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Ovarian Function
Chatterton, R. | Dunaif, A. | Mayo, K. |
Shea, Lonnie |
Stack, S. |
Woodruff, T.
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Robert T. Chatterton, Jr., Ph.D.
Department Obstetrics and Gynecology
Ph.D., Cornell University
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Studies of the effect of stress on reproduction are presently focused on biochemical and
molecular studies of the effects of glucocorticoids on testosterone biosynthesis. We have
demonstrated a high degree of cooperativity in binding of LH to its testicular receptor.
Binding of the second molecule of LH is more than 500 times the binding affinity of the
first. Corticosterone inhibits testosterone secretion by a post-receptor mechanism and is
exerted on cytochrome P45017. The mechanism by which this effect is mediated is the topic
of current investigation.
We have investigated the
role of the adrenal androgens, particularly dehydroepiandrosterone sulfate (DS), in
rheumatoid arthritis, hemophilia, and HIV infection. In each of these conditions DS levels
decline in proportion to the severity of the condition. The role of the cytokines IL-1 and
TNF in mediation of this response and the significance of the loss of the
immunostimulatory effects of DS are under investigation.
We are continuing studies
of the effects of diet on hormone levels, particularly DS, cortisol, and estrogens, as
these hormones relate to susceptibility to breast cancer, with colleagues in the
Department of Preventive Medicine. We are also examining the relation between steroid
hormones and the formation of growth factors by breast tissue.
Studies on contraceptive
development have continued with the evaluation of tissue-specific actions of
antiestrogens. The contraceptive steroid anordrin was compared to the stilbene
antiestrogen clomiphene. Having completed all of the preclinical testing of anordrin, a
phase I clinical trial of this compound is expected to be initiated in the Clinical
Research Center at Northwestern this year. We also expect to begin studies on a steroidal
male contraceptive this year.
Recent Publications:
Chatterton RT Jr, Geiger AS, Mateo ET, Helenowski IB, Gann PH. Comparison of hormone levels in nipple aspirate fluid (NAF) of pre- and post-menopausal women: effect of oral contraceptives and hormone replacement. J Clin Endocrinol Metab. 2004 Mar;90(3):1686-91.
Hill PD, Wilhelm PA, Aldag JC, Chatterton RT Jr. Breast augmentation & lactation outcome: a case report. MCN Am J Matern Child Nurs. 2004 Jul-Aug;29(4):238-42. Review.
Chatterton RT Jr, Geiger AS, Khan SA, Helenowski IB, Jovanovic BD, Gann PH. Variation in estradiol, estradiol precursors, and estrogen-related products in nipple aspirate fluid from normal premenopausal women. Cancer Epidemiol Biomarkers Prev. 2004 Jun;13(6):928-35.
Hill PD, Aldag JC, Chatterton RT, Zinaman M. Comparison of milk output between mothers of preterm and term infants: The first 6 weeks after birth. J.Hum. Lact. 21:22-30, 2005.
Hill PD, Aldag JC, Chatterton RT, Zinaman M. Primary and secondary mediators influence on milk output in lactating mothers of preterm and term infants. J Hum. Lact. 21:138-150, 2005.
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Andrea Dunaif, M.D.
Division of Endocrinology
M.D., Columbia University College of Physicians
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The research themes of the Dunaif lab are the genetics of polycystic ovary syndrome (PCOS), the cellular molecular mechanisms of insulin resistance and the mechanisms underlying the association between metabolism and reproduction. There are three major research projects currently ongoing. The approaches range from large-scale family studies through intensive patient-oriented research to animal models and cellular and molecular biology. PCOS is the human disease model. This syndrome is characterized by increased androgen biosynthesis and disordered gonadotropin secretion. It is among the most common endocrine disorders of women, the leading cause of hormonally-related infertility and a major risk factor for type 2 diabetes mellitus.
The Genetic Basis of PCOS
This research program focuses on identifying the susceptibility genes for PCOS, performing genotype-phenotype analyses and identifying environmental and genetic factors contributing to PCOS familial phenotypes. Studies include family studies with linkage analysis and detailed analyses of reproductive function and insulin action in women with PCOS and their relatives. The approaches include statistical genetics and in vivo studies of insulin action and secretion, as well as pulsatile gonadotropin secretion. One susceptibility gene region has been identified on chromosome 19p13.2 close to the insulin receptor gene. This research is supported by the NIH-NICHD National Cooperative Program for Infertility Research.
Insulin Action and Secretion in PCOS
These studies are focused on identifying the cellular and molecular mechanisms of defects in insulin action and secretion in PCOS. Approaches include detailed in vivo studies of these parameters utilizing techniques such as the euglycemic glucose clamp, frequently sampled intravenous glucose intolerance test with minimal model analysis and graded glucose infusions. Insulin receptor signal transduction is examined in human skeletal muscle biopsies, as well as in human skeletal muscle and adipocyte cultures. Intrinsic defects in insulin receptor signaling have been identified and the mechanisms of these abnormalities are currently under investigation. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Fetal Origins of PCOS
These studies examine the impact of prenatal androgen exposure on insulin action in rodent, primate and sheep models. Studies include examination of lipolysis and insulin signaling in skeletal muscle and adipose tissue and the molecular mechanism of fetal programming. These studies are supported by an NIH-NICHD-ORWH Specialized Center of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health.
Recent Publications
Dunaif A. Hyperandrogenemia is necessary but not sufficient for polycystic ovary syndrome. Fertil Steril 2003;2:262-3.
Urbanek M, Du Y, Silander, Collins FS, Steppan CM, Strauss JR, A Dunaif , Spielman RS, Legro RS. Variation in resistin gene promoter not associated with polycystic ovary syndrome (PCOS). Diabetes 52:214-217, 2003
Jabara S, Christenson LK, Wang CY, McCallister JM, Javitt NB, A Dunaif, Strauss JF. Stromal cells of the human postmenopausal ovary display a distinctive biochemical and molecular phenotype. J Clin Endocrinol Metab 88:484-492, 2003
Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab. 2003;8:365-70.
Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A. Insulin Resistance in the Skeletal Muscle of Women with Polycystic Ovary Syndrome Involves both Intrinsic and Acquired Defects in Insulin Signaling. Am J Physiol Endocrinol Metab. 2004 Dec 21; [Epub ahead of print]
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Kelly E. Mayo, Ph.D.
Department of Biochemistry, Molecular
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Our laboratory investigates cell signaling and gene expression in the mammalian reproductive axis.
Our research program in reproductive biology seeks to understand how hormones secreted from the pituitary gland (FSH and LH) act on the ovary to bring about the changes in cell proliferation, cell differentiation and gene expression that will result in ovulation and luteinization of the ovarian follicle during each reproductive cycle. We use the genes encoding the hormones inhibin and activin, which are produced in the ovary and act on the pituitary gland to regulate reproductive hormone secretion, as a model system to address these questions. We are presently focused on two major research directions. We are investigating the dynamic regulation of inhibin expression during the reproductive cycle, and are exploring the roles of cAMP-responsive transcription factors (CREB and ICER) as well as the related orphan nuclear receptors steroidogenic factor-1 (SF-1) and liver receptor homologue-1 (LRH-1), in this process. We are also investigating developmental pathways in the ovary involved in the initial formation and growth of ovarian follicles, and are attempting to understand how inhibin and activin regulate normal follicle development and how their misexpression might contribute to the formation of abnormal follicles. Our work focuses on molecular mechanisms regulating normal reproductive function, but is substantially informed by, and relevant to, reproductive disorders that impact fertility.
Recent Publications:
Burkart, A.D., Mukherjee, A., Sterneck, E., Johnson, P.F., and Mayo, K.E. (2005). Repression of the Inhibin a Subunit Gene by the Transcription Factor CCAAT/Enhancer Binding Protein Beta (C/EBPb). Endocrinology 146:1909-1921.
Bristol-Gould, S.K., Hutten, C.G., Sturgis, C., Kilen, S.M., Mayo, K.E., and Woodruff, T.K. (2005) The Development of a Mouse Model of Ovarian Endosalpingiosis. Endocrinology 146:5228-5236.
Burkart, A.D., Mukherjee, A., and Mayo, K.E. (2006) Mechanism of Repression of the Inhibin a Subunit Gene by Inducible cAMP Early Repressor Molecular Endocrinology 20:584-97.
Little, T.H., Zhang, Y., Matulis, C.K., Weck, J., Zhang, Z., Ramachandran, A., Mayo, K.E., and Radhakrishnan, I. (2006) Sequence-Specific DNA Recognition by Steroidogenic Factor 1: A Helix at the Carboxy-Terminus of the DNA Binding Domain is Necessary for Complex Stability. Molecular Endocrinology 20:831-843.
Weck, J., and Mayo, K.E. (2006) Switching of NR5A Proteins Associated with the Inhibin a-Subunit Gene Promoter Following Activation of the Gene in Granulosa Cells. Molecular Endocrinology 20:1090-1103.
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Lonnie Shea, PhD
Department of Chemical and Biological Engineering
PhD, University of Michigan
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My laboratory develops and employs biomaterials and controlled delivery (protein, DNA) systems to create synthetic environments for directing and analyzing cellular functions, which have applications to tissue regeneration and development, and diagnostics assays. Biomaterial scaffolds can create three-dimensional culture environments that regulate cell-cell and cell-matrix interactions, and to provide a controlled release of protein and DNA. In a highly collaborative project with Teresa Woodruff, we are developing scaffolds for the in vitro maturation of ovarian follicles. Follicles from several stages of development are encapsulated within designer hydrogels, cultured, and the resulting oocyte are isolated and examined for meiotic competence and fertilization. This system is being applied to examine the basic biology underlying follicle development, and may provide a critical technology that will enable the preservation of fertility for chemotherapy-induced sterility or other reproductive disorders.
Recent Publications:
P.K. Kreeger, J. Deck, T.K. Woodruff, and L.D. Shea. ÒReconstructed Basement Membrane Regulation of Murine Follicle Maturation in a Three-Dimensional Culture System.Ó Society for the Study of Reproduction. Vancouver, Canada. August 2004. USDA Merit Award
P.K. Kreeger, C.B. Berkholtz, N.N. Fernandes, T.K. Woodruff, and L.D. Shea,. ÒGonadotrophin Supplementation Enhances Development for Murine Preantral Follicles Cultured in a Three-Dimensional System.Ó Society for the Study of Reproduction. Vancouver, Canada. August 2004.
Berkholtz, C.B., T.K. Woodruff, and L.D. Shea ÒNGF enhances survival in 3D primary follicle cultures in vitro.Ó Society for the Study of Reproduction. Vancouver, Canada. August 2004
Kreeger, P.K., "Alginate Scaffolds for the Culture of Ovarian Follicles in a Stage Specific Manner" 2004 Annual AIChE meeting, Austin, TX, November 2004, Meet the Faculty Candidates
Whittlesey, K.J., C. Rives, L. De Laporte, and L.D. Shea, ÒDegradable Multilumen Scaffolds To Potentiate Regeneration By Gene DeliveryÓ Society for Neuroscience, November 2004.
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M. Sharon Stack, Ph.D.
Cell & Molecular Biology
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Recent Publications:
Graves LE, Ariztia EV, Navari JR, Matzel HJ, Stack MS, Fishman DA. Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. Cancer Res. 2004 Oct 1;64(19):7045-9.
Munshi HG, Wu YI, Mukhopadhyay S, Ottaviano AJ, Sassano A, Koblinski JE, Platanias LC,
Stack MS. Differential regulation of membrane type 1-matrix metalloproteinase activity by ERK 1/2- and p38 MAPK-modulated tissue inhibitor of metalloproteinases 2 expression controls transforming growth factor-beta1-induced pericellular collagenolysis. J Biol Chem. 2004 Sep 10;279(37):39042-50.
Lorch JH, Klessner J, Park JK, Getsios S, Wu YL, Stack MS, Green KJ. Epidermal growth factor receptor inhibition promotes desmosome assembly and strengthens intercellular adhesion in squamous cell carcinoma cells. J Biol Chem. 2004 Aug 27;279(35):37191-200.
Mukhopadhyay S, Munshi HG, Kambhampati S, Sassano A, Platanias LC, Stack MS. Calcium-induced matrix metalloproteinase 9 gene expression is differentially regulated by ERK1/2 and p38 MAPK in oral keratinocytes and oral squamous cell carcinoma. J Biol Chem. 2004 Aug 6;279(32):33139-46.
Tam EM, Morrison CJ, Wu YI, Stack MS, Overall CM. Membrane protease proteomics: Isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. Proc Natl Acad Sci U S A. 2004 May 4;101(18):6917-22.
DeClerck YA, Mercurio AM, Stack MS, Chapman HA, Zutter MM, Muschel RJ, Raz A, Matrisian LM, Sloane BF, Noel A, Hendrix MJ, Coussens L, Padarathsingh M. Proteases, extracellular matrix, and cancer: a workshop of the path B study section. Am J Pathol. 2004 Apr;164(4):1131-9.
Wu YI, Munshi HG, Sen R, Snipas SJ, Salvesen GS, Fridman R, Stack MS. Glycosylation broadens the substrate profile of membrane type 1 matrix metalloproteinase. J Biol Chem. 2004 Feb 27;279(9):8278-89.
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Teresa K. Woodruff, Ph.D.
Center for Medical Endocrinology,
Metabolism and Nutrition Center/NBP
Ph.D., Northwestern University
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An understanding of the
biological, cellular, and molecular mechanisms that regulate the reproductive axis is the
goal of the laboratory. Hormones and locally produced growth factors of the gonads,
pituitary, and hypothalamus interact to maintain reproductive cyclicity in the female and
tonic sperm production in the male. The integration of endocrine, paracrine, and autocrine
mechanisms provides the precision demanded by nature to maintain the germ line of the
species.
The study of normal reproduction function requires measurement of fluctuating hormone
levels, identification of local factors involved in reproductive management, and an
understanding of the signaling mechanisms that cue cellular action. Diseases involving
reproductive systems include infertility (male and female), polycystic ovarian disease,
endometriosis, premature ovarian failure, preterm labor and delivery, and ovarian, breast,
testicular, and prostate cancer.
The specific focus of the laboratory at this time is the female reproductive axis. Our
approach requires an integrated view of the axis as a whole, however, emphasis is placed
on ovarian-regulated events. We seek to understand the hormonal signals produced by the
ovaries, the mechanics of follicular growth, the hormonal and neuronal effectors of
follicle selection and maturation, the factors involved in the development of oocytes, the
events surrounding follicle wall rupture and wound healing, and the interplay between
oocyte and somatic cells. Our scientific approach toward an understanding of
ovarian-directed reproductive events is to identify and study factors produced by the
ovary which regulate local and distal events.
The protein molecules that we are currently evaluating are inhibin and activin. While
our aims are broad, the utility of the inhibin and activin hormone family is that they
provide specific investigative tools. These hormones are integral factors in normal
ovarian function and may be inappropriately regulated in disease states.
We will extend our scope of inquiry to other areas of reproductive function with time.
For example, we are keenly interested in the regulation of the reproductive axis by cues
emanating from the brain, adrenal, and uterus. Signals involved in oocyte implantation,
maintenance of pregnancy, and onset of labor and delivery will be studied. Additionally,
male-specific normative and aberrant reproductive function will be studied. Further, our
work, can be extended to the preservation of the germ line of endangered species. We
anticipate that as we uncover new mechanisms of hormone action and effector function, we
will be more able to understand the biological, cellular, and molecular controls that
regulate the reproductive axis.
Recent Publications:
Park Y, Maizels ET, Feiger ZJ, Alam H, Peters CA, Woodruff TK, Unterman TG, Lee EJ, Jameson JL, Hunzicker-Dunn M. Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad. J Biol Chem. 2004 Dec 21; PMID: 15613482
Bernard DJ, Woodruff TK, Plant TM. Cloning of a novel inhibin alpha cDNA from rhesus monkey testis. Reprod Biol Endocrinol. 2004 Oct 07;2(1):71.
Thompson TB, Cook RW, Chapman SC, Jardetzky TS, Woodruff TK. Beta A versus beta B: is it merely a matter of expression? Mol Cell Endocrinol. 2004 Oct 15;225(1-2):9-17.
Cook RW, Thompson TB, Jardetzky TS, Woodruff TK. Molecular biology of inhibin action. Semin Reprod Med. 2004 Aug;22(3):269-76.
Tomic D, Miller KP, Kenny HA, Woodruff TK, Hoyer P, Flaws JA. Ovarian follicle development requires Smad3. Mol Endocrinol. 2004 Sep;18(9):2224-40.
Klein NA, Houmard BS, Hansen KR, Woodruff TK, Sluss PM, Bremner WJ, Soules MR. Age-related analysis of inhibin A, inhibin B, and activin a relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. J Clin Endocrinol Metab. 2004 Jun;89(6):2977-81.
Phillips DJ, Woodruff TK. Inhibin: actions and signalling. Growth Factors. 2004 Mar;22(1):13-8.
Bristol SK, Woodruff TK. Follicle-restricted compartmentalization of transforming growth factor beta superfamily ligands in the feline ovary. Biol Reprod. 2004 Mar;70(3):846-59.
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