Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 77
Filter
1.
Minerva Endocrinol ; 32(4): 245-61, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18091662

ABSTRACT

Turner syndrome (TS) is a relatively common disorder of female development caused by loss of all or part of one sex chromosome. Because short stature and premature ovarian failure are cardinal features of the syndrome, pediatric endocrinologists have taken the lead in care for these girls. Congenital cardiovascular disease affects approximately 50% of individuals and is the major cause of premature mortality in adults. Unfortunately, teenage girls are often lost to follow up after discharge from pediatric clinic. This review describes the spectrum of cardiovascular defects in TS with emphasis on identifying patients at risk for aortic dissection/rupture. Updated consensus guidelines for cardiac screening and care are reviewed and genetic pathways implicated in Turner cardiovascular disease, including premature coronary artery disease, are discussed. This material is of particular importance because cardiac care for adults with TS appears seriously deficient at present.


Subject(s)
Body Height , Cardiovascular Diseases/congenital , Cardiovascular Diseases/genetics , Chromosomes, Human, X , Heart Defects, Congenital/genetics , Turner Syndrome/complications , Adolescent , Adult , Aortic Aneurysm/genetics , Aortic Aneurysm/prevention & control , Aortic Rupture/genetics , Aortic Rupture/prevention & control , Cardiovascular Diseases/pathology , Child , Female , Human Growth Hormone/metabolism , Humans , Mass Screening , Population Surveillance , Primary Ovarian Insufficiency/genetics , Puberty , Turner Syndrome/genetics
2.
Brain Res Mol Brain Res ; 135(1-2): 225-31, 2005 Apr 27.
Article in English | MEDLINE | ID: mdl-15857685

ABSTRACT

Members of the catenin family of proteins are thought to play a major role in the folding and lamination of the cerebral cortex. We have used in situ hybridization to determine the cellular expression patterns of four members of this family, Alpha-E-, Alpha-N-, Beta-, and Gamma-catenins (CTNNA1, CTNNA2, CTNNB1, and JUP respectively) in the adult primate dorsolateral prefrontal cortex (DLPFC) and hippocampus. CTNNA2, CTNNB1, and JUP mRNAs were detected in all layers of the DLPFC and in all neuronal subregions of the hippocampal formation, however CTNNA1 mRNA, coding for an 'epithelial' specific catenin, was not detected in any region of the cortex or hippocampus. CTNNA2, a 'neuronal-specific' catenin, and CTNNB1 mRNAs were abundant in both DLPFC and hippocampus, with a distinct neuronal localization. CTNNA2 mRNA was concentrated in both granular/stellate cells and large pyramidal cell bodies, while CTNNB1 expression was more strongly associated with granular cell bodies throughout the DLPFC, with expression in pyramidal cells confined mainly to cortical Layers III and VI. CTNNA2 and CTNNB1 mRNAs were also abundant in the granule cells of the dentate gyrus and pyramidal cells of Ammon's horn, apparently co-expressed in the same neurons. JUP mRNA was rather diffusely localized in the DLPFC without the distinct laminar patterns seen for CTNNA2 and CTNNB1 but was distinctly localized in the granule cells of the dentate gyrus and pyramidal cells of Ammon's horn. These studies demonstrate a distinct neuronal pattern of gene expression for catenin family members in primate brain structures characterized by high degrees of folding and strong lamination. The high level expression of these transcripts supports the notion of a major role for catenins even in the adult brain. Such an understanding is also important in view of the multiple interactions that catenins have with many other proteins in the adult and ageing brain. This may also have implications for understanding the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, as well as emerging neuronal stem cell therapies.


Subject(s)
Cadherins/classification , Cadherins/metabolism , Cytoskeletal Proteins/metabolism , Gene Expression/physiology , Hippocampus/metabolism , Prefrontal Cortex/metabolism , Animals , Autoradiography/methods , Cadherins/genetics , Cytoskeletal Proteins/genetics , Desmoplakins , Female , In Situ Hybridization/methods , Macaca mulatta , RNA, Messenger/metabolism
3.
J Neurosci Res ; 76(3): 306-14, 2004 May 01.
Article in English | MEDLINE | ID: mdl-15079859

ABSTRACT

Estrogen protects neurons from a variety of experimental insults in vitro, and is thought to protect from acute and chronic neurodegenerative processes in vivo. Estrogen also enhances higher-level cognitive functions that are centered in the dorsolateral prefrontal cortex (DLPFC) in human and non-human primates. To investigate genomic mechanisms involved in estrogenic effects on the primate brain in vivo, we compared transcription factor mRNA and protein expression in the DLPFC of ovariectomized rhesus monkeys treated with either vehicle or estradiol (E2). c-FOS, E2F1, and general transcription factor IIB (TFIIB) mRNA and protein expression were altered significantly by short-term E2 treatment, as shown by DNA array, in situ hybridization, and immunohistochemical and immunoblot evaluations. C-FOS expression was increased significantly whereas E2F1 and TFIIB levels were decreased in the DLPFC of E2-treated animals. These transcription factors were concentrated in cortical pyramids, as were estrogen receptors alpha and beta. These data indicate that estrogen may have direct as well as indirect effects on neuronal gene expression in the primate prefrontal cortex.


Subject(s)
Cell Cycle Proteins , Estradiol/physiology , Neurons/metabolism , Prefrontal Cortex/metabolism , Transcription Factors/genetics , Transcriptional Activation/physiology , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , E2F Transcription Factors , E2F1 Transcription Factor , Female , Gene Expression Regulation/physiology , Immunohistochemistry , In Situ Hybridization , Macaca mulatta , Oligonucleotide Array Sequence Analysis , Prefrontal Cortex/cytology , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/analysis , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Transcription Factor TFIIB/metabolism , Transcription Factors/metabolism
4.
J Endocrinol ; 180(2): 247-55, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14765976

ABSTRACT

The possibility that growth hormone (GH) has effects on long bone growth independent of insulin-like growth factor-I (IGF-I) has long been debated. If this is true, then long bone growth should be more profoundly affected by the absence of GH (since both GH and GH-stimulated IGF-I effects are absent) than by the absence of IGF-I alone (since GH is still present and actually elevated). To test this hypothesis, we compared long bone growth in mice with targeted deletions of Igf1 vs growth hormone receptor (Ghr). Tibial linear growth rate was reduced by approximately 35% in Igf1 null mice and by about 65% in Ghr null mice between postnatal days 20 and 40, a time of peak GH effect during normal longitudinal growth. The Igf1 null mouse growth plate demonstrated significant enlargement of the germinal zone; chondrocyte proliferation and numbers were normal but chondrocyte hypertrophy was significantly reduced. In contrast, the Ghr null mouse germinal zone was hypoplastic, chondrocyte proliferation and numbers were significantly reduced, and chondrocyte hypertrophy was also reduced. We have previously demonstrated that IGF-II is highly expressed in growth plate germinal and proliferative zones, so we considered the possibility that GH-stimulated IGF-II production might promote germinal zone expansion and maintain normal proliferation in the Igf1 null mouse growth plate. Supporting this view, IGF-II mRNA was increased in the Igf1 null mouse and decreased in the Ghr null mouse growth plate.Thus, in the complete absence of IGF-I but in the presence of elevated GH in the Igf1 null mouse, reduction in chondrocyte hypertrophy appears to be the major defect in longitudinal bone growth. In the complete absence of a GH effect in the Ghr null mouse, however, both chondrocyte generation and hypertrophy are compromised, leading to a compound deficit in long bone growth. These observations support dual roles for GH in promoting longitudinal bone growth: an IGF-I-independent role in growth plate chondrocyte generation and an IGF-I-dependent role in promoting chondrocyte hypertrophy. The question of whether GH has direct effects on chondrocyte generation is still not settled, however, since it now appears that IGF-II may medicate some of these effects on the growth plate.


Subject(s)
Bone Development/physiology , Growth Hormone/physiology , Insulin-Like Growth Factor I/metabolism , Receptors, Somatotropin/metabolism , Tibia/physiology , Animals , Chondrocytes/physiology , Gene Deletion , Growth Plate/cytology , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor II/genetics , Insulin-Like Growth Factor II/metabolism , Mice , Mice, Knockout , RNA, Messenger/analysis , Receptors, Somatotropin/genetics
5.
J Neurosci Res ; 75(2): 218-224, 2004 Jan 15.
Article in English | MEDLINE | ID: mdl-14705142

ABSTRACT

The docking protein p62Dok-1 (Dok-1) has a central role in cell signaling mediated by a wide range of protein tyrosine kinases, including intrinsic membrane kinases, such as the insulin-like growth factor-1 (IGF-1) receptor. To elucidate potential IGF signaling mechanisms, we used DNA array technology to investigate novel kinase targets expressed in the primate dorsolateral prefrontal cortex (DLPFC). Dok-1 transcripts were among the most abundant found in this structure. Because Dok-1 expression has not been characterized in brain, we evaluated its expression pattern using immunoblotting, in situ hybridization, and immunohistochemistry in the rhesus monkey prefrontal cortex and hippocampal formation. Dok-1 antibodies identified a 62-kDa band in lysates from the DLPFC, consistent with the known size for Dok-1. In situ hybridization showed that Dok-1 mRNA was expressed in all layers of the DLPFC and in all neuronal subregions of the hippocampal formation. Immunohistochemical analysis showed Dok-1 immunoreactivity concentrated in pyramidal neurons of cortical layers IV-V and throughout Ammon's horn and in granule neurons of the dentate gyrus. Dok-1 expression was also identified in endothelial cells of cerebral blood vessels. These expression patterns are very similar to those of the IGF-1 receptor and suggest that Dok-1 could be among the downstream targets of IGF signaling in areas of the primate brain involved in learning and memory.


Subject(s)
DNA-Binding Proteins/metabolism , Hippocampus/metabolism , Macaca mulatta/metabolism , Neurons/metabolism , Phosphoproteins/metabolism , Prefrontal Cortex/metabolism , RNA-Binding Proteins/metabolism , Animals , DNA-Binding Proteins/genetics , Dentate Gyrus/cytology , Dentate Gyrus/metabolism , Endothelial Cells/cytology , Endothelial Cells/metabolism , Female , Gene Expression/physiology , Hippocampus/cytology , Insulin-Like Growth Factor I/metabolism , Learning/physiology , Macaca mulatta/anatomy & histology , Phosphoproteins/genetics , Prefrontal Cortex/cytology , Pyramidal Cells/cytology , Pyramidal Cells/metabolism , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , Receptor, IGF Type 1/metabolism , Signal Transduction/physiology
6.
Reprod Domest Anim ; 38(4): 247-58, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12887564

ABSTRACT

The aim of the present paper is to make a comparative study of the expression of the elements of the insulin-like growth factor (IGF) system in different mammalian species and thus illuminate their potential role in the process of ovarian folliculogenesis in mammals. In most mammalian species, IGFs and IGFBPs (in particular IGFBP-2 and IGFBP-4) are considered, respectively, as stimulators and inhibitors of follicular growth and maturation. In mammalian species, IGFs might play a key role in sensitizing ovarian granulosa cells to FSH action during terminal follicular growth. Concentrations of IGFBP-2 and IGFBP-4 in follicular fluid strongly decrease and increase during follicular growth and atresia, respectively, leading to an increase and a decrease in IGF bioavailability, respectively. The decrease in these IGFBPs is because of a decrease in mRNA expression (IGFBP-2) and an increase in proteolytic degradation by PAPP-A in follicular fluid (IGFBP-2, IGFBP-4 and IGFBP-5), and likely participates in the selection of dominant follicles. In contrast, levels and/or sites of expression of IGF-I, IGF-II, IGFBP-4, IGFBP-5 and type II receptor in follicular cells strongly differ between mammalian species, suggesting that these phenomena might play species-specific or secondary roles in ovarian folliculogenesis.


Subject(s)
Animals, Domestic/metabolism , Insulin-Like Growth Factor Binding Proteins/metabolism , Ovarian Follicle/physiology , Somatomedins/metabolism , Animals , Female , Gene Expression , Insulin-Like Growth Factor Binding Protein 2/metabolism , Insulin-Like Growth Factor Binding Protein 4/metabolism , RNA, Messenger/metabolism , Receptor, IGF Type 1/metabolism , Species Specificity
7.
Histol Histopathol ; 17(4): 1239-67, 2002 10.
Article in English | MEDLINE | ID: mdl-12371151

ABSTRACT

Despite the recognition that degenerative cartilage disorders like osteoarthritis (OA) and osteochondritis dissecans (OCD) may have nutritional abnormalities at the root of their pathogenesis, balanced dietary supplementation programs have played a secondary role in their management. This review emphasizes the importance and role of nutritional factors such as glucose and glucose-derived sugars (i.e. glucosamine sulfate and vitamin C) in the development, maintenance, repair, and remodeling of cartilage. Chondrocytes, the cells of cartilage, consume glucose as a primary substrate for ATP production in glycolysis and utilize glucosamine sulfate and other sulfated sugars as structural components for extracellular matrix synthesis and are dependent on hexose uptake and delivery to metabolic and biosynthetic pools. Data from several laboratories suggests that chondrocytes express multiple isoforms of the GLUT/SLC2A family of glucose/polyol transporters. These facilitative glucose transporter proteins are expressed in a tissue and cell-specific manner, exhibit distinct kinetic properties, and are developmentally regulated. They may also be regulated by endocrine factors like insulin and insulin-like growth factor I (IGF-I) and cytokines such as interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha). Recent studies suggest that degeneration of cartilage may be triggered by metabolic disorders of glucose balance and that OA occurs coincident with metabolic disease, endocrine dysfunction and diabetes mellitus. Based on these metabolic, endocrine and developmental considerations we present a novel hypothesis regarding the role of glucose transport and metabolism in cartilage physiology and pathophysiology and speculate that supplementation with sugar-derived vitamins and nutraceuticals may benefit patients with degenerative joint disorders.


Subject(s)
Bone Development/physiology , Cartilage/pathology , Chondrocytes/metabolism , Chondrogenesis/physiology , Glucose/metabolism , Osteoarthritis/pathology , Animals , Ascorbic Acid/physiology , Bone and Bones/blood supply , Cartilage/ultrastructure , Cartilage, Articular/anatomy & histology , Cartilage, Articular/pathology , Cartilage, Articular/physiology , Chondrocytes/pathology , Endocrine Glands/physiology , Humans , Monosaccharide Transport Proteins/metabolism , Nutritional Physiological Phenomena , Regional Blood Flow
8.
Hum Reprod ; 17(8): 2096-100, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12151443

ABSTRACT

BACKGROUND: Auto-immune adrenal insufficiency is a potentially fatal disorder. Young women with spontaneous premature ovarian failure (POF) are at increased risk of developing this condition. METHODS: We further characterized auto-immune adrenal insufficiency in this population by conducting an in-depth cross-sectional evaluation of adrenal function in a series of 123 women. RESULTS: We uncovered a new diagnosis of adrenal insufficiency in four women [3.2%, 95% confidence interval (CI) 0.2-6.4%]. All four tested positive for adrenal antibodies as detected by a clinically available indirect immunofluorescence assay. A positive adrenal antibody test was highly associated with adrenal insufficiency while a negative test was associated with normal adrenal function in all cases (P < 0.001). Adrenal antibodies increased the pretest probability of adrenal insufficiency from 3.2 to 67%. As a screening method the cortisol response during a standard adrenocorticotrophic hormone (ACTH) stimulation test gave two false positive results (1.7%, upper 95% confidence limit 5.0%). CONCLUSIONS: Our findings suggest that measuring adrenal antibodies would be an effective screening method by which to detect auto-immune adrenal insufficiency in young women with spontaneous POF. The standard ACTH stimulation test should be reserved to confirm adrenal insufficiency in women with adrenal antibodies, or those with signs and symptoms of adrenal insufficiency.


Subject(s)
Adrenal Glands/immunology , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/etiology , Autoantibodies/analysis , Autoimmune Diseases/diagnosis , Autoimmune Diseases/etiology , Primary Ovarian Insufficiency/complications , Adrenal Insufficiency/blood , Adrenal Insufficiency/immunology , Adrenocorticotropic Hormone , Adult , Autoimmune Diseases/blood , Autoimmune Diseases/immunology , Cross-Sectional Studies , Female , Fluorescent Antibody Technique, Indirect , Humans , Hydrocortisone/blood , Polyendocrinopathies, Autoimmune/diagnosis
9.
J Neurosci Res ; 64(4): 341-7, 2001 May 15.
Article in English | MEDLINE | ID: mdl-11340640

ABSTRACT

The dentate gyrus is selectively reduced in size in the insulin-like growth factor 1 (IGF1) null mouse brain. The purpose of this study was to determine whether this defect is due to reduced granule cell numbers, and if so, to determine whether altered cell proliferation, survival, or both contribute to attenuation of dentate gyrus size. At postnatal day 10 (P10), granule cell numbers were not significantly different in IGF1 null and littermate wildtype (WT) dentate gyri. The subgranular zone cell population, however, was relatively increased, and the granule cell layer population relatively decreased in the IGF1 null dentate gyrus. By P50, total dentate cell numbers were decreased by 20% (P = 0.01) in the IGF1 null mouse, although IGF1 null subgranular zone progenitor cells remained relatively increased compared with WT (38%, P < 0.05). IGF1 null dentate cell proliferation, assessed by thymidine analogue incorporation, was actually increased at P10 (33%, P < 0.05) and P50 (167%, P = 0.001). Dentate granule cell death, assessed by the appearance of pycnotic cells and DNA fragmentation, was also significantly increased in the IGF1 null dentate (61%, P < 0.05 and 101%, P = 0.03). These data suggest that endogenous IGF1 serves an important role in dentate granule cell survival during the course of postnatal brain development. In addition, this work suggests the potential of a compensatory mechanism promoting increased dentate cell proliferation in the face of impaired cell survival during postnatal neurogenesis. J. Neurosci. Res. 64:341-347, 2001. Published 2001 Wiley-Liss, Inc.


Subject(s)
Dentate Gyrus/cytology , Insulin-Like Growth Factor I/physiology , Animals , Brain/cytology , Cell Count , Cell Survival/physiology , Insulin-Like Growth Factor I/deficiency , Mice , Mice, Mutant Strains , Organ Size/physiology
10.
FASEB J ; 15(6): 907-15, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11292650

ABSTRACT

Estrogen has many positive effects on neural tissue in experimental model systems, including stimulation of neurite growth and neurotransmitter synthesis and protection against diverse types of neural injury. In humans, estrogen treatment is reputed to protect against Alzheimer's disease. To investigate potential mediators of estrogen's action and determine whether selective estrogen receptor modulators (SERMs) such as tamoxifen have estrogen-like effects in the primate brain, we evaluated the expression of glucose transporters and insulin-like growth factor 1 (IGF1) and its receptor in the frontal cortex of ovariectomized rhesus monkeys. We treated one group for 3 days with vehicle, another with 17 beta estradiol (E2), and a third with tamoxifen. The expression of facilitative glucose transporters (Gluts) 1, 3, and 4 was investigated using in situ hybridization, immunohistochemistry, and immunoblot analysis. Gluts 3 and 4 were concentrated in cortical neurons and Glut1 in capillaries and glial cells. E2 treatment induced two- to fourfold increases in Glut3 and Glut4 mRNA levels and lesser but significant increases in Glut3 and 4 protein levels. E2 treatment induced an approximately 70% increase in parenchymal Glut1 mRNA levels, but did not appreciably affect vascular Glut1 gene expression. IGF1 and IGF1 receptor mRNAs were concentrated in cortical neurons in a distribution similar to Gluts 3 and 4. IGF1 mRNA levels were significantly increased in E2-treated animals but IGF1 receptor mRNA levels were not altered by hormone treatment. Tamoxifen increased cerebral cortical Glut3 and 4 mRNA levels, but did not affect Glut1, IGF1, or IGF1 receptor expression. This study provides novel data showing that Gluts 3 and 4 and IGF1 are coexpressed by primate cerebral cortical neurons, where their expression is enhanced by estrogen. These findings suggest that up-regulation of glucose transporter and IGF1 expression may contribute to estrogen's salutary effects on neural tissue. Tamoxifen, an antiestrogen at the breast, is shown to have estrogen-like effects on higher brain centers in the monkey, suggesting that some SERMs may share estrogen's neuroprotective potential for menopausal women.


Subject(s)
Cerebral Cortex/drug effects , Estradiol/pharmacology , Gene Expression/drug effects , Insulin-Like Growth Factor I/biosynthesis , Monosaccharide Transport Proteins/biosynthesis , Muscle Proteins , Nerve Tissue Proteins , Animals , Antineoplastic Agents, Hormonal/pharmacology , Cerebral Cortex/metabolism , Female , Glucose Transporter Type 3 , Glucose Transporter Type 4 , Macaca mulatta , Monosaccharide Transport Proteins/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/drug effects , Receptor, IGF Type 1/biosynthesis , Tamoxifen/pharmacology
11.
J Investig Med ; 49(1): 47-55, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11217147

ABSTRACT

BACKGROUND: Insulin-like growth factor 1 (IGF1) plays a critical role in estrogen-induced uterine proliferation, but it is unclear whether this estromedin function occurs in other estrogen-sensitive tissues such as the mammary gland. To elucidate this possibility, we investigated the cellular localization and hormonal regulation of mRNAs for IGF1 and 2, their cognate receptors (IGF1R, IGF2R), and IGF binding proteins 2-5 (BPs 2-5) in the rhesus monkey mammary gland. METHODS: Ovariectomized monkeys were treated with placebo, estradiol (E2), and E2 plus progesterone (E2/P4) for 3 days, after which mammary tissue was harvested for in situ hybridization and immunohistochemical analyses. RESULTS: IGF1 and IGF2 mRNA levels were significantly increased and BP2 mRNA decreased by E2 and by E2/P4 treatment. IGF1R mRNA was increased by combined E2/P treatment but not by E2 alone. BP5 mRNA was decreased by E2/P4. No differences in IGF2R, BP3, and BP4 mRNA levels were detected in any treatment group. Mammary IGF1 and IGF2 mRNA levels were both positively correlated with local epithelial proliferation, assessed by immunodetection of the proliferation-specific antigen, Ki67.IGF1 and IGF1R expression were negatively correlated with local programmed cell death, as assessed by the in situ TUNEL method. In contrast, BP2 expression was negatively correlated with epithelial proliferation and positively correlated with programmed cell death. IGF2R, BP3, BP4, and BP5 levels were not significantly correlated with either proliferation or death. CONCLUSIONS: Thus, E2-induced proliferation is associated with upregulation of both IGF1 and IGF2 expression and downregulation of BP2 expression. These data suggest that the local mammary IGF system is involved in sex steroid-induced mammary epithelial cell hyperplasia.


Subject(s)
Mammary Glands, Animal/metabolism , Somatomedins/metabolism , Animals , Estradiol/pharmacology , Female , Insulin-Like Growth Factor Binding Proteins/genetics , Insulin-Like Growth Factor Binding Proteins/metabolism , Macaca mulatta , Mammary Glands, Animal/cytology , Mammary Glands, Animal/drug effects , Progesterone/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Somatomedin/genetics , Receptors, Somatomedin/metabolism , Somatomedins/genetics
12.
Nat Genet ; 26(3): 267-8, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11062459

ABSTRACT

Maternal effect genes produce mRNA or proteins that accumulate in the egg during oogenesis. We show here that Mater, a mouse oocyte protein dependent on the maternal genome, is essential for embryonic development beyond the two-cell stage. Females lacking the maternal effect gene Mater are sterile. Null males are fertile.


Subject(s)
Antigens , Egg Proteins/physiology , Embryonic and Fetal Development/genetics , Genes , Genomic Imprinting/genetics , Mice/genetics , Animals , Blastocyst/pathology , Egg Proteins/genetics , Female , Fetal Resorption/genetics , Infertility, Female/genetics , Leucine Zippers/genetics , Leucine Zippers/physiology , Mice/embryology , Mice, Knockout , Oocytes/metabolism , Ovary/metabolism , RNA, Messenger, Stored/genetics
13.
FASEB J ; 14(12): 1725-30, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10973921

ABSTRACT

This study investigated the effect of sex steroids and tamoxifen on primate mammary epithelial proliferation and steroid receptor gene expression. Ovariectomized rhesus monkeys were treated with placebo, 17beta estradiol (E2) alone or in combination with progesterone (E2/P) or testosterone (E2/T), or tamoxifen for 3 days. E2 alone increased mammary epithelial proliferation by approximately sixfold (P:<0.0001) and increased mammary epithelial estrogen receptor (ERalpha) mRNA expression by approximately 50% (P:<0.0001; ERbeta mRNA was not detected in the primate mammary gland). Progesterone did not alter E2's proliferative effects, but testosterone reduced E2-induced proliferation by approximately 40% (P:<0.002) and entirely abolished E2-induced augmentation of ERalpha expression. Tamoxifen had a significant agonist effect in the ovariectomized monkey, producing a approximately threefold increase in mammary epithelial proliferation (P:<0.01), but tamoxifen also reduced ERalpha expression below placebo level. Androgen receptor (AR) mRNA was detected in mammary epithelium by in situ hybridization. AR mRNA levels were not altered by E2 alone but were significantly reduced by E2/T and tamoxifen treatment. Because combined E2/T and tamoxifen had similar effects on mammary epithelium, we investigated the regulation of known sex steroid-responsive mRNAs in the primate mammary epithelium. E2 alone had no effect on apolipoprotein D (ApoD) or IGF binding protein 5 (IGFBP5) expression, but E2/T and tamoxifen treatment groups both demonstrated identical alterations in these mRNAs (ApoD was decreased and IGFBP5 was increased). These observations showing androgen-induced down-regulation of mammary epithelial proliferation and ER expression suggest that combined estrogen/androgen hormone replacement therapy might reduce the risk of breast cancer associated with estrogen replacement. In addition, these novel findings on tamoxifen's androgen-like effects on primate mammary epithelial sex steroid receptor expression suggest that tamoxifen's protective action on mammary gland may involve androgenic effects.


Subject(s)
Estrogens/pharmacology , Gene Expression/drug effects , Receptors, Estrogen/biosynthesis , Testosterone/pharmacology , Animals , Cell Division/drug effects , Drug Interactions , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Female , Macaca mulatta , Progesterone/pharmacology , Receptors, Androgen/metabolism , Receptors, Estrogen/genetics , Tamoxifen/pharmacology
14.
Proc Natl Acad Sci U S A ; 97(18): 10236-41, 2000 Aug 29.
Article in English | MEDLINE | ID: mdl-10954733

ABSTRACT

The brain has enormous anabolic needs during early postnatal development. This study presents multiple lines of evidence showing that endogenous brain insulin-like growth factor 1 (Igf1) serves an essential, insulin-like role in promoting neuronal glucose utilization and growth during this period. Brain 2-deoxy-d- [1-(14)C]glucose uptake parallels Igf1 expression in wild-type mice and is profoundly reduced in Igf1-/- mice, particularly in those structures where Igf1 is normally most highly expressed. 2-Deoxy-d- [1-(14)C]glucose is significantly reduced in synaptosomes prepared from Igf1-/- brains, and the deficit is corrected by inclusion of Igf1 in the incubation medium. The serine/threonine kinase Akt/PKB is a major target of insulin-signaling in the regulation of glucose transport via the facilitative glucose transporter (GLUT4) and glycogen synthesis in peripheral tissues. Phosphorylation of Akt and GLUT4 expression are reduced in Igf1-/- neurons. Phosphorylation of glycogen synthase kinase 3beta and glycogen accumulation also are reduced in Igf1-/- neurons. These data support the hypothesis that endogenous brain Igf1 serves an anabolic, insulin-like role in developing brain metabolism.


Subject(s)
Brain/physiology , Deoxyglucose/pharmacokinetics , Glucose/metabolism , Insulin-Like Growth Factor I/physiology , Muscle Proteins , Neurons/physiology , Protein Serine-Threonine Kinases , Animals , Brain/drug effects , Brain/growth & development , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Gene Expression Regulation , Glucose Transporter Type 4 , Glycogen/biosynthesis , Glycogen Synthase Kinase 3 , Glycogen Synthase Kinases , Insulin-Like Growth Factor I/deficiency , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/pharmacology , Male , Mice , Mice, Knockout , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Monosaccharide Transport Proteins/genetics , Monosaccharide Transport Proteins/metabolism , Phosphorylation , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Rats , Rats, Sprague-Dawley , Signal Transduction , Transcription, Genetic
15.
Growth Horm IGF Res ; 10(3): 111-7, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10942631

ABSTRACT

Granulosa cells provide nutritional and trophic support for growing oocytes in ovarian follicles. The granulosa cells closest to the oocyte produce abundant insulin-like growth factor 1 (IGF1) and the IGF1 receptor is highly expressed by oocytes, suggesting that granulosa-derived IGF1 may have trophic effects on oocyte growth and development. To investigate this possibility, in the present study we used in situ hybridization and immunohistochemistry to examine glucose transporter (GLUTs 1, 3 & 4) expression in follicles from pre-pubertal Igf1-/- and littermate wildtype (wt) mice. Pre-pubertal mice were used for this study because the Igf1 null mice do not mature sexually. GLUT1 mRNA and immunoreactivity were most abundant in oocytes and in granulosa cells immediately surrounding the oocyte. Expression of this transporter was significantly reduced in Igf1 null oocytes and granulosa cells and was restored by exogenous IGF1 treatment to wt levels. These effects on GLUT expression were significant at both the mRNA and immunoreactive protein levels. Oestrogen treatment significantly increased GLUT1 levels in oocytes and granulosa from both wt and Igf1-/-, although the latter were still significantly lower than wt. Oocyte glycogen stores, determined by PAS staining, did not appear different in Igf1-/- and wt mice.GLUT3 was expressed in thecal cells surrounding growing follicles and was not appreciably different in Igf1 null compared with wt ovaries. GLUT4 expression was not detected in the prepubertal mouse ovary. Together with observations from previous studies showing that ovulation is blocked in Igf1 null mice, the present data suggest that IGF1's augmentation of granulosal and oocyte GLUT1 expression may be essential for oocyte maturation and successful ovulation.


Subject(s)
Gene Expression Regulation , Insulin-Like Growth Factor I/physiology , Monosaccharide Transport Proteins/genetics , Nerve Tissue Proteins , Oocytes/physiology , Ovarian Follicle/physiology , Transcription, Genetic , Animals , Estradiol/analysis , Female , Glucose Transporter Type 1 , Glucose Transporter Type 3 , Glycogen/analysis , Homozygote , Immunohistochemistry , Insulin-Like Growth Factor I/deficiency , Insulin-Like Growth Factor I/genetics , Mice , Mice, Knockout , Monosaccharide Transport Proteins/analysis , Oocytes/cytology , Ovarian Follicle/cytology , RNA, Messenger/genetics
16.
FASEB J ; 13(14): 1985-90, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10544181

ABSTRACT

Longitudinal bone growth, and hence stature, are functions of growth plate chondrocyte proliferation and hypertrophy. Insulin-like growth factor 1 (Igf1) is reputed to augment longitudinal bone growth by stimulating growth plate chondrocyte proliferation. In this study, however, we demonstrate that chondrocyte numbers and proliferation are normal in Igf1 null mice despite a 35% reduction in the rate of long bone growth. Igf1 null hypertrophic chondrocytes differentiate normally in terms of expressing specialized proteins such as collagen X and alkaline phosphatase, but are smaller than wild-type at all levels of the hypertrophic zone. The terminal hypertrophic chondrocytes, which form the scaffold on which long bone growth extends, are reduced in linear dimension by 30% in Igf1 null mice, accounting for most of their decreased longitudinal growth. The expression of the insulin-sensitive glucose transporter, GLUT4, is significantly decreased and the insulin-regulated enzyme glycogen synthase kinase 3beta (GSK3) is hypo-phosphorylated in Igf1 null chondrocytes. Glycogen levels were significantly decreased and ribosomal RNA levels were reduced by almost 75% in Igf1 null chondrocytes. These data suggest that Igf1 promotes longitudinal bone growth by 'insulin-like' anabolic actions which augment chondrocyte hypertrophy.


Subject(s)
Chondrocytes/pathology , Growth Plate/physiology , Insulin-Like Growth Factor I/physiology , Insulin/physiology , Muscle Proteins , Animals , Cell Division , Glucose Transporter Type 4 , Glycogen/metabolism , Hypertrophy , Mice , Monosaccharide Transport Proteins/analysis , RNA, Ribosomal/analysis
17.
Hum Reprod ; 14(9): 2328-32, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10469704

ABSTRACT

It has recently been shown that androgens increase the growth of immature follicles in the primate ovary. In the present study the effect of androgens on ovarian insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression was investigated. The study groups included five follicular phase, placebo-treated controls, and four testosterone- and three dihydrotestosterone (DHT)-treated rhesus monkeys. The treatment period was 5 days. Both testosterone and DHT treatment resulted in significant, 3-4-fold increases in IGF-I mRNA concentration in granulosa, thecal and interstitial compartments. Likewise, both androgens induced significant increases in the amount of IGF-I receptor mRNA, most notably in thecal cells and less markedly in granulosa and interstitium (P < 0.05). These changes in amounts of IGF system mRNA were documented in growing follicles up to the small antral (

Subject(s)
Dihydrotestosterone/pharmacology , Gene Expression/drug effects , Insulin-Like Growth Factor I/genetics , Ovary/metabolism , Receptor, IGF Type 1/genetics , Testosterone/pharmacology , Animals , Female , Follicular Phase , Macaca mulatta , Placebos , RNA, Messenger/analysis
18.
J Clin Endocrinol Metab ; 84(8): 2951-6, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10443703

ABSTRACT

We have previously shown that androgens stimulate early stages of follicular development and that granulosal androgen receptor (AR) gene expression is positively correlated with follicular growth. The present study was aimed at elucidating potential interactions between FSH and androgens in follicular development. Study groups included eight normal cycling rhesus monkeys (five follicular and three luteal-phase), eight testosterone (T)-treated, and four FSH-treated animals. Examination of sequential ovary sections revealed selective colocalization of AR and FSH receptor (FSHR) messenger RNAs (mRNAs) in healthy, growing follicles. Moreover, individual follicles demonstrate a highly significant (P < 0.001) positive correlation between FSHR and AR mRNA levels in all study groups. Androgen treatment significantly increased granulosa cell FSHR mRNA abundance (by approximately 50-100%, depending on follicle size). FSH treatment increased granulosa AR mRNA levels only in primary follicles. The finding that T augments follicular FSHR expression suggests that androgens promote follicular growth and estrogen biosynthesis indirectly, by amplifying FSH effect, and may partially explain the enhanced responsiveness to gonadotropin stimulation noted in women with polycystic ovary syndrome.


Subject(s)
Androgens/pharmacology , Follicle Stimulating Hormone/pharmacology , Ovarian Follicle/drug effects , Animals , Aromatase/genetics , Female , Macaca mulatta , Ovarian Follicle/physiology , Ovulation , Polycystic Ovary Syndrome/physiopathology , RNA, Messenger/analysis , Receptors, Androgen/genetics , Receptors, FSH/genetics
19.
Biol Reprod ; 61(2): 353-7, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10411511

ABSTRACT

In the study reported here, we investigated the effect of androgens on recruitment of resting, primordial follicles into the actively growing pool. Healthy, random-cycling female rhesus monkeys were treated with testosterone, dihydrotestosterone (DHT), or vehicle for 3-10 days, after which ovaries were collected for histological analysis. The first stage of follicle growth is the formation of the primary follicle, consisting of an oocyte surrounded by a single layer of cuboidal granulosa cells. The number of primary follicles was significantly increased over time in testosterone-treated animals. In situ hybridization showed that androgen treatment resulted in an increase to 3-fold in insulin-like growth factor I (IGF-I) and to 5-fold in IGF-I receptor mRNA in primordial follicle oocytes. DHT effects were comparable to those of testosterone, showing that these are androgen receptor-mediated phenomena. These data show that androgens promote initiation of primordial follicle growth and implicate oocyte-derived IGF-I in this activation process.


Subject(s)
Androgens/pharmacology , Insulin-Like Growth Factor I/biosynthesis , Macaca mulatta/growth & development , Oocytes/drug effects , Oocytes/metabolism , Ovarian Follicle/growth & development , Animals , Dihydrotestosterone/pharmacology , Female , Insulin-Like Growth Factor I/genetics , RNA, Messenger/analysis , Receptor, IGF Type 1/biosynthesis , Receptor, IGF Type 1/genetics , Testosterone/pharmacology
20.
Proc Natl Acad Sci U S A ; 96(6): 3287-91, 1999 Mar 16.
Article in English | MEDLINE | ID: mdl-10077676

ABSTRACT

Insulin-like growth factor 1 (IGF1) has been proposed as a "G1-progression factor" and as a mediator of estradiol's (E2) mitogenic effects on the uterus. To test these hypotheses, we compared E2's mitogenic effects on the uteri of Igf1-targeted gene deletion (null) and wild-type littermate mice. The proportion of uterine cells involved in the cell cycle and G1- and S-phase kinetics were not significantly different in wild-type and Igf1-null mice. However, the appearance of E2-induced mitotic figures and cell number increases were profoundly retarded in Igf1-null uterine tissue. There was a significant increase in nuclear DNA concentration in Igf1-null cells, consistent with a G2 arrest. Interestingly, apoptotic cells were also significantly reduced in abundance, and the normal massive apoptotic response to E2 withdrawal was absent in the Igf1-null uterus. These data show that Igf1 is an essential mediator of E2's mitogenic effects, with a critical role not in G1 progression but in G2 progression.


Subject(s)
Estradiol/pharmacology , G2 Phase/genetics , Insulin-Like Growth Factor I/genetics , Mitosis/genetics , Uterus/cytology , Animals , DNA Replication , Female , G2 Phase/drug effects , Mice , Mitosis/drug effects , Mitotic Index
SELECTION OF CITATIONS
SEARCH DETAIL
...