Endocrine_Disorders RSS : Gourt

Glucagon in Stress and Energy Homeostasis.

Glucagon in Stress and Energy Homeostasis. Endocrinology. 2012 Jan 31; Authors: Jones BJ, Tan T, Bloom SR Abstract Glucagon is traditionally thought of as an antihypoglycemic hormone, for example in response to starvation. However, it actually increases energy expenditure and has other actions not in line with protection from hypoglycemia. Furthermore, it is often found to be elevated when glucose is also raised, for example in circumstances of psychological and metabolic stress. These findings seem more in keeping with glucagon having some role as a hormone enhancing the response to stress. PMID: 22294753 [PubMed - as supplied by publisher]

Dynamic Regulation of Wnt7a Expression in the Primate Endometrium: Implications for Postmenstrual Regeneration and Secretory Transformation.

Dynamic Regulation of Wnt7a Expression in the Primate Endometrium: Implications for Postmenstrual Regeneration and Secretory Transformation. Endocrinology. 2012 Jan 31; Authors: Fan X, Krieg S, Hwang JY, Dhal S, Kuo CJ, Lasley BL, Brenner RM, Nayak NR Abstract Despite the vital physiological role of endometrial regeneration during the menstrual cycle and the various pathological implications of abnormal growth of endometrial epithelial cells, the local factors and regulatory mechanisms involved in endometrial regeneration and growth have not been well characterized. Here, we examine the pattern, hormone dependence, and potential functions of Wnt7a (wingless-type MMTV integration site family member 7a), , which is known to play a critical role in the formation of the mouse endometrial epithelium during embryonic development, in both human and artificially cycling rhesus macaque endometrium, and using a potent Wnt-antagonist in a mouse model of endometrial regeneration. Wnt7a transcript levels were examined using quantitative real-time PCR and in situ hybridization, and immunohistochemistry was performed to detect Ki-67 and 3,5-bromodeoxyuridine. Stringent, fully conditional Wnt inhibition was achieved by adenoviral expression of Dickkopf-1 during artificial endometrial regeneration in mice. In macaques, Wnt7a expression was confined to the newly formed luminal epithelium (LE) and upper glands during the postmenstrual repair phase. The signal increased in the LE during the proliferative phase but decreased in the upper glands and was undetectable in the glands by the late proliferative phase. Interestingly, Wnt7a was completely suppressed in the LE and remained undetectable in other cell types after 7 d of progesterone treatment. The pattern of Wnt7a expression in the human endometrium was similar to that in macaques. Blockade of Wnt signaling during endometrial regeneration in mice resulted in a dramatic delay in reepithelialization and degeneration of glands and LE. These results strongly suggest, for the first time, a role for Wnt7a in postmenstrual regeneration and proliferation of endometrial glands and LE in primates, and its dramatic suppression by progesterone is likely essential for secretory transformation of the epithelium. PMID: 22294752 [PubMed - as supplied by publisher]

Live Imaging Reveals the Link Between Decreased Glucose Uptake in Ovarian Cumulus Cells and Impaired Oocyte Quality in Female Diabetic Mice.

Live Imaging Reveals the Link Between Decreased Glucose Uptake in Ovarian Cumulus Cells and Impaired Oocyte Quality in Female Diabetic Mice. Endocrinology. 2012 Jan 31; Authors: Wang Q, Chi MM, Moley KH Abstract Maternal diabetes has been demonstrated to adversely affect preimplantation embryo development and pregnancy outcomes. Emerging data suggest that these effects are associated with compromised oocyte quality. However, direct evidence of a pathway by which maternal diabetes exerts its effects on the oocyte is still lacking. Cumulus cells are metabolically coupled to oocytes, and bidirectional communication between them is essential for the development and functions of both compartments. The primary focus of this work was to evaluate the connection between glucose uptake in cumulus cells and oocyte quality in diabetic mice. This experiment has been difficult, because cumulus cells need to be separated from oocytes and labeled with isotope in the process of measuring glucose uptake. Here, we report a method for live imaging glucose transport in single cumulus-oocyte complexes using a fluorescent glucose analog (6-(N-(7-nitrobenz-2-oxa-1,3-diazol- 4-yl)amino)-6-deoxyglucose). By tracking the ATP content and spindle/chromosome status in individual oocytes surrounded by cumulus cells with differing glucose uptake activity, we reveal that compromised oocyte quality in diabetic mice is linked to decreased glucose uptake in cumulus cells. PMID: 22294751 [PubMed - as supplied by publisher]

Long-Term Fgf23 Deficiency Does Not Influence Aging, Glucose Homeostasis, or Fat Metabolism in Mice with a Nonfunctioning Vitamin D Receptor.

Long-Term Fgf23 Deficiency Does Not Influence Aging, Glucose Homeostasis, or Fat Metabolism in Mice with a Nonfunctioning Vitamin D Receptor. Endocrinology. 2012 Jan 31; Authors: Streicher C, Zeitz U, Andrukhova O, Rupprecht A, Pohl E, Larsson TE, Windisch W, Lanske B, Erben RG Abstract It is still controversial whether the bone-derived hormone fibroblast growth factor-23 (FGF23) has additional physiological functions apart from its well-known suppressive actions on renal phosphate reabsorption and vitamin D hormone synthesis. Here we analyzed premature aging, mineral homeostasis, carbohydrate metabolism, and fat metabolism in 9-month-old male wild-type (WT) mice, vitamin D receptor mutant mice (VDR(Δ)(/)(Δ)) with a nonfunctioning vitamin D receptor, and Fgf23(-/-)/VDR(Δ)(/)(Δ) compound mutant mice on both a standard rodent chow and a rescue diet enriched with calcium, phosphorus, and lactose. Organ atrophy, lung emphysema, and ectopic tissue or vascular calcifications were absent in compound mutants. In addition, body weight, glucose tolerance, insulin tolerance, insulin secretory capacity, pancreatic beta cell volume, and retroperitoneal and epididymal fat mass as well as serum cholesterol and triglycerides were indistinguishable between vitamin D receptor and compound mutants. In contrast to VDR(Δ)(/)(Δ) and Fgf23(-/-)/VDR(Δ)(/)(Δ) mice, which stayed lean, WT mice showed obesity-induced insulin resistance. To rule out alopecia and concomitantly elevated energy expenditure present in 9-month-old VDR(Δ)(/)(Δ) and Fgf23(-/-)/VDR(Δ)(/)(Δ) mice as a confounding factor for the lacking effect of Fgf23 deficiency on fat mass, we analyzed whole-body composition in WT, Fgf23(-/-), VDR(Δ)(/)(Δ), and Fgf23(-/-)/VDR(Δ)(/)(Δ) mice at the age of 4 wk, when the coat in VDR(Δ)(/)(Δ) mice is still normal. Whole-body fat mass was reduced in Fgf23(-/-) mice but almost identical in WT, VDR(Δ)(/)(Δ), and Fgf23(-/-)/VDR(Δ)(/)(Δ) mice. In conclusion, our data indicate that Fgf23 has no molecular vitamin D-independent role in aging, insulin signaling, or fat metabolism in mice. PMID: 22294750 [PubMed - as supplied by publisher]

FOXL2 Is Involved in the Synergy between Activin and Progestins on the Follicle-Stimulating Hormone β-Subunit Promoter.

FOXL2 Is Involved in the Synergy between Activin and Progestins on the Follicle-Stimulating Hormone β-Subunit Promoter. Endocrinology. 2012 Jan 31; Authors: Ghochani Y, Saini JK, Mellon PL, Thackray VG Abstract Differential regulation of gonadotropin hormone production in the pituitary is critical for fertility. Activin and progesterone signaling in gonadotrope cells is important for Fshb gene expression. Previously, we reported that synergy between activin and progestins required the binding of SMAD proteins and the progesterone receptor (PR) to the murine Fshb promoter. In this study, we demonstrate that the FOXL2 transcription factor is also necessary for the full synergistic response between activin and progestins. We show that this synergy occurs in a species-specific manner and that multiple elements in the Fshb promoter that bind forkhead box L2 (FOXL2), SMA/mothers against decapentaplegic homologs (SMAD), and PR are required. Furthermore, we demonstrate that FOXL2 can physically interact with PR and SMAD3. Thus, it is likely that protein-protein interactions among FOXL2, SMAD, and PR recruited to the Fshb promoter play a key role in facilitating Fshb transcription before the secondary FSH surge in rodents. PMID: 22294749 [PubMed - as supplied by publisher]

The Ubiquitin Ligase Siah2 Regulates PPARγ Activity in Adipocytes.

The Ubiquitin Ligase Siah2 Regulates PPARγ Activity in Adipocytes. Endocrinology. 2012 Jan 31; Authors: Kilroy G, Kirk-Ballard H, Carter LE, Floyd ZE Abstract Moderate reductions in peroxisome proliferator-activated receptor (PPAR)γ levels control insulin sensitivity as effectively as activation of PPARγ in adipocytes by the thiazolidinediones. That observation suggests that PPARγ activity can be regulated by modulating the amount of PPARγ protein in adipocytes. Activation of PPARγ in adipocytes is linked to changes in PPARγ protein levels via increased degradation of PPARγ proteins by the ubiquitin proteasome system. Identification of the ubiquitin ligase or ligases that recognize ligand bound PPARγ is an essential step in determining the physiological significance of the relationship between activation and ubiquitin-dependent degradation of PPARγ. Using an RNA interference-based screen, we identified five RING (really interesting new gene)-type ubiquitin ligases that alter PPARγ protein levels in adipocytes. Here, we demonstrate that Drosophila seven-in-absentia homolog 2 (Siah2), a mammalian homolog of Drosophila seven-in-absentia, regulates PPARγ ubiquitylation and ligand-dependent activation of PPARγ in adipocytes. We also demonstrate that Siah2 expression is up-regulated during adipogenesis and that PPARγ interacts with Siah2 during adipogenesis. In addition, Siah2 is required for adipogenesis. These data suggest that modulation of PPARγ protein levels by the ubiquitin ligase Siah2 is essential in determining the physiological effects of PPARγ activation in adipocytes. PMID: 22294748 [PubMed - as supplied by publisher]

Evidence for Differential Regulation of GnRH Signaling via Heterodimerization among GnRH Receptor Paralogs in the Protochordate, Ciona intestinalis.

Evidence for Differential Regulation of GnRH Signaling via Heterodimerization among GnRH Receptor Paralogs in the Protochordate, Ciona intestinalis. Endocrinology. 2012 Jan 31; Authors: Sakai T, Aoyama M, Kawada T, Kusakabe T, Tsuda M, Satake H Abstract The endocrine and neuroendocrine systems for reproductive functions have diversified as a result of the generation of species-specific paralogs of peptide hormones and their receptors including GnRH and their receptors (GnRHR), which belong to the class A G protein-coupled receptor family. A protochordate, Ciona intestinalis, has been found to possess seven GnRH (tGnRH-3 to -8 and Ci-GnRH-X) and four GnRHR (Ci-GnRHR1 to -4). Moreover, Ci-GnRHR4 (R4) does not bind to any Ciona GnRH and activate any signaling pathways. Here we show novel functional diversification of GnRH signaling pathways via G protein-coupled receptor heterodimerization among Ciona GnRHR. R4 was shown to heterodimerize with R2 specifically in test cells of vitellogenic oocytes by coimmunoprecipitation. The R2-R4 heterodimerization in human embryonic kidney 293 cells cotransfected with R2 and R4 was also observed by coimmunoprecipitation and fluorescent energy transfer analyses. Of particular interest is that the R2-R4 heterodimer decreases the cAMP production in a nonligand-selective manner via shift of activation of Gs protein to Gi protein by R2, compared with R2 monomer/homodimer. Considering that the R1-R4 heterodimer elicits 10-fold more potent Ca(2+) mobilization than R1 monomer/homodimer in a ligand-selective manner but does not affect cAMP production, these results indicate that R4 regulates differential GnRH signaling cascades via heterodimerization with R1 and R2 as an endogenous allosteric modulator. Collectively, the present study suggests that the heterodimerization among GnRHR paralogs, including the species-specific orphan receptor subtype, is involved in rigorous and diversified GnRHergic signaling of the protochordate, which lacks a hypothalamus-pituitary gonad axis. PMID: 22294747 [PubMed - as supplied by publisher]

Excess DAX1 Leads to XY Ovotesticular Disorder of Sex Development (DSD) in Mice by Inhibiting Steroidogenic Factor-1 (SF1) Activation of the Testis Enhancer of SRY-box-9 (Sox9).

Excess DAX1 Leads to XY Ovotesticular Disorder of Sex Development (DSD) in Mice by Inhibiting Steroidogenic Factor-1 (SF1) Activation of the Testis Enhancer of SRY-box-9 (Sox9). Endocrinology. 2012 Jan 31; Authors: Ludbrook LM, Bernard P, Bagheri-Fam S, Ryan J, Sekido R, Wilhelm D, Lovell-Badge R, Harley VR Abstract Human DAX1 duplications cause dosage-sensitive sex reversal (DSS) whereby chromosomally XY individuals can develop as females due to gonadal dysgenesis. However, the mechanism of DSS-adrenal hypoplasia congenita on X, gene 1 (DAX1) action in the fetal testis is unknown. We show that in fetal testes from XY Dax1-overexpressing transgenic mice, the expression of the key testis-promoting gene sex-determining region on Y (SRY)-box-9 (Sox9) is reduced. Moreover, in XY Sox9 heterozygotes, in which testis development is usually normal, Dax1 overexpression results in ovotestes, suggesting a DAX1-SOX9 antagonism. The ovarian portion of the XY ovotestes was characterized by expression of the granulosa cell marker, Forkhead box-L2, with complete loss of the Sertoli cell markers, SOX9 and anti-Müllerian hormone, and the Leydig cell marker CYP17A1. However, the expression of SRY and steroidogenic factor-1 (SF1), two key transcriptional regulators of Sox9, was retained in the ovarian portion of the XY ovotestes. Using reporter mice, Dax1 overexpression reduced activation of TES, the testis enhancer of Sox9, indicating that DAX1 might repress Sox9 expression via TES. In cultured cells, increasing levels of DAX1 antagonized SF1-, SF1/SRY-, and SF1/SOX9-mediated activation of TES, due to reduced binding of SF1 to TES, providing a likely mechanism for DSS. PMID: 22294746 [PubMed - as supplied by publisher]

Impact of Oatp1c1 Deficiency on Thyroid Hormone Metabolism and Action in the Mouse Brain.

Impact of Oatp1c1 Deficiency on Thyroid Hormone Metabolism and Action in the Mouse Brain. Endocrinology. 2012 Jan 31; Authors: Mayerl S, Visser TJ, Darras VM, Horn S, Heuer H Abstract Organic anion-transporting polypeptide 1c1 (Oatp1c1) (also known as Slco1c1 and Oatp14) belongs to the family of Oatp and has been shown to facilitate the transport of T(4). In the rodent brain, Oatp1c1 is highly enriched in capillary endothelial cells and choroid plexus structures where it may mediate the entry of T(4) into the central nervous system. Here, we describe the generation and first analysis of Oatp1c1-deficient mice. Oatp1c1 knockout (KO) mice were born with the expected frequency, were not growth retarded, and developed without any overt neurological abnormalities. Serum T(3) and T(4) concentrations as well as renal and hepatic deiodinase type 1 expression levels were indistinguishable between Oatp1c1 KO mice and control animals. Hypothalamic TRH and pituitary TSH mRNA levels were not affected, but brain T(4) and T(3) content was decreased in Oatp1c1-deficient animals. Moreover, increased type 2 and decreased type 3 deiodinase activities indicate a mild hypothyroid situation in the brain of Oatp1c1 KO mice. Consequently, mRNA expression levels of gene products positively regulated by T(3) in the brain were down-regulated. This central nervous system-specific hypothyroidism is presumably caused by an impaired passage of T(4) across the blood-brain barrier and indicates a unique function of Oatp1c1 in facilitating T(4) transport despite the presence of other thyroid hormone transporters such as Mct8. PMID: 22294745 [PubMed - as supplied by publisher]

Glucocorticoids Enhance Intestinal Glucose Uptake Via the Dimerized Glucocorticoid Receptor in Enterocytes.

Glucocorticoids Enhance Intestinal Glucose Uptake Via the Dimerized Glucocorticoid Receptor in Enterocytes. Endocrinology. 2012 Jan 31; Authors: Reichardt SD, Föller M, Rexhepaj R, Pathare G, Minnich K, Tuckermann JP, Lang F, Reichardt HM Abstract Glucocorticoid (GC) treatment of inflammatory disorders, such as inflammatory bowel disease, causes deranged metabolism, in part by enhanced intestinal resorption of glucose. However, the underlying molecular mechanism is poorly understood. Hence, we investigated transcriptional control of genes reported to be involved in glucose uptake in the small intestine after GC treatment and determined effects of GC on electrogenic glucose transport from transepithelial currents. GR(villinCre) mice lacking the GC receptor (GR) in enterocytes served to identify the target cell of GC treatment and the requirement of the GR itself; GR(dim) mice impaired in dimerization and DNA binding of the GR were used to determine the underlying molecular mechanism. Our findings revealed that oral administration of dexamethasone to wild-type mice for 3 d increased mRNA expression of serum- and GC-inducible kinase 1, sodium-coupled glucose transporter 1, and Na(+)/H(+) exchanger 3, as well as electrogenic glucose transport in the small intestine. In contrast, GR(villinCre) mice did not respond to GC treatment, neither with regard to gene activation nor to glucose transport. GR(dim) mice were also refractory to GC, because dexamethasone treatment failed to increase both, gene expression and electrogenic glucose transport. In addition, the rise in blood glucose levels normally observed after GC administration was attenuated in both mutant mouse strains. We conclude that enhanced glucose transport in vivo primarily depends on gene regulation by the dimerized GR in enterocytes, and that this mechanism contributes to GC-induced hyperglycemia. PMID: 22294744 [PubMed - as supplied by publisher]

Rapid and Widespread Effects of 17β-Estradiol on Intracellular Signaling in the Male Songbird Brain: A Seasonal Comparison.

Rapid and Widespread Effects of 17β-Estradiol on Intracellular Signaling in the Male Songbird Brain: A Seasonal Comparison. Endocrinology. 2012 Jan 31; Authors: Heimovics SA, Prior NH, Maddison CJ, Soma KK Abstract Across vertebrate species, 17β-estradiol (E(2)) acts on the brain via both genomic and nongenomic mechanisms to influence neuronal physiology and behavior. Nongenomic E(2) signaling is typically initiated by membrane-associated estrogen receptors that modulate intracellular signaling cascades, including rapid phosphorylation of ERK. Phosphorylated ERK (pERK) can, in turn, rapidly phosphorylate tyrosine hydroxylase (TH) and cAMP response element-binding protein (CREB). Recent data suggest that the rapid effects of E(2) on mouse aggressive behavior are more prominent during short photoperiods (winter) and that acute aromatase inhibition reduces songbird aggression in winter only. To date, seasonal plasticity in the rapid effects of E(2) on intracellular signaling has not been investigated. Here, we compared the effects of acute (15 min) E(2) treatment on pERK, pTH, and pCREB immunoreactivity in male song sparrows (Melospiza melodia) pretreated with the aromatase inhibitor fadrozole during the breeding and nonbreeding seasons. We examined immunoreactivity in 14 brain regions including portions of the song control system, social behavior network, and the hippocampus (Hp). In both seasons, E(2) significantly decreased pERK in nucleus taeniae of the amygdala, pTH in ventromedial hypothalamus, and pCREB in mesencephalic central gray, robust nucleus of the arcopallium, and caudomedial nidopallium. However, several effects were critically dependent upon season. E(2) decreased pERK in caudomedial nidopallium in the breeding season only and decreased pCREB in the medial preoptic nucleus in the nonbreeding season only. Remarkably, E(2) decreased pERK in Hp in the breeding season but increased pERK in Hp in the nonbreeding season. Together, these data demonstrate that E(2) has rapid effects on intracellular signaling in multiple regions of the male brain and also demonstrate that rapid effects of E(2) can be profoundly different across the seasons. PMID: 22294743 [PubMed - as supplied by publisher]

Preclinical Characterization of a Novel Diphenyl Benzamide Selective ERα Agonist for Hormone Therapy in Prostate Cancer.

Preclinical Characterization of a Novel Diphenyl Benzamide Selective ERα Agonist for Hormone Therapy in Prostate Cancer. Endocrinology. 2012 Jan 31; Authors: Coss CC, Jones A, Parke DN, Narayanan R, Barrett CM, Kearbey JD, Veverka KA, Miller DD, Morton RA, Steiner MS, Dalton JT Abstract Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass. PMID: 22294742 [PubMed - as supplied by publisher]

A Covalently Dimerized Recombinant Human Bone Morphogenetic Protein-15 Variant Identifies Bone Morphogenetic Protein Receptor Type 1B as a Key Cell Surface Receptor on Ovarian Granulosa Cells.

A Covalently Dimerized Recombinant Human Bone Morphogenetic Protein-15 Variant Identifies Bone Morphogenetic Protein Receptor Type 1B as a Key Cell Surface Receptor on Ovarian Granulosa Cells. Endocrinology. 2012 Jan 31; Authors: Pulkki MM, Mottershead DG, Pasternack AH, Muggalla P, Ludlow H, van Dinther M, Myllymaa S, Koli K, Ten Dijke P, Laitinen M, Ritvos O Abstract Genetic studies have identified bone morphogenetic protein-15 (BMP15) as an essential regulator of female fertility in humans and in sheep. Oocyte-derived BMP15 is a noncovalently linked dimeric growth factor mediating its effects to ovarian somatic cells in a paracrine manner. Although receptor ectodomains capable of binding BMP15 have previously been reported, no cell surface receptor complex involved in BMP15 signaling has previously been characterized. Here we have expressed and purified recombinant human BMP15 noncovalent and covalent dimer variants. The biological effects of these BMP15 variants were assessed in cultured human granulosa-luteal cells or COV434 granulosa cell tumor cells using BMP-responsive transcriptional reporter assays and an inhibin B ELISA. Biochemical characterization of ligand-receptor interactions was performed with affinity-labeling experiments using [(125)I]iodinated BMP15 variants. Both ligand variants were shown to form homodimers and to stimulate Smad1/5/8 signaling and inhibin B production in human granulosa cells in a similar manner. [(125)I]Iodination of both ligands was achieved, but only the covalent dimer variant retained receptor binding capacity. The [(125)I]BMP15(S356C) variant bound preferentially to endogenous BMP receptor 1B (BMPR1B) and BMPR2 receptors on COV434 cells. Binding experiments in COS cells with overexpression of these receptors confirmed that the [(125)I]BMP15(S356C) variant binds to BMPR1B and BMPR2 forming the BMP15 signaling complex. The results provide the first direct evidence in any species on the identification of specific cell surface receptors for a member of the GDF9/BMP15 subfamily of oocyte growth factors. The fact that BMP15 uses preferentially BMPR1B as its type I receptor suggests an important role for the BMPR1B receptor in human female fertility. The result is well in line with the demonstration of ovarian failure in a recently reported human subject with a homozygous BMPR1B loss-of-function mutant. PMID: 22294741 [PubMed - as supplied by publisher]

The -258 A/G (SNP rs12885300) polymorphism of the human type-2 deiodinase gene is associated with a shift in the pattern of secretion of thyroid hormones following a TRH-induced acute rise in TSH.

The -258 A/G (SNP rs12885300) polymorphism of the human type-2 deiodinase gene is associated with a shift in the pattern of secretion of thyroid hormones following a TRH-induced acute rise in TSH. Eur J Endocrinol. 2012 Feb 3; Authors: Peltsverger MY, Butler PW, Alberobello AT, Smith S, Guevara Y, Dubaz OM, Luzon JA, Linderman JD, Celi F Abstract Objective: Type-2 deiodinase gene (DIO2) polymorphisms have been associated with changes in pituitary-thyroid axis homeostasis. The -258 A/G (SNP rs12885300) polymorphism has been associated with increased enzymatic activity, but data are conflicting. To characterize the effects of the -258 A/G polymorphism on intra-thyroidal T4 to T3 conversion and thyroid hormone secretion pattern we studied the effects of acute, TRH-mediated, TSH stimulation of the thyroid gland.Design: Retrospective analysis.Methods: The thyroid hormone secretion in response to 500 mcg iv TRH injection was studied in 45 healthy volunteers.Results: Twenty-six subjects (16 females, 10 males, 32.8±10.4 years) were homozygous for the ancestral (-258 A/A) allele, 19 (11 females, 8 males, 31.1±10.9 years) were carrier of the (-258 G/x) variant. While no differences in the peak TSH and T3 levels were observed, carriers of the -258G/x allele showed a blunted rise in free T4 (p<0.01). The -258G/x 92Thr/Thr haplotype, compared to the other groups, had lower TSH values at 60' (p<0.03). No differences were observed between genotypes in baseline thyroid hormone levels.Conclusions: The -258G/x DIO2 polymorphism variant is associated with a decreased rate of acute TSH-stimulated free T4 secretion with a normal T3 release from the thyroid consistent with a shift in the reaction equilibrium toward the product. These data indicate that the -258G DIO2 polymorphism cause changes in the pattern of hormonal secretion. These findings are a proof-of-concept that common polymorphisms in the DIO2 can subtly affect the circulating levels of thyroid hormone and might modulate the thyroid hormone homeostasis. PMID: 22307573 [PubMed - as supplied by publisher]

Secular trends in sex hormones and fractures in men and women.

Secular trends in sex hormones and fractures in men and women. Eur J Endocrinol. 2012 Feb 3; Authors: Trimpou P, Lindahl A, Lindstedt G, Oleröd G, Wilhelmsen L, Landin-Wilhelmsen K Abstract Objective: To study secular trends in sex hormones, anthropometry, bone measures and fractures.Design: A random population sample was studied twice and subjects of similar age were compared 13 years apart.Methods: X-ray verified fractures were retrieved in a random population sample of 2,400 men and women (participants 1,616, =67%) aged 25-64 years from the WHO, MONICA Project in Gothenburg, Sweden, in 1995 and 2008. Fasting serum hormones and calcaneal ultrasound were measured in every 4th subject. In fertile women measurements were performed on cycle day interval 7-9.Results: In 2008, men had lower serum free testosterone than men of similar age in 1995 (p<0.001). Body composition, physical activity and fracture incidence were similar. In women, oestrogen replacement therapy (HRT) was lower in 2008; 7 % vs. 28 % (p<0.0001), as was serum oestradiol, while use of tranquilisers and leisure time physical activity were higher. In 2008, the fracture incidence was higher in postmenopausal women; 29% vs. 17% (p<0.001), and vertebral crush had increased from 8% to 19% of all fractures (p=0.031). Serum cholesterol and triglycerides were lower in all subjects in 2008 compared with 1995.Conclusions: Secular trends were seen, with lower serum testosterone in men in 2008, but no effect was seen on the fracture incidence in these fairly young men. In postmenopausal women in 2008, there was a higher fracture incidence along with more vertebral compressions. Lower HRT use, lower serum oestradiol and higher fall risk exposure due to more tranquilisers and leisure time physical activity in 2008, may explain the results. PMID: 22307572 [PubMed - as supplied by publisher]