Dihydrotestosterone

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Androgen modulates the kinetics of the delayed rectifying K+ current in the electric organ of a weakly electric fish

DEVELOPMENTAL NEUROBIOLOGY, Issue 12 2007
M. Lynne McAnelly
Abstract Weakly electric fish such as Sternopygus macrurus utilize a unique signal production system, the electric organ (EO), to navigate within their environment and to communicate with conspecifics. The electric organ discharge (EOD) generated by the Sternopygus electric organ is quasi-sinusoidal and sexually dimorphic; sexually mature males produce long duration EOD pulses at low frequencies, whereas mature females produce short duration EOD pulses at high frequencies. EOD frequency is set by a medullary pacemaker nucleus, while EOD pulse duration is determined by the kinetics of Na+ and K+ currents in the electric organ. The inactivation of the Na+ current and the activation of the delayed rectifying K+ current of the electric organ covary with EOD frequency such that the kinetics of both currents are faster in fish with high (female) EOD frequency than those with low (male) EOD frequencies. Dihydrotestosterone (DHT) implants masculinize the EOD centrally by decreasing frequency at the pacemaker nucleus (PMN). DHT also acts at the electric organ, broadening the EO pulse, which is at least partly due to a slowing of the inactivation kinetics of the Na+ current. Here, we show that chronic DHT treatment also slows the activation and deactivation kinetics of the electric organ's delayed rectifying K+ current. Thus, androgens coregulate the time-varying kinetics of two distinct ion currents in the EO to shape a sexually dimorphic communication signal. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source]


Masculinizing Effect of Dihydrotestosterone on Growth Hormone Secretion is Inhibited in Ovariectomized Rats with Anterolateral Deafferentation of the Medial Basal Hypothalamus or in Intact Female Rats

JOURNAL OF NEUROENDOCRINOLOGY, Issue 4 2000
Tamura
There is a striking sex difference in the pattern of growth hormone (GH) secretion in rats. Our previous studies showed that short-term administration of pharmacological doses of testosterone or dihydrotestosterone (DHT) masculinized the GH secretory pattern in ovariectomized (OVX) rats. The locus where testosterone or DHT interacts with the somatotropic axis is believed to be the hypothalamus. To obtain insights into this phenomenon, we administered a single dose of DHT s.c. to adult OVX rats at 0.01, 0.1 or 1 mg/rat. Blood GH concentrations were measured in unanaesthetized rats. Six to12 h after the s.c. administration of all three doses of DHT, the GH secretory pattern revealed a male-like secretory pattern as shown by episodic bursts occurring at 2,3-h intervals with low or undetectable trough levels. When anterolateral deafferentation of the medial basal hypothalamus (ALC) was performed, the blood concentrations revealed irregularly occurring small fluctuations, instead of the usual high bursts, but the basal GH concentration was significantly higher than that of OVX-sham-operated rats. DHT treatment did not elicit pulsatile GH secretion or alter GH concentrations in OVX rats with ALC. When intact adult female rats received DHT at a dose of 1 mg/rat, the male-like GH secretory pattern was not induced. These results suggest that neural inputs from the anterolateral direction to the medial basal hypothalamus are necessary for the masculinizing effect of DHT on the GH secretory pattern in OVX rats, and that oestrogen in intact female rats prevents the masculinizing effect of DHT. [source]


Fine temporal analysis of DHT transcriptional modulation of the ATM/Gadd45g signaling pathways in the mouse uterus

MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 3 2009
Mahinè Ivanga
Abstract In rodents, the uterus of a mature female undergoes changes during the uterine cycle, under the control of steroid hormones. 5,-Dihydrotestosterone (DHT) is recognized to play an important role in the regulation of androgen action in normal endometrium. Using microarray technology, a screening analysis of genes responding to DHT in the uterus of ovariectomized mice, has allowed us to highlight multiple genes of the ATM/Gadd45g pathway that are modulated following exposure to DHT. Two phases of regulation were identified. In the early phase, the expression of genes involved in the G2/M arrest is rapidly increased, followed by the repression of genes of the G1/S checkpoint, and by the induction of transcriptional regulators. Later, i.e. from 12 to 24 hr, genes involved in G2/M transition, cytoarchitectural and lipid-related genes are stimulated by DHT while immunity-related genes appear to be differentially regulated by the hormone. These results show that a physiological dose of DHT induces the transcription of genes promoting the cell cycle progression in mice. Profile determination of temporal uterine gene expression at the transcriptional level enables us to suggest that the DHT modulation of genes involved in ATM/Gadd45g signaling in an ATM- or p53-independent manner, could play an important role in the cyclical changes of uterine cells in the mouse uterus. Mol. Reprod. Dev. 76: 278,288, 2009. © 2008 Wiley-Liss, Inc. [source]


Dihydrotestosterone activates the MAPK pathway and modulates maximum isometric force through the EGF receptor in isolated intact mouse skeletal muscle fibres

THE JOURNAL OF PHYSIOLOGY, Issue 3 2010
M. M. Hamdi
It is generally believed that steroid hormones have both genomic and non-genomic (rapid) actions. Although the latter form an important component of the physiological response of these hormones, little is known about the cellular signalling pathway(s) mediating these effects and their physiological functions in adult mammalian skeletal muscle fibres. Therefore, the primary aim of this study was to investigate the non-genomic actions of dihydrotestosterone (DHT) and their physiological role in isolated intact mammalian skeletal muscle fibre bundles. Our results show that treating the fibre bundles with physiological concentrations of DHT increases both twitch and tetanic contractions in fast twitch fibres. However, it decreases them in slow twitch fibres. These changes in force are accompanied by an increase in the phosphorylation of MAPK/ERK1/2 in both fibre types and that of regulatory myosin light chains in fast twitch fibres. Both effects were insensitive to inhibitors of Src kinase, androgen receptor, insulin-like growth factor 1 receptor and platelet-derived growth factor receptor. However, they were abolished by the MAPK/ERK1/2 kinase inhibitor PD98059 and the epidermal growth factor (EGF) receptor inhibitor tyrphostin AG 1478. In contrast, testosterone had no effect on force and increased the phosphorylation of ERK1/2 in slow twitch fibres only. From these results we conclude that sex steroids have non-genomic actions in isolated intact mammalian skeletal muscle fibres. These are mediated through the EGF receptor and one of their main physiological functions is the enhancement of force production in fast twitch skeletal muscle fibres. [source]


Estrogen signaling and disruption of androgen metabolism in acquired androgen-independence during cadmium carcinogenesis in human prostate epithelial cells

THE PROSTATE, Issue 2 2007
Lamia Benbrahim-Tallaa
Abstract BACKGROUND Lethal prostate cancers often become androgen-independent due to androgen receptor (AR) overexpression. The role of cadmium in prostate tumor progression was determined. METHODS Control and cadmium-transformed prostate epithelial cells (CTPE) were compared for steroid-induced proliferation, steroid receptor expression, and androgen metabolism. RESULTS CTPE cells showed rapid proliferation in complete medium and sustained proliferation in steroid-reduced medium. Androgens stimulated significantly less cell proliferation and AR-related genes expression in CTPE cells. 5,-Dihydrotestosterone increased PSA expression more effectively in control cells. Flutamide reduced 5,-dihydrotestosterone-stimulated growth less effectively in CTPE cells compared to control. CTPE cells showed decreased p27 expression. Estrogen receptors were overexpressed and estradiol markedly stimulated proliferation in CTPE cells. In CTPE cells 5,-aromatase was markedly increased, while 5,-reductase was decreased. CONCLUSIONS Cadmium-induced malignant transformation stimulates androgen independence, unrelated to AR expression or activity. Increased estrogen receptor and 5,-aromatase expression suggest estrogen signaling may be critical to this process. Prostate © 2006 Wiley-Liss, Inc. [source]


Safety aspects of androgen treatment with 5,-dihydrotestosterone

ANDROLOGIA, Issue 6 2007
S. Sakhri
Summary 5,-Dihydrotestosterone (DHT), the most powerful naturally occurring androgen, is commercially available since 1982 as a gel. In view of its considerably higher biopotency (three to six times) than of testosterone, side effects, particularly on the main target organ of androgens, the prostate, are anticipated. In fact, DHT appears to be a prostate-sparing androgen for two reasons. Unlike testosterone, it does not undergo any further amplification in biopotency through 5, reduction in the prostate. Secondly, it is likely to lead to less aromatisation of testosterone to oestradiol in the prostate, thus reducing local oestradiol concentrations. Oestrogens have been implicated in the aetiology of benign prostate hyperplasia and prostate cancer. However, aromatisation of testosterone has appeared to be essential for the maintenance of bone mineral density. Administration of DHT reduces circulating oestradiol levels, but the levels remain above the levels critical for the antiresorptive effect of oestrogens on bone. Effects of DHT on erythropoiesis and on lipids are very similar to those of testosterone. Safety concerns regarding androgen treatment with DHT are similar to those of treatment with testosterone, while the effects of DHT on the prostate are likely to be less biopotent. [source]


Managing the progression of lower urinary tract symptoms/benign prostatic hyperplasia: therapeutic options for the man at risk

BJU INTERNATIONAL, Issue 2 2007
Mark Emberton
There are two fairly divergent reviews in this month's issue. The first is a paper which concentrates on the progression of LUTS and BPH. Previous papers on LUTS and BPH were focused on changes in urinary flow rates and symptom scores, a rather static view of things. The first author in this review introduced the concept of dynamic variables in LUTS and BPH, and this, along with the idea of progression of the disease which the MTOPS study brought to our notice, has lead to a major change to our approach to trials of therapy in LUTS and BPH. The second review is really statement of a theory, an expression of a concept being proposed by the author, which hopefully will be of interest to the reader. In benign prostatic hyperplasia (BPH), increased prostate volume has been shown to be associated with future symptom deterioration and progression to acute urinary retention (AUR) or BPH-related surgery. Dihydrotestosterone (DHT) is the primary androgen responsible for prostate growth. Inhibition by 5,-reductase inhibitors (5-ARIs) of the enzyme responsible for the production of DHT decreases prostate volume. This translates to an overall improvement in symptoms and a reduction in the risk of AUR and/or BPH-related surgery. Selective blockage of ,1 -adrenoceptors, principally in the region of the prostate, results in rapid symptom relief for the patient but this does not translate into a long-term reduction in the risk of AUR or BPH-related surgery. Given their different modes of action the rationale has always existed for using 5ARIs and ,-blockers together in men deemed to be both symptomatic and at risk of progression. The factors that predict this progression and the methods available to reduce the risk of it occurring are the subjects of this review. [source]


DHEA improves impaired activation of Akt and PKC ,/,-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats

ACTA PHYSIOLOGICA, Issue 3 2009
K. Sato
Abstract Aim:, Addition of dehydroepiandrosterone (DHEA) to a cultured skeletal muscle locally synthesizes 5,-dihydrotestosterone (DHT). It induced activation of glucose metabolism-related signalling pathway via protein kinase B (Akt) and protein kinase C zeta/lambda (PKC ,/,)-glucose transporter-4 (GLUT4) proteins. However, such an effect of DHEA in vivo remains unclear. Methods:, Using streptozotocin (STZ)-induced rats with type 1 diabetes mellitus, we tested the hypothesis that a single bout of DHEA injection in the rats improves hyperglycaemia and muscle GLUT4-regulated signalling pathway. After 1 week of STZ injection (55 mg kg,1) with male Wistar rats, fasting glucose concentrations were determined in a blood sample taken from the tail vein. Blood glucose levels were then monitored for 180 min after DHEA or sesame oil (control) was injected (n = 10 for each group). Results:, Blood glucose levels decreased significantly for 30,150 min after 2 mg DHEA injection in the STZ rats. In the skeletal muscle, expression and translocation of GLUT4 protein, phosphorylation of Akt and PKC ,/,, and phosphofructokinase and hexokinase enzyme activities increased significantly by DHEA injection. However, DHEA-induced improvements in Akt and PKC ,/,-GLUT4 pathways were blocked by a DHT inhibitor. Conclusion:, These results suggest that a single bout of DHEA injection can improve hyperglycaemia and activate the glucose metabolism-related signalling pathway via Akt and PKC ,/,-GLUT4 proteins of skeletal muscles in rats. Moreover, these results show that a DHEA-induced increase in muscle glucose uptake and utilization might contribute to improvement in hyperglycaemia in type 1 diabetes mellitus. [source]


Androgen replacement therapy improves function in male rat muscles independently of hypertrophy and activation of the Akt/mTOR pathway

ACTA PHYSIOLOGICA, Issue 4 2009
C. Hourdé
Abstract Aim:, We analysed the effect of physiological doses of androgens following orchidectomy on skeletal muscle and bone of male rats, as well as the relationships between muscle performance, hypertrophy and the Akt/mammalian target of rapamycin (mTOR) signalling pathway involved in the control of anabolic and catabolic muscle metabolism. Methods:, We studied the soleus muscle and tibia from intact rats (SHAM), orchidectomized rats treated for 3 months with vehicle (ORX), nandrolone decanoate (NAN) or dihydrotestosterone (DHT). Results:, Orchidectomy had very little effect on the soleus muscle. However, maximal force production by soleus muscle (+69%) and fatigue resistance (+35%) in NAN rats were both increased when compared with ORX rats. In contrast, DHT treatment did not improve muscle function. The relative number of muscle fibres expressing slow myosin heavy chain and citrate synthase activity were not different in NAN and ORX rats. Moreover, NAN and DHT treatments did not modify muscle weights and cross-sectional area of muscle fibres. Furthermore, phosphorylation levels of downstream targets of the Akt/mTOR signalling pathway, Akt, ribosomal protein S6 and eukaryotic initiation factor 4E-binding protein 1 were similar in muscles of NAN, DHT and ORX rats. In addition, trabecular tibia from NAN and DHT rats displayed higher bone mineral density and bone volume when compared with ORX rats. Only in NAN rats was this associated with increased bone resistance to fracture. Conclusion:, Physiological doses of androgens are beneficial to muscle performance in orchidectomized rats without relationship to muscle and fibre hypertrophy and activation of the Akt/mTOR signalling pathway. Taken together our data clearly indicate that the activity of androgens on muscle and bone could participate in the global improvement of musculoskeletal status in the context of androgen deprivation induced by ageing. [source]


Testosterone metabolites differentially maintain adult morphology in a sexually dimorphic neuromuscular system

DEVELOPMENTAL NEUROBIOLOGY, Issue 4 2010
Tom Verhovshek
Abstract The lumbar spinal cord of rats contains the sexually dimorphic, steroid-sensitive spinal nucleus of the bulbocavernosus (SNB). Androgens are necessary for the development of the SNB neuromuscular system, and in adulthood, continue to influence the morphology and function of the motoneurons and their target musculature. However, estrogens are also involved in the development of the SNB system, and are capable of maintaining function in adulthood. In this experiment, we assessed the ability of testosterone metabolites, estrogens and nonaromatizable androgens, to maintain neuromuscular morphology in adulthood. Motoneuron and muscle morphology was assessed in adult normal males, sham-castrated males, castrated males treated with testosterone, dihydrotestosterone, estradiol, or left untreated, and gonadally intact males treated with the 5,-reductase inhibitor finasteride or the aromatase inhibitor fadrozole. After 6 weeks of treatment, SNB motoneurons were retrogradely labeled with cholera toxin-HRP and reconstructed in three dimensions. Castration resulted in reductions in SNB target muscle size, soma size, and dendritic morphology. Testosterone treatment after castration maintained SNB soma size, dendritic morphology, and elevated target muscle size; dihydrotestosterone treatment also maintained SNB dendritic length, but was less effective than testosterone in maintaining both SNB soma size and target muscle weight. Treatment of intact males with finasteride or fadrozole did not alter the morphology of SNB motoneurons or their target muscles. In contrast, estradiol treatment was completely ineffective in preventing castration-induced atrophy of the SNB neuromuscular system. Together, these results suggest that the maintenance of adult motoneuron or muscle morphology is strictly mediated by androgens. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 70: 206,221, 2010. [source]


Organizational effects of maternal testosterone on reproductive behavior of adult house sparrows

DEVELOPMENTAL NEUROBIOLOGY, Issue 14 2008
Jesko Partecke
Abstract Despite the well-known, long-term, organizational actions of sex steroids on phenotypic differences between the sexes, studies of maternal steroids in the vertebrate egg have mainly focused on effects seen in early life. Long-term organizational effects of yolk hormones on adult behavior and the underlying mechanisms that generate them have been largely ignored. Using an experiment in which hand-reared house sparrows (Passer domesticus) from testosterone- or control-treated eggs were kept under identical conditions, we show that testosterone treatment in the egg increased the frequency of aggressive, dominance, and sexual behavior of 1-year-old, reproductively competent house sparrows. We also show that circulating plasma levels of progesterone, testosterone, 5,-dihydrotestosterone, and 17,-estradiol did not differ between treatment groups. Thus, a simple change in adult gonadal hormone secretion is not the primary physiological cause of long-term effects of maternal steroids on adult behavior. Rather, differences in adult behavior caused by exposure to yolk testosterone during embryonic development are likely generated by organizational modifications of brain function. Furthermore, our data provide evidence that hormone-mediated maternal effects are an epigenetic mechanism causing intra-sexual variation in adult behavioral phenotype. © 2008 Wiley Periodicals, Inc. Develop Neurobiol 2008 [source]


Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats

DEVELOPMENTAL NEUROBIOLOGY, Issue 10 2007
Mark D. Spritzer
Abstract Past research suggested that androgens may play a role in the regulation of adult neurogenesis within the dentate gyrus. We tested this hypothesis by manipulating androgen levels in male rats. Castrated or sham castrated male rats were injected with 5-Bromo-2,deoxyuridine (BrdU). BrdU-labeled cells in the dentate gryus were visualized and phenotyped (neural or glial) using immunohistochemistry. Castrated males showed a significant decrease in 30-day cell survival within the dentate gyrus but there was no significant change in cell proliferation relative to control males, indicating that androgens positively affect cell survival, but not cell proliferation. To examine the role of testosterone on hippocampal cell survival, males were injected with testosterone s.c. for 30 days starting the day after BrdU injection. Higher doses (0.5 and 1.0 mg/kg) but not a lower dose (0.25 mg/kg) of testosterone resulted in a significant increase in neurogenesis relative to controls. We next tested the role of testosterone's two major metabolites, dihydrotestosterone (DHT), and estradiol, upon neurogenesis. Thirty days of injections of DHT (0.25 and 0.50 mg/kg) but not estradiol (0.010 and 0.020 mg/kg) resulted in a significant increase in hippocampal neurogenesis. These results suggest that testosterone enhances hippocampal neurogenesis via increased cell survival in the dentate gyrus through an androgen-dependent mechanism. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007. [source]


Brain aromatase, 5,-reductase, and 5,-reductase change seasonally in wild male song sparrows: Relationship to aggressive and sexual behavior

DEVELOPMENTAL NEUROBIOLOGY, Issue 3 2003
Kiran K. Soma
Abstract In many species, territoriality is expressed only during the breeding season, when plasma testosterone (T) is elevated. In contrast, in song sparrows (Melospiza melodia morphna), males are highly territorial during the breeding (spring) and nonbreeding (autumn) seasons, but not during molt (late summer). In autumn, plasma sex steroids are basal, and castration has no effect on aggression. However, inhibition of aromatase reduces nonbreeding aggression, suggesting that neural steroid metabolism may regulate aggressive behavior. In wild male song sparrows, we examined the neural distribution of aromatase mRNA and seasonal changes in the activities of aromatase, 5,-, and 5,-reductase, enzymes that convert T to 17,-estradiol, 5,-dihydrotestosterone (5,-DHT, a potent androgen), or 5,-DHT (an inactive metabolite), respectively. Enzyme activities were measured in the diencephalon, ventromedial telencephalon (vmTEL, which includes avian amygdala), caudomedial neostriatum (NCM), and the hippocampus of birds captured during spring, molt, or autumn. Aromatase and 5,-reductase changed seasonally in a region-specific manner. Aromatase in the diencephalon was higher in spring than in molt and autumn, similar to seasonal changes in male sexual behavior. Aromatase activity in the vmTEL was high in both spring and autumn but significantly reduced at molt, similar to seasonal changes in aggression. 5,-Reductase was not elevated during molt, suggesting that low aggression during molt is not a result of increased inactivation of androgens. These data highlight the relevance of neural steroid metabolism to the expression of natural behaviors by free-living animals. © 2003 Wiley Periodicals, Inc. J Neurobiol 56: 209,221, 2003 [source]


N-cadherin is regulated by gonadal steroids in adult sexually dimorphic spinal motoneurons

DEVELOPMENTAL NEUROBIOLOGY, Issue 4 2001
Douglas A. Monks
Abstract Gonadal steroids influence the morphology and function of neurons in the adult spinal cord through cellular and molecular mechanisms that are largely unknown. The cadherins are cell adhesion molecules that participate in the formation and organization of the CNS during embryonic development, and recent evidence suggests that the cadherins continue to regulate neural structure and function in adulthood. Using degenerate oligonucleotides coding conserved regions of the catenin-binding domain of classical cadherins in a RT-PCR cloning strategy, we identified several cadherin subtypes, the most frequently cloned being N-, E-, and R-cadherin, suggesting that these are the major classical cadherin subtypes present in the adult male rat lumbosacral spinal cord. We then examined cadherin expression levels of these cadherin subtypes under steroid conditions known to induce plastic changes in spinal motoneurons. Semiquantitative PCR revealed that mRNA levels of N-cadherin, but not E-cadherin or R-cadherin, are elevated in castrated rats treated with testosterone, 17,-estradiol, or dihydrotestosterone relative to castrate rats not treated with steroids. Immunolocalization of N-cadherin revealed that steroid treatment increased N-cadherin expression levels in functionally related neural populations whose morphology and function are regulated by steroids. These results suggest a role for N-cadherin in steroid-induced neuroplastic change in the adult lumbar spinal cord. © 2001 John Wiley & Sons, Inc. J Neurobiol 47: 255,264, 2001 [source]


Detection of environmental androgens: A novel method based on enzyme-linked immunosorbent assay of spiggin, the stickleback (Gasterosteus aculeatus) glue protein

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2002
Ioanna Katsiadaki
Abstract We report the development and validation of a novel in vivo biomarker test for waterborne androgens. During breeding, male sticklebacks (Gasterosteus aculeatus) manufacture a glue protein, spiggin, in their kidneys that they use to build their nests. Spiggin production is under the control of androgens. Until now, however, it has only been possible to quantify its production by measurement of the height of kidney epithelial cells. In the present study, we report the development of an enzyme-linked immunosorbent assay (ELISA) for spiggin and demonstrate its application to the measurement of spiggin in the kidneys of female sticklebacks that have been exposed to androgens in water. Results from the ELISA procedure revealed a strong correlation with measurement of kidney epithelial cell height (r2 = 0.93). However, the ELISA was much quicker and had a considerably higher response range (100,000-fold vs fourfold). Clear, graded responses in spiggin production were obtained by exposing intact females to increasing concentrations of 17,-methyltestosterone and 5,-dihydrotestosterone over three-week test periods. The lowest effective concentrations for these two steroids were 100 ng/L and 3 ,g/L, respectively. Female sticklebacks that were exposed to pulp mill effluent also produced spiggin in their kidneys. Possession of an androgen-regulated protein by the female stickleback makes it a unique bioassay organism for detecting androgenic contamination in the aquatic environment. [source]


Changes in estrogenic and androgenic activities at different stages of treatment in wastewater treatment works

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 5 2002
Lucy A. Kirk
Abstract Estrogenic and androgenic activities of wastewater were determined during treatment in five wastewater treatment works (WWTWs) in the Untied Kingdom. With one exception, both estrogenic and androgenic activities decreased markedly as wastewater progressed through the plants; removal rates were generally 70% or higher, sometimes reaching 100%. Most of the reduction in activity occurred during secondary (biological) treatment. In both influents and effluents, estrogenic and androgenic activities were appreciably lower in samples collected in August, when the amount of rain had been substantial, compared with samples collected in April and May. Most final effluents contained very low (or nondetectable) estrogenic activity (undetectable to 13 ng/L of estradiol equivalents) and androgenic activity (undetectable to 143 ng/L of dihydrotestosterone [DHT] equivalents), although one (from a WWTW that had only primary treatment) contained relatively high activities (40 ng/L of estradiol equivalents; 4,033 ng/L of DHT equivalents). The type of treatment available at the various WWTWs also affected the activity of the final effluent. The biological significance of these results will depend upon which chemicals contribute to the estrogenic and androgenic activities, because of widely different potencies of different estrogenic chemicals, and on the degree of dilution of the effluents in their receiving waters. [source]


Estrogen modulates neuronal movements within the developing preoptic area,anterior hypothalamus

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2007
John Gabriel Knoll
Abstract The preoptic area,anterior hypothalamus (POA-AH) is characterized by sexually dimorphic features in a number of vertebrates and is a key region of the forebrain for regulating physiological responses and sexual behaviours. Using live-cell fluorescence video microscopy with organotypic brain slices, the current study examined sex differences in the movement characteristics of neurons expressing yellow fluorescent protein (YFP) driven by the Thy-1 promoter. Cells in slices from embryonic day 14 (E14), but not E13, mice displayed significant sex differences in their basal neuronal movement characteristics. Exposure to 10 nm estradiol-17, (E2), but not 100 nm dihydrotestosterone, significantly altered cell movement characteristics within minutes of exposure, in a location-specific manner. E2 treatment decreased the rate of motion of cells located in the dorsal POA-AH but increased the frequency of movement in cells located more ventrally. These effects were consistent across age and sex. To further determine whether early-developing sex differences in the POA-AH depend upon gonadal steroids, we examined cell positions in mice with a disruption of the steroidogenic factor-1 gene, in which gonads do not form. An early-born cohort of cells were labelled with the mitotic indicator bromodeoxyuridine (BrdU) on E11. More cells were found in the POA-AH of females than males on the day of birth (P0) regardless of gonadal status. These results support the hypothesis that estrogen partially contributes to brain sexual dimorphism through its influence on cell movements during development. Estrogen's influence may be superimposed upon a pre-existing genetic bias. [source]


Sexual dimorphism in the spontaneous recovery from spinal cord injury: a gender gap in beneficial autoimmunity?

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2002
Ehud Hauben
Abstract Immune cells have been shown to contribute to spontaneous recovery from central nervous system (CNS) injury. Here we show that adult female rats and mice recover significantly better than their male littermates from incomplete spinal cord injury (ISCI). This sexual dimorphism is wiped out and recovery is worse in adult mice deprived of mature T cells. After spinal cord contusion in adult rats, functional recovery (measured by locomotor scores in an open field) was significantly worse in females treated with dihydrotestosterone prior to the injury than in placebo-treated controls, and significantly better in castrated males than in their noncastrated male littermates. Post-traumatic administration of the testosterone receptor antagonist flutamide promoted the functional recovery in adult male rats. These results, in line with the known inhibitory effect of testosterone on cell-mediated immunity, suggest that androgen-mediated immunosuppression plays a role in ISCI-related immune dysfunction and can therefore partly explain the worse outcome of ISCI in males than in female. We suggest that females, which are more prone to develop autoimmune response than males, benefit from this response in cases of CNS insults. [source]


New developments in our understanding of acne pathogenesis and treatment

EXPERIMENTAL DERMATOLOGY, Issue 10 2009
Ichiro Kurokawa
Abstract:, Interest in sebaceous gland physiology and its diseases is rapidly increasing. We provide a summarized update of the current knowledge of the pathobiology of acne vulgaris and new treatment concepts that have emerged in the last 3 years (2005,2008). We have tried to answer questions arising from the exploration of sebaceous gland biology, hormonal factors, hyperkeratinization, role of bacteria, sebum, nutrition, cytokines and toll-like receptors (TLRs). Sebaceous glands play an important role as active participants in the innate immunity of the skin. They produce neuropeptides, excrete antimicrobial peptides and exhibit characteristics of stem cells. Androgens affect sebocytes and infundibular keratinocytes in a complex manner influencing cellular differentiation, proliferation, lipogenesis and comedogenesis. Retention hyperkeratosis in closed comedones and inflammatory papules is attributable to a disorder of terminal keratinocyte differentiation. Propionibacterium acnes, by acting on TLR-2, may stimulate the secretion of cytokines, such as interleukin (IL)-6 and IL-8 by follicular keratinocytes and IL-8 and -12 in macrophages, giving rise to inflammation. Certain P. acnes species may induce an immunological reaction by stimulating the production of sebocyte and keratinocyte antimicrobial peptides, which play an important role in the innate immunity of the follicle. Qualitative changes of sebum lipids induce alteration of keratinocyte differentiation and induce IL-1 secretion, contributing to the development of follicular hyperkeratosis. High glycemic load food and milk may induce increased tissue levels of 5,-dihydrotestosterone. These new aspects of acne pathogenesis lead to the considerations of possible customized therapeutic regimens. Current research is expected to lead to innovative treatments in the near future. [source]


Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris

EXPERIMENTAL DERMATOLOGY, Issue 10 2009
Bodo C. Melnik
Abstract:, It is the purpose of this viewpoint article to delineate the regulatory network of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signalling during puberty, associated hormonal changes in adrenal and gonadal androgen metabolism, and the impact of dietary factors and smoking involved in the pathogenesis of acne. The key regulator IGF-1 rises during puberty by the action of increased GH secretion and correlates well with the clinical course of acne. In acne patients, associations between serum levels of IGF-1, dehydroepiandrosterone sulphate, dihydrotestosterone, acne lesion counts and facial sebum secretion rate have been reported. IGF-1 stimulates 5,-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation and lipogenesis. Milk consumption results in a significant increase in insulin and IGF-1 serum levels comparable with high glycaemic food. Insulin induces hepatic IGF-1 secretion, and both hormones amplify the stimulatory effect of GH on sebocytes and augment mitogenic downstream signalling pathways of insulin receptors, IGF-1 receptor and fibroblast growth factor receptor-2b. Acne is proposed to be an IGF-1-mediated disease, modified by diets and smoking increasing insulin/IGF1-signalling. Metformin treatment, and diets low in milk protein content and glycaemic index reduce increased IGF-1 signalling. Persistent acne in adulthood with high IGF-1 levels may be considered as an indicator for increased risk of cancer, which may require appropriate dietary intervention as well as treatment with insulin-sensitizing agents. [source]


Androgen action on human skin , from basic research to clinical significance

EXPERIMENTAL DERMATOLOGY, Issue 2004
Christos C. Zouboulis
Abstract:, Androgens affect several functions of the human skin, such as sebaceous gland growth and differentiation, hair growth, epidermal barrier homeostasis and wound healing. Their effects are mediated by binding to nuclear androgen receptors. Androgen activation and deactivation are mainly intracellular events. They differ from cell type to cell type and between cells at different locations. The major circulating androgens, dehydroepiandrosterone sulfate and androstenedione, are predominantly produced in the adrenal glands, and testosterone and 5,-dihydrotestosterone are mainly synthesized in the gonads. Testosterone in women and 5,-dihydrotestosterone in both genders are also synthesized in the skin. Skin cells express all androgen metabolizing enzymes required for the independent cutaneous synthesis of androgens and the development of hyperandrogenism-associated conditions and diseases, such as seborrhea, acne, hirsutism and androgenetic alopecia. The major thrust of drug design for the treatment of androgen-associated disorders has been directed against several levels of androgen function and metabolism. Partial effectiveness has only been achieved either by androgen depletion, inhibition of androgen metabolism or blockade of the androgen receptor. [source]


17,-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo

EXPERIMENTAL DERMATOLOGY, Issue 4 2002
R. Hoffmann
Abstract: For topical treatment of androgenetic alopecia (AGA) in women, solutions containing either estradiol benzoate, estradiol valerate, 17,- or 17,-estradiol are commercially available in Europe and some studies show an increased anagen and decreased telogen rate after treatment as compared with placebo. At present it is not precisely known how estrogens mediate their beneficial effect on AGA-affected hair follicles. We have shown recently that 17,-estradiol is able to diminish the amount of dihydrotestosterone (DHT) formed by human hair follicles after incubation with testosterone, while increasing the concentration of weaker steroids such as estrogens. Because aromatase is involved in the conversion of testosterone to estrogens and because there is some clinical evidence that aromatase activity may be involved in the pathogenesis of AGA, we addressed the question whether aromatase is expressed in human hair follicles and whether 17,-estradiol is able to modify the aromatase activity. Herewith we were able to demonstrate that intact, microdissected hair follicles from female donors express considerably more aromatase activity than hair follicles from male donors. Using immunohistochemistry, we detected the aromatase mainly in the epithelial parts of the hair follicle and not in the dermal papilla. Furthermore, we show that in comparison to the controls, we noticed in 17,-estradiol-incubated (1 nM) female hair follicles a concentration- and time-dependent increase of aromatase activity (at 24 h: 1 nM = +18%, 100 nM = +25%, 1 µM = +57%; 24 h: 1 nM = +18%, 48 h: 1 nM = +25%). In conclusion, our ex vivo experiments suggest that under the influence of 17,-estradiol an increased conversion of testosterone to 17,-estradiol and androstendione to estrone takes place, which might explain the beneficial effects of estrogen treatment of AGA. [source]


The role of steroid hormones in the regulation of vasopressin and oxytocin release and mRNA expression in hypothalamo neurohypophysial explants from the rat

EXPERIMENTAL PHYSIOLOGY, Issue 2000
Celia D. Sladek
Vasopressin and oxytocin release from the neural lobe, and the vasopressin and oxytocin mRNA contents of the supraoptic and paraventricular nuclei are increased by hypertonicity of the extracellular fluid. The factors regulating these parameters can be conveniently studied in perifused explants of the hypothalamo-neurohypophysial system that include the supraoptic nucleus (but not the paraventricular nucleus) with its axonal projections to the neural lobe. Vasopressin and oxytocin release and the mRNA content of these explants respond appropriately to increases in the osmolality of the perifusate. This requires synaptic input from the region of the organum vasculosum of the lamina terminalis. Glutamate is a likely candidate for transmitting osmotic information from the organum vasculosum of the lamina terminalis to the magnocellular neurones, because agonists for excitatory amino acid receptors stimulate vasopressin and oxytocin release, and because increased vasopressin release and mRNA content induced in hypothalamo-neurohypophysial explants by a ramp increase in osmolality are blocked by antagonists of both NMDA (N -methyl-D-aspartate) and non-NMDA glutamate receptors. Osmotically stimulated vasopressin release is also blocked by testosterone, dihydrotestosterone, oestradiol and corticosterone. Both oestrogen and dihydrotestosterone block NMDA stimulation of vasopressin release, and in preliminary studies oestradiol blocked AMPA stimulation of vasopressin release. Thus, steroid inhibition of osmotically stimulated vasopressin secretion may reflect inhibition of mechanisms mediated by excitatory amino acids. Recent studies have demonstrated numerous mechanisms by which steroid hormones may impact upon neuronal function. Therefore, additional work is warranted to understand these effects of the steroid hormones on vasopressin and oxytocin secretion and to elucidate the potential contribution of these mechanisms to regulation of hormone release in vivo. [source]


Androgen receptor function is modulated by the tissue-specific AR45 variant

FEBS JOURNAL, Issue 1 2005
Isabelle Ahrens-Fath
A naturally occurring variant of the human androgen receptor (AR) named AR45 has been identified. It lacks the entire region encoded by exon 1 of the AR gene and is composed of the AR DNA-binding domain, hinge region and ligand-binding domain, preceded by a novel seven amino-acid long N-terminal extension. A survey of human tissues revealed that AR45 was expressed mainly in heart and skeletal muscle. In cotransfection experiments, AR45 inhibited AR function, an effect necessitating intact DNA- and ligand-binding properties. Overexpression of AR45 reduced the proliferation rate of the androgen-dependent LNCaP cells, in line with the repressive effects of AR45 on AR growth-promoting function. AR45 interacted with the AR N-terminal domain in two-hybrid assays, suggesting that AR inhibition was due to the formation of AR,AR45 heterodimers. Under conditions where the transcriptional coactivator TIF2 or the oncogene ,-catenin were overexpressed, AR45 stimulated androgen-dependent promoters in presence of dihydrotestosterone. AR45 activity was triggered additionally by the adrenal androgen androstenedione in presence of exogenous TIF2. Altogether, the data suggest an important role of AR45 in modulating AR function and add a novel level of complexity to the mode of action of androgens. [source]


Progestin upregulates G-protein-coupled receptor 30 in breast cancer cells

FEBS JOURNAL, Issue 10 2002
Tytti M. Ahola
A differential display method was used to study genes the expression of which is altered during growth inhibition induced by medroxyprogesterone acetate (MPA). A transcript of G-protein-coupled receptor 30 (GPR30) was upregulated by MPA in estrogen-treated MCF-7 breast cancer cells. Northern-blot analysis showed a progestin-specific primary target gene, which was enhanced by progesterone and different progestins, but not by dihydrotestosterone or dexamethasone, and which was abrogated by antiprogestin RU486. The dose-dependent and time-dependent increase in GPR30 mRNA expression correlated with MPA-induced growth inhibition in MCF-7 cells. Additionally, GPR30 upregulation by progestin correlated with growth inhibition when a comparison was made between different breast cancer cell lines. The ERK1/ERK2 pathway is capable of inducing progesterone receptor-dependent and ligand-dependent transcription. Thus we sought to establish whether different MAPK pathway inhibitors affect progestin-induced GPR30 mRNA regulation. The regulation of GPR30 was independent of ERK pathway activation, but the p38 pathway inhibitor induced GPR30 expression, which suggested a potential gene regulation pathway. These data demonstrate a new progestin target gene, the expression of which correlates with growth inhibition. [source]


Determinants of within- and among-clutch variation in levels of maternal hormones in Black-Headed Gull eggs

FUNCTIONAL ECOLOGY, Issue 3 2002
Groothuis T. G.
Summary 1.,Females of egg-laying vertebrates may adjust the development of their offspring to prevailing environmental conditions by regulating the deposition of hormones into their eggs. Within- and amng-clutch variation in levels of steroid hormones were studied in the egg yolks of the Black-Headed Gull (Larus ridibundus, Linnaeus) in relation to environmental conditions at the nest site. This species breeds in colonies of different densities and in different habitats, and the chicks hatch asynchronously. 2.,Egg yolks contained very high levels of androstenedione, substantial levels of testosterone and moderate levels of 5,-dihydrotestosterone. Oestrogen (17,-oestradiol) was not detected. 3.,Androgen levels increased strongly with laying order, irrespective of egg or yolk mass. This may compensate for the disadvantages of the later hatching chicks. These results have implications for adaptive hypotheses that were proposed for asynchronous incubation. 4.,Eggs of lighter clutches contained more androgens, perhaps to compensate for a lower nutritional quality of these eggs. 5.,Birds breeding in the periphery of a colony, being relatively more aggressive and having relatively large territories, laid eggs that contained more androgens than those of birds breeding in the centre. These high yolk androgen levels may facilitate growth and motor development of the chicks, which may be especially important for chicks developing at the periphery of a colony. Reduced levels may be adaptive for birds breeding in the centre, where risk of infectious diseases is high, since steroids may be immunosuppressive. 6.,Corrected for nest distance, clutches of birds in high vegetation, where predation risk is less severe and therefore competition for nest sites perhaps high, contained relatively high levels of androgens. It is suggested that the level of yolk androgens reflects the hormonal condition of the female, that in turn is influenced by her characteristics such as her age and aggressiveness, and the level of social stimulation. [source]


Combined effect of the finasteride and doxazosin on rat ventral prostate morphology and physiology

INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 3 2010
Luis A. Justulin Jr
Summary Finasteride (Fin) and Doxazosin (Dox), alone or in combination, have been widely used in treatment of benign prostatic hyperplasia (BPH) symptoms and recently have been suggested as potential drugs for prostate cancer (PCa)prevention and treatment. However, little is known about the effects of the combination therapy on prostate tissue morphology, physiology and matrix metalloproteinases (MMPs) activity, a special set of enzymes closely related to PCa progression and metastasis. In this study, adult Wistar rats were treated with Fin + Dox (25 mg/kg per day) and the ventral prostate (VP) was excised at days 3 and 30 of treatment to evaluate morphology, cell proliferation, death, transforming growth factor-beta1 (TGF-,1) protein expression, MMP-2, MMP-9 activities and MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA expression. Fin + Dox treatment induced a transient increase in testosterone (T) plasma concentration and a permanent reduction in dihydrotestosterone (DHT). The VP and epithelial cell proliferation were reduced and the stromal collagen fibre volume fraction and apoptosis of the epithelial cell were increased. Fin + Dox treatment also increased the TGF-,1 immunoreaction in the epithelium and in the stroma. The mRNAs for MMP-2, TIMPs-1 and -2 expressions after 30 days of treatment were decreased. The mRNA for MMP-9 was not detected in any of the groups analysed. Fin + Dox treatment for 30 days promoted a decrease in gelatinolytic activity of MMP-2 and an increase in MMP-9. In conclusion, combined treatment with Fin and Dox interferes in the epithelial cell behaviour and in the MMPs activity, potentially via TGF-,1-mediated and androgen pathways. Our results contribute to a better understanding of the clinical data and also of the molecular mechanisms behind isolated or combined Fin and Dox long-term treatment. [source]


Effects of steroids on oxytocin secretion by the human prostate in vitro

INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 1 2004
S. J. Assinder
Summary Oxytocin (OT) concentrations are elevated in prostate tissue of patients with benign prostatic hyperplasia (BPH). Oxytocin specifically increases growth, 5 , -reductase activity and contractility in the prostate. In the rat prostatic OT concentrations are regulated by gonadal steroids, with androgens reducing but oestrogens increasing OT concentrations. The regulation of prostatic oxytocin in man is not understood. This study investigates the effects of gonadal steroids on oxytocin production by the human prostate. Primary explants (approx. 1 mm3) of prostate tissue from patients with BPH were incubated in Dulbecco's modified Eagle's media in the absence or presence of 10 nmol/L testosterone (T), 10 nmol/L dihydrotestosterone (DHT), T or DHT plus 100 nmol/L of the anti-androgen cyproterone acetate (CPA), 55 pmol/L diethylstilbestrol (DES), or DES plus DHT. The amount of oxytocin secreted into the media after 3 days was measured by radioimmunoassay. Testosterone and DHT significantly increased oxytocin concentrations secreted into the media from 0.86 ± 0.11 ng/g of tissue (control) to 1.51 ± 0.14 ng/g (p < 0.01) and 1.54 ± 0.13 ng/g (p < 0.05), respectively. Incubation of tissue samples with CPA resulted in oxytocin concentrations similar to control levels. Treatment with DES caused a significant increase from 1.99 ± 0.71 to 3.98 ± 1.36 ng/g (p < 0.05). A similar increase was measured in media of tissue incubated in DES plus DHT (p < 0.001). The results demonstrate that, unlike the rat where androgens decrease oxytocin, in hyperplastic human prostate tissue both androgens and oestrogens increase oxytocin. This imbalance in the regulation of oxytocin may result in promoting prostatic overgrowth in the pathogenesis of BPH. [source]


The CAG repeat polymorphism within the androgen receptor gene and maleness,

INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 2 2003
Michael Zitzmann
Summary The androgen testosterone and its metabolite dihydrotestosterone exert their effects on gene expression and thus effect maleness via the androgen receptor (AR). A diverse range of clinical conditions starting with complete androgen insensitivity has been correlated with mutations in the AR. Subtle modulations of the transcriptional activity induced by the AR have also been observed and frequently assigned to a polyglutamine stretch of variable length within the N-terminal domain of the receptor. This stretch is encoded by a variable number of CAG triplets in exon 1 of the AR gene located on the X chromosome. First observations of pathologically elongated AR CAG repeats in patients with X-linked spino-bulbar muscular atrophy showing marked hypoandrogenic traits were supplemented by partially conflicting findings of statistical significance also within the normal range of CAG repeat length: an involvement of prostate tissue, spermatogenesis, bone density, hair growth, cardiovascular risk factors and psychological factors has been demonstrated. The highly polymorphic nature of glutamine residues within the AR protein implies a subtle gradation of androgenicity among individuals within an environment of normal testosterone levels providing relevant ligand binding to ARs. This modulation of androgen effects may be small but continuously present during a man's lifetime and, hence, exerts effects that are measurable in many tissues as various degrees of androgenicity and represents a relevant effector of maleness. It remains to be elucidated whether these insights are important enough to become part of individually useful laboratory assessments. [source]


Mechanical Strain Stimulates Osteoblast Proliferation Through the Estrogen Receptor in Males as Well as Females

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2000
E. Damien
Abstract Mechanical strain, testosterone, and estrogen all stimulate proliferation of primary cultures of male rat long bone (LOB)-derived osteoblast-like cells as determined by [3H]thymidine incorporation. The maximum proliferative effect of a single period of mechanical strain (3400 ,,, 1 Hz, and 600 cycles) is additional to that of testosterone (10,8 M) or estrogen (10,8 M). The cells' proliferative response to strain is abolished both by concentrations of tamoxifen that cause proliferation (10,8 M) and by those that have no effect (10,6 M). Strain-related proliferation also is reduced by the estrogen antagonist ICI 182,780 (10,8 M) but is unaffected by the androgen receptor antagonist hydroxyflutamide (10,7 M). Tamoxifen, ICI 182,780, and the aromatase inhibitor 4-dihydroandrostenedione, at concentrations that have no effect on basal proliferation, significantly reduce the proliferative effect of the aromatizable androgen testosterone but not that of the nonaromatizable androgen 5,-dihydrotestosterone. Hydroxyflutamide, at a concentration that has no effect on basal proliferation (10,7 M), eliminates the proliferative effect of 5,-dihydro-testosterone but had no significant effect on that caused by testosterone. Proliferation associated with strain is blocked by neutralizing antibody to insulin-like growth factor II (IGF-II) but not by antibody to IGF-I. Proliferation associated with testosterone is blocked by neutralizing antibody to IGF-I but is unaffected by antibody to IGF-II. These data suggest that in rat osteoblast-like cells from males, as from females, strain-related proliferation is mediated through the estrogen receptor (ER) in a manner that does not compete with estrogen but that can be blocked by ER modulators. Proliferation associated with testosterone appears to follow its aromatization to estrogen and is mediated through the ER, whereas proliferation associated with 5,-dihydrotestosterone is mediated by the androgen receptor. Strain-related proliferation in males, as in females, is mediated by IGF-II, whereas proliferation associated with estrogen and testosterone is mediated by IGF-I. [source]