concentrations were significantly lower in 442 men (age, 52.6 ± 11.9 years [mean ± SD]) than in 137 women (53.2 ± 12.0 years) but not different between pre- and postmenopausal women. In mice, ovariectomy did not alter plasma adiponectin levels. In contrast, high levels of plasma adiponectin were found in castrated mice. Testosterone treatment reduced plasma adiponectin concentration in both sham-operated and castrated mice. In 3T3-L1 adipocytes, testosterone reduced adiponectin secretion into the culture media, using pulse-chase study. Castration-induced increase in plasma adiponectin was associated with a significant improvement of insulin sensitivity. Our results indicate that androgens decrease plasma adiponectin and that androgen-induced hypoadiponectinemia may be related to the high risks of insulin resistance and atherosclerosis in men.

Abstract: Steroid hormones, particularly estrogens and glucocorticoids, may play roles in the pathogenesis of neurodegenerative disorders, but their mechanisms of action are not known. We report that estrogens protect cultured hippocampal neurons against glutamate toxicity, glucose deprivation, FeSO4 toxicity, and amyloid beta-peptide (A beta) toxicity. The toxicity of each insult was significantly attenuated in cultures pretreated for 2 h with 100 nM-10 microM 17 beta-estradiol, estriol, or progesterone. In contrast, corticosterone exacerbated neuronal injury induced by glutamate, FeSO4, and A beta. Several other steroids, including testosterone, aldosterone, and vitamin D, had no effect on neuronal vulnerability to the different insults. The protective actions of estrogens and progesterone were not blocked by actinomycin D or cycloheximide. Lipid peroxidation induced by FeSO4 and A beta was significantly attenuated in neurons and isolated membranes pretreated with estrogens and progesterone, suggesting that these steroids possess antioxidant activities. Estrogens and progesterone also attenuated A beta- and glutamate-induced elevation of intracellular free Ca2+ concentrations. We conclude that estrogens, progesterone, and corticosterone can directly affect neuronal vulnerability to excitotoxic, metabolic, and oxidative insults, suggesting roles for these steroids in several different neurodegenerative disorders.

Abstract: Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-alpha. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12-14 weeks) and late (34-36 weeks) gestation. Body composition, plasma TNF-alpha, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-alpha was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 +/- 1.2 vs. 8.1 +/- 0.8 10(-2) mg. kg(-1) fat-free mass. min(-1). microU(-1). ml(-1)). TNF-alpha, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-alpha (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-alpha was inversely correlated with insulin sensitivity (r = -0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF-alpha from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r = -0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF-alpha was the most significant independent predictor of insulin sensitivity (r = -0.67, P < 0.0001), even after adjustment for fat mass by covariance (r = 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF-alpha in a new paradigm to explain insulin resistance in pregnancy.

Abstract: The endocrine system coordinates development of the mammary gland with reproductive development and the demand of the offspring for milk. Three categories of hormones are involved. The levels of the reproductive hormones, estrogen, progesterone, placental lactogen, prolactin, and oxytocin, change during reproductive development or function and act directly on the mammary gland to bring about developmental changes or coordinate milk delivery to the offspring. Metabolic hormones, whose main role is to regulate metabolic responses to nutrient intake or stress, often have direct effects on the mammary gland as well. The important hormones in this regard are growth hormone, corticosteroids, thyroid hormone, and insulin. A third category of hormones has recently been recognized, mammary hormones. It currently includes growth hormone, prolactin, PTHrP, and leptin. Because a full-term pregnancy in early life is associated with a reduction in breast carcinogenesis, an understanding of the mechanisms by which these hormones bring about secretory differentiation may offer clues to the prevention of breast cancer.

Abstract: OBJECTIVE —To determine the prospective association between endogenous sex hormones and the development of type 2 diabetes in older men and women. RESEARCH DESIGN AND METHODS —A standardized medical history was obtained, an oral glucose tolerance test was performed, and plasma samples for sex hormones and covariates were collected from ambulatory, community-dwelling men and women at baseline from 1984 to 1987. Approximately 8 years later (1992–1996), another medical history was obtained, an oral glucose tolerance test was performed, fasting and 2-h insulin levels were measured, and the homeostasis model assessment for insulin resistance (HOMA-IR) was evaluated. This report is based on the 294 men and 233 women, aged 55–89 years, who completed both visits and who did not have diabetes as determined by history or glucose tolerance test at baseline, as well as women who were postmenopausal and not taking replacement estrogen. RESULTS —In age-adjusted correlation analyses, total testosterone was inversely and significantly related to subsequent levels of fasting and postchallenge glucose and insulin in men, whereas bioavailable testosterone and bioavailable estradiol were positively and significantly related to fasting and postchallenge glucose and insulin in women (all P <0.05). There was similar significant association with insulin resistance (HOMA-IR) in unadjusted and multiply adjusted analyses ( P <0.05). There were 26 men and 17 women with new (incident) diabetes. The odds for new diabetes were 2.7 (95% CI 1.1–6.6) for men in the lowest quartile of total testosterone and 2.9 (1.1–8.4) for women in the highest quartile of bioavailable testosterone. CONCLUSIONS —Low testosterone levels in men and high testosterone levels in women predict insulin resistance and incident type 2 diabetes in older adults.

Abstract: In this review we summarize data obtained from animal studies showing that glucocorticoid hormones have a facilitatory role on behavioural responses to psychostimulant drugs such as locomotor activity, self-administration and relapse. These behavioural effects of glucocorticoids involve an action on the meso-accumbens dopamine system, one of the major systems mediating the addictive properties of drugs of abuse. The effects of glucocorticoids in the nucleus accumbens are site-specific; these hormones modify dopamine transmission in only the shell of this nucleus without modifying it in the core. Studies with corticosteroid receptor antagonists suggest that the dopaminergic effects of these hormones depend mostly on glucocorticoid, not on mineralocorticoid receptors. These data suggest that an increase in glucocorticoid hormones, through an action on mesolimbic dopamine neurons, could increase vulnerability to drug abuse. We also discuss the implications of this finding with respect to the physiological role of glucocorticoids. It is proposed that an increase in glucocorticoids, by activating the reward pathway, could counteract the aversive effects of stress. During chronic stress, repeated increases in glucocorticoids and dopamine would result in sensitization of the reward system. This sensitized state, which can persist after the end of the stress, would render the subject more responsive to drugs of abuse and consequently more vulnerable to the development of addiction.

Abstract: Thyroxine and tri-iodothyronine are essential for normal organ growth, development and function. These hormones regulate the basal metabolic rate of all cells, including hepatocytes, and thereby modulate hepatic function; the liver in turn metabolizes the thyroid hormones and regulates their systemic endocrine effects. Thyroid dysfunction may perturb liver function, liver disease modulates thyroid hormone metabolism, and a variety of systemic diseases affect both organs. We highlight the intricate relations between the thyroid gland and the liver in health and disease.

Abstract: Thyroid hormone is essential for normal brain development. However, little is known about the molecular and cellular mechanisms that mediate thyroid hormone action on the developing brain or the developmental events selectively affected. Consequently, although a large number of environmental chemicals interfere with the thyroid system, there are few neurodevelopmental end points to recruit for toxicological studies. Therefore, my goal here is to review what is known about the relative timing of normal brain construction and thyroid system development, with special focus on the period of in utero development in humans and the comparable developmental period in laboratory rats. These data are presented as a timeline to aid in the identification of thyroid-sensitive end points in brain development and to highlight important data gaps. I discuss the known influence of certain synthetic chemicals on the thyroid system and include a brief review of the effects of developmental exposure to chemicals on thyroid system function. The relationship between the thyroid hormone and retinoic acid systems, as well as the thyroid hormone sensitivity of the developing cochlea, is also discussed.

Abstract: Among the most critical actions of thyroid hormone in man and other mammals are those exerted on brain development. Severe hypothyroidism during the neonatal period leads to structural alterations, including hypomyelination and defects of cell migration and differentiation, with long-lasting, irreversible effects on behavior and performance. A complex regulatory mechanism operates in brain involving regulation of the concentration of the active hormone, T3, and the control of gene expression. Most brain T3 is formed locally from its precursor, T4, by the action of type II deiodinase which is expressed in glial cells, tanycytes, and astrocytes. Type III deiodinase (DIII) is also involved in the regulation of T3 concentrations, especially during the embryonic and early post-natal periods. DIII is expressed in neurons and degrades T4 and T3 to inactive metabolites. The action of T3 is mediated through nuclear receptors, which are expressed mainly in neurons. The receptors are ligand-modulated transcription factors, and a number of genes have been identified as regulated by thyroid hormone in brain. The regulated genes encode proteins of myelin, mitochondria, neurotrophins and their receptors, cytoskeleton, transcription factors, splicing regulators, cell matrix proteins, adhesion molecules, and proteins involved in intracellular signaling pathways. The role of thyroid hormone is to accelerate changes of gene expression that take place during development. Surprisingly, null-mutant mice for the T3 receptors show almost no signs of central nervous system involvement, in contrast with the severe effects of hypothyroidism. The resolution of this paradox is essential to understand the role of thyroid hormone and its receptors in brain development and function.

Abstract: Steroid hormones regulate cellular processes by binding to intracellular receptors that, in turn, interact with discrete nucleotide sequences to alter gene expression. Because most steroid receptors in target cells are located in the cytoplasm, they need to get into the nucleus to alter gene expression. This process typically takes at least 30 to 60 minutes. In contrast, other regulatory actions of steroid hormones are manifested within seconds to a few minutes. These time periods are far too rapid to be due to changes at the genomic level and are therefore termed nongenomic or rapid actions, to distinguish them from the classical steroid hormone action of regulation of gene expression. The rapid effects of steroid hormones are manifold, ranging from activation of mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC), and heterotrimeric guanosine triphosphate-binding proteins (G proteins). In some cases, these rapid actions of steroids are mediated through the classical steroid receptor that can also function as a ligand-activated transcription factor, whereas in other instances the evidence suggests that these rapid actions do not involve the classical steroid receptors. One candidate target for the nonclassical receptor-mediated effects are G protein-coupled receptors (GPCRs), which activate several signal transduction pathways. One characteristic of responses that are not mediated by the classical steroid receptors is insensitivity to steroid antagonists, which has contributed to the notion that a new class of steroid receptors may be responsible for part of the rapid action of steroids. Evidence suggests that the classical steroid receptors can be localized at the plasma membrane, where they may trigger a chain of reactions previously attributed only to growth factors. Identification of interaction domains on the classical steroid receptors involved in the rapid effects, and separation of this function from the genomic action of these receptors, should pave the way to a better understanding of the rapid action of steroid hormones.

Abstract: The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underlying mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationships between thyroid hormones and the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is consistently reported while decreased cortical 5-HT concentrations and 5-HT2A receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone administration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system. Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, and by increasing 5-HT2 receptor sensitivity.

Abstract: Steroid hormones regulate cellular processes by binding to intracellular receptors that, in turn, interact with discrete nucleotide sequences to alter gene expression. Because most steroid receptors in target cells are located in the cytoplasm, they need to get into the nucleus to alter gene expression. This process typically takes at least 30 to 60 minutes. In contrast, other regulatory actions of steroid hormones are manifested within seconds to a few minutes. These time periods are far too rapid to be due to changes at the genomic level and are therefore termed nongenomic or rapid actions, to distinguish them from the classical steroid hormone action of regulation of gene expression. The rapid effects of steroid hormones are manifold, ranging from activation of mitogen-activated protein kinases (MAPKs), adenylyl cyclase (AC), protein kinase C (PKC), and heterotrimeric guanosine triphosphate-binding proteins (G proteins). In some cases, these rapid actions of steroids are mediated through the classical steroid receptor that can also function as a ligand-activated transcription factor, whereas in other instances the evidence suggests that these rapid actions do not involve the classical steroid receptors. One candidate target for the nonclassical receptor-mediated effects are G protein-coupled receptors (GPCRs), which activate several signal transduction pathways. One characteristic of responses that are not mediated by the classical steroid receptors is insensitivity to steroid antagonists, which has contributed to the notion that a new class of steroid receptors may be responsible for part of the rapid action of steroids. Evidence suggests that the classical steroid receptors can be localized at the plasma membrane, where they may trigger a chain of reactions previously attributed only to growth factors. Identification of interaction domains on the classical steroid receptors involved in the rapid effects, and separation of this function from the genomic action of these receptors, should pave the way to a better understanding of the rapid action of steroid hormones.

Abstract: Prolactin, growth hormone and placental lactogen are members of a family of polypeptide hormones which share structural similarities and biological activities. Numerous functions have been attributed to these hormones, among which stand out their recently discovered effects on angiogenesis, the process by which new blood vessels are formed from the pre-existing microvasculature. Prolactin, growth hormone and placental lactogen, along with two non-classical members of the family, proliferin and proliferin-related protein, can act both as circulating hormones and as paracrine/autocrine factors to either stimulate or inhibit various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, migration, protease production and apoptosis. Such opposing actions can reside in similar but independent molecules, as is the case of proliferin and proliferin-related protein, which stimulate and inhibit angiogenesis respectively. The potential to exert opposing effects on angiogenesis can also reside within the same molecule as the parent protein can promote angiogenesis (i.e. prolactin, growth hormone and placental lactogen), but after proteolytic processing the resulting peptide fragment acquires anti-angiogenic properties (i.e. 16 kDa prolactin, 16 kDa growth hormone and 16 kDa placental lactogen). The unique properties of the peptide fragments versus the full-length molecules, the regulation of the protease responsible for specific protein cleavage, the selective expression of specific receptors and their associated signal transduction pathways are issues that are being investigated to further establish the precise contribution of these hormones to angiogenesis under both physiological and pathological situations. In this review article, we summarize the known and speculative issues underlying the effects of the prolactin, growth hormone and placental lactogen family of proteins on angiogenesis, and address important remaining enigmas in this field of research.

Abstract: The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSH/TSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pitdw/pitdw) or of a functional TSHR (tshrhyt/tshrhyt and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.

Abstract: Changes in thyroid status markedly influence cardiac contractile and electrical activity. The predominant route by which triiodothyronine (T3) affects cardiac action is by exerting a direct effect in cardiac myocytes through binding to thyroid hormone nuclear receptor isoforms. In addition, T3 modifies cardiac action by alterations in the vascular system and decreases afterload of the left ventricle by subtle modification related to the sympathetic system. The importance of T3 nuclear receptor function has been further demonstrated by studies in null mutant mice in which thyroid hormone receptor-alpha (TRalpha) and thyroid hormone receptor-beta (TRbeta) or both are deleted. In mice with null mutations of the TRalpha, a markedly decreased heart rate and decreased contractile performance occurs in contrast to mice with deletion of TRbeta that have a normal heart rate and a normal contractile performance under baseline conditions. Thyroid hormone influences on heart rate are exerted by specific ion channel proteins in the sinus node of the left atrium. Some of these ion channels, such as the IF channel, the sodium/calcium exchanger protein, the L-type and T-type calcium channel, and the ryanodine channel are targets for thyroid hormone action. The increased contractile performance induced by T3 is largely mediated by increased expression of the calcium adenosine triphosphatase (ATPase) of the sarcoplasmic reticulum and decreased expression of phospholamban and T3 increases the phosphorylation status of phospholamban. The significant influence that is exerted by thyroid hormone signaling system related to contractile and electrical activity in the heart and the molecular basis for these alterations continues to be clarified.

Abstract: Steroids play a role as essential hormones in plants as well as in animals. Plants produce numerous steroids and sterols, some of which are recognized as hormones in animals ([Geuns, 1978][1]; [Jones and Roddick, 1988][2]). Brassinolide (BL) is the most bioactive form of the growth-promoting plant

Abstract: BACKGROUND. Long-term thyroid hormone (TH) therapy aiming at the suppression of serum thyrotropin (TSH) has been traditionally used in the management of well differentiated thyroid cancer (ThyrCa). However, formal validation of the effects of thyroid hormone suppression therapy (THST) through randomized controlled trials is lacking. Additionally, the role--if any--of TSH effect at low ambient concentrations upon human thyroid tumorigenesis remains unclear. AIM: Evaluation of the effect of THST on the clinical outcomes of papillary and/or follicular ThyrCa. METHODS. By using a quantitative research synthesis approach in a cumulative ThyrCa cohort, we evaluated the effect of THST on the likelihood of major adverse clinical events (disease progression/recurrence and death). A total of 28 clinical trials published during the period 1934-2001 were identified; only 10 were amenable to meta-analysis. Causality was assessed by Hill criteria. RESULTS: Out of 4, 174 patients with ThyrCa, 2, 880 (69%) were reported ...

Abstract: Extranuclear or nongenomic actions of thyroid hormone do not require formation of a nuclear complex between the hormone and its traditional 3,5,3'-triiodo-L-thyronine (T3) receptor (TR). Among nongenomic actions of iodothyronines that are relevant to the heart are those on membrane ion channels or pumps. These include stimulation of the sarcolemmal Na+ channel, inward-rectifying K+ channel, voltage-activated potassium channels, and calcium pump (Ca2+-adenosine triphosphatases [ATPases]) and have been shown in intact cells or isolated membranes. Because circulating levels of thyroid hormone are relatively stable, actions on channels or pumps may contribute to setting of basal activity of these transport functions. The mechanism of certain of these membrane effects may involve actions of the hormone on signal transducing protein kinases that modulate levels of activity of plasma membrane channels. Thyroid hormone nongenomically enhances myocardial contractility in isolated myocardial cells, in the isolated perfused rat heart and in human subjects. Iodothyronines also decrease vasomotor tone in a variety of models and in man by a mechanism independent of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), or nitric oxide generation. Acutely increased myocardial mitochondrial respiration has been demonstrated in isolated organelles exposed to thyroid hormone. Genomic and nongenomic actions of thyroid hormone can interface, e.g., at the level of sarcoplasmic reticulum Ca2+-ATPase, where gene expression is regulated by the TR-T3 complex and activity of the enzyme can be modulated nongenomically. The relevance of nongenomic actions of thyroid hormone on the heart has been demonstrated in acute effects of the hormone on cardiac output and systemic vascular resistance in human subjects.

Abstract: Growth hormone, prolactin, the fish hormone, somatolactin, and related mammalian placental hormones, including placental lactogen, form a family of polypeptide hormones that share a common tertiary structure. They produce their biological effects by interacting with and dimerizing specific single transmembrane-domain receptors. The receptors belong to a superfamily of cytokine receptors with no intrinsic tyrosine kinase, which use the Jak-Stat cascade as a major signalling pathway. Hormones and receptors are thought to have arisen as a result of gene duplication and subsequent divergence early in vertebrate evolution. Mammalian growth hormone and prolactin show a slow basal evolutionary rate of change, but with episodes of accelerated evolution. These occurred for growth hormone during the evolution of the primates and artiodactyls and for prolactin in lineages leading to rodents, elephants, ruminants, and man. Placental lactogen has probably evolved independently on three occasions, from prolactin in rodents and ruminants and from growth hormone in man. Receptor sequences also show variable rates of evolution, corresponding partly, but not completely, with changes in the ligand. A principal biological role of growth hormone, the control of postnatal growth, has remained quite consistent throughout vertebrate evolution and is largely mediated by insulin-like growth factors. Prolactin has many and diverse roles. In relation to lactation, the relative roles of growth hormone and prolactin vary between species. Correlation between the molecular and functional evolution of these hormones is very incomplete, and it is likely that many important functional adaptations involved changes in regulatory elements, for example, altering tissue of origin or posttranscriptional processing, rather than change of the structures of the proteins themselves.

Abstract: Numerous investigations have confirmed an important role for multidrug-resistance gene 1-type P-glycoproteins (MDR1-type P-gps) in the blood-brain barrier, protecting the brain against the accumulation of a wide range of toxic xenobiotics and drugs. Several studies have provided evidence in vitro that certain steroid hormones are transported by MDR1-type P-gps; however, the question of whether this might also apply to the situation in vivo still remained to be determined. We used mice deficient for both murine mdr1a and mdr1b P-gps [mdr1a/1b(-/-)] to determine the uptake of [3H]-cortisol, [3H]-corticosterone, [3H]-aldosterone and [3H]-progesterone into the plasma, brain, testes, liver, spleen, pituitary and adrenal glands. We provide evidence that the access of the endogenous steroid hormones corticosterone, cortisol and aldosterone is regulated by MDR1-type P-gps in vivo. As peripherally administered steroid hormones accumulate in the brain of mice deficient for MDR1-type P-gps, mdr1a/1b proteins are likely to transport these hormones out of the brain, providing a kinetic barrier to their entry. Intracerebral progesterone concentrations are influenced by MDR1-type P-gp function as well; however, the effects are only small. In addition, all four endogenous glucocorticoid hormones accumulated in the testes of mdr1a/1b(-/-) mice. Our findings underline the importance of MDR1-type P-gps as an endogenous barrier system controlling the access of endogenous steroid hormones at the blood-brain barrier to maintain homeostatic control and to protect central nervous system neurones.

Abstract: The orexigenic and anabolic gastric hormone ghrelin is secreted in response to acute and chronic energy requirements. While pre-prandial increases and post-prandial decreases of plasma ghrelin levels in rodents and humans seem to indicate a role for the novel peptide hormone as an afferent meal initiator or “hunger hormone”, the precise mechanisms which are suppressing ghrelin secretion in response to caloric intake remain largely unknown. We show here that human ghrelin levels decrease by almost 50% under hyperinsulinemic euglycemic clamp conditions (no.=4, p=0.001), revealing physiologically relevant increases of insulin levels as an independent determinant of circulating ghrelin levels. In a second study, 3–4-fold increased plasma free fatty acid levels, as another metabolic candidate for the modulation of circulating ghrelin concentrations, were generated by constant lipid infusion, but failed to change plasma ghrelin. Simultaneous elevation of free fatty acids and insulin again markedly decreased ghrelin concentration (no.=4, p=0.01). Insulin induced suppression of circulating ghrelin levels (or the lack thereof) could be a mechanism with relevance for the understanding of the (patho-) physiology of meal initiation and termination, the pathogenesis of the metabolic syndrome and for the development of respective therapeutic perspectives.

Abstract: Endocrine-disrupting chemicals (EDCs) are hormone-like agents present in the environment that alter the endocrine system of wildlife and humans. Most EDCs have potencies far below those of the natural hormone 17beta-E2 when acting through the classic estrogen receptors (ERs). Here, we show that the environmental estrogen Bisphenol-A and the native hormone 17beta-E2 activate the transcription factor, cAMP-responsive element binding protein (CREB) with the same potency. Phosphorylated CREB (P-CREB) was increased after only a 5-minute application of either BPA or 17beta-E2 in a calcium-dependent manner. The effect was reproduced by the membrane-impermeable molecule E2 conjugated to horseradish peroxidase (E-HRP). The increase in P-CREB was not modified by the anti-estrogen ICI 182,780. Therefore, low-dose of BPA activates the transcription factor CREB via an alternative mechanism, involving a non-classical membrane estrogen receptor. Because these effects are elicited at concentrations as low as 10(-9) M, this observation is of environmental and public health relevance.