Board-invited review: Estrogen and progesterone signaling: genomic and nongenomic actions in domestic ruminants.

Progesterone and estrogens play key roles in regulating various physiological phenomena related to normal growth, development, and reproduction of domestic animals. This review focuses on the mechanisms by which progesterone and estrogens regulate the reproductive processes in these animals. The majority of research on the actions of progesterone and estrogens on the reproductive systems of cattle, sheep, and pigs has been genomic in nature and represents attempts to better understand how these steroids regulate gene expression. Results of recent research suggest that progesterone and estrogens can alter target cell responses nongenomically via membrane receptors. The characteristics of membrane receptors for progesterone and estrogen in various cell types are described and the intracellular signal pathways defined. Estrogens acting via membrane receptors can suppress LH secretion by gonadotropes and stimulate rapid increases in uterine blood flow. Progesterone acting via a membrane receptor has been shown to inhibit binding of oxytocin to oxytocin receptors in isolated endometrial plasma membranes and stimulate capacitation of spermatozoa. Results of research suggest that progesterone and estrogens can act nongenomically to alter target cell responses in domestic animals. The biological implications of this mode of action in these animals are discussed.

[1]  T. Nett,et al.  Regulation of GnRH receptor gene expression in sheep and cattle. , 2019, Journal of reproduction and fertility. Supplement.

[2]  A. Herbison Neurochemical identity of neurones expressing oestrogen and androgen receptors in sheep hypothalamus. , 2019, Journal of reproduction and fertility. Supplement.

[3]  R. Sainson,et al.  A Conserved Mechanism for Steroid Receptor Translocation to the Plasma Membrane* , 2007, Journal of Biological Chemistry.

[4]  Margaret Warner,et al.  Estrogen receptors: how do they signal and what are their targets. , 2007, Physiological reviews.

[5]  D. H. Poole,et al.  EXPRESSION OF mRNA FOR MEMBRANE PROGESTERONE RECEPTORS BY BOVINE T LYMPHOCYTES , 2007 .

[6]  J. Dong,et al.  Activation of the novel estrogen receptor G protein-coupled receptor 30 (GPR30) at the plasma membrane. , 2007, Endocrinology.

[7]  A. Lewellyn,et al.  The role of Xenopus membrane progesterone receptor beta in mediating the effect of progesterone on oocyte maturation. , 2007, Molecular endocrinology.

[8]  S. Hammes,et al.  Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. , 2007, Annual review of physiology.

[9]  D. Edwards,et al.  The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. , 2007, Molecular endocrinology.

[10]  Jan J. Brosens,et al.  Human Homologs of the Putative G Protein-Coupled Membrane Progestin Receptors (mPRα, β, and γ) Localize to the Endoplasmic Reticulum and Are Not Activated by Progesterone , 2006 .

[11]  C. Lange,et al.  Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells , 2006, Molecular and Cellular Biology.

[12]  C. Clay,et al.  Cloning and characterization of an ovine intracellular seven transmembrane receptor for progesterone that mediates calcium mobilization. , 2006, Endocrinology.

[13]  J. Peluso,et al.  Progesterone membrane receptor component 1 expression in the immature rat ovary and its role in mediating progesterone's antiapoptotic action. , 2006, Endocrinology.

[14]  F. Stormshak,et al.  Nongenomic action of progesterone inhibits oxytocin-induced phosphoinositide hydrolysis and prostaglandin F2alpha secretion in the ovine endometrium. , 2006, Endocrinology.

[15]  S. Safe,et al.  Estrogen regulates transcription of the ovine oxytocin receptor gene through GC-rich SP1 promoter elements. , 2006, Endocrinology.

[16]  M. Beato,et al.  Progestin activation of nongenomic pathways via cross talk of progesterone receptor with estrogen receptor beta induces proliferation of endometrial stromal cells. , 2005, Molecular endocrinology.

[17]  P. Thomas,et al.  Steroid-Induced Oocyte Maturation in Atlantic Croaker (Micropogonias undulatus) Is Dependent on Activation of the Phosphatidylinositol 3-Kinase/Akt Signal Transduction Pathway , 2005, Biology of reproduction.

[18]  E. Lam,et al.  Regulated expression of putative membrane progestin receptor homologues in human endometrium and gestational tissues. , 2005, The Journal of endocrinology.

[19]  Martin J. Kelly,et al.  Diversity of ovarian steroid signaling in the hypothalamus , 2005, Frontiers in Neuroendocrinology.

[20]  T. Nett,et al.  A Nongenomic Action of 17β-Estradiol as the Mechanism Underlying the Acute Suppression of Secretion of Luteinizing Hormone1 , 2005, Biology of reproduction.

[21]  C. Lange,et al.  Integration of progesterone receptor mediated rapid signaling and nuclear actions in breast cancer cell models: Role of mitogen-activated protein kinases and cell cycle regulators , 2005, Steroids.

[22]  J. Kotwica,et al.  Non-genomic effect of steroids on oxytocin-stimulated intracellular mobilization of calcium and on prostaglandin F2alpha and E2 secretion from bovine endometrial cells. , 2005, Prostaglandins & other lipid mediators.

[23]  Eric R. Prossnitz,et al.  A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling , 2005, Science.

[24]  T. A. Richter,et al.  Progesterone Can Block the Preovulatory Gonadotropin‐Releasing Hormone/Luteinising Hormone Surge in the Ewe by a Direct Inhibitory Action on Oestradiol‐Responsive Cells within the Hypothalamus , 2005, Journal of neuroendocrinology.

[25]  M. Montecino,et al.  A Gβγ stimulated adenylyl cyclase is involved in xenopus laevis oocyte maturation , 2005 .

[26]  J. Peluso,et al.  Involvement of an unnamed protein, RDA288, in the mechanism through which progesterone mediates its antiapoptotic action in spontaneously immortalized granulosa cells. , 2004, Endocrinology.

[27]  Christopher J. Barnes,et al.  The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Bert W O'Malley,et al.  Coregulator function: a key to understanding tissue specificity of selective receptor modulators. , 2004, Endocrine reviews.

[29]  P. Thomas Rapid, nongenomic steroid actions initiated at the cell surface: lessons from studies with fish , 2003, Fish Physiology and Biochemistry.

[30]  F. Barrantes,et al.  Steroid structural requirements for stabilizing or disrupting lipid domains. , 2003, Biochemistry.

[31]  B. O’Malley,et al.  Unfolding the Action of Progesterone Receptors* , 2003, Journal of Biological Chemistry.

[32]  F. DeMayo,et al.  Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  R. Ivell,et al.  Transcriptional Regulation of the Bovine Oxytocin Receptor Gene1 , 2003, Biology of reproduction.

[34]  P. Thomas,et al.  Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Thomas,et al.  Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Edwards,et al.  Progesterone receptor interacting coregulatory proteins and cross talk with cell signaling pathways , 2002, The Journal of Steroid Biochemistry and Molecular Biology.

[37]  W. J. Silvia,et al.  Direct Inhibitory Effect of Progesterone on Oxytocin-Induced Secretion of Prostaglandin F2α from Bovine Endometrial Tissue1 , 2002, Biology of reproduction.

[38]  T. Bramley,et al.  Non-genomic steroid receptors in the bovine ovary. , 2002, Domestic animal endocrinology.

[39]  E. Baldi,et al.  Characterization of membrane nongenomic receptors for progesterone in human spermatozoa , 2002, Steroids.

[40]  P. Thomas,et al.  Progestin membrane receptors involved in the meiotic maturation of teleost oocytes: a review with some new findings , 2002, Steroids.

[41]  G. Mann,et al.  Expression of oxytocin, oestrogen and progesterone receptors in uterine biopsy samples throughout the oestrous cycle and early pregnancy in cows. , 2001, Reproduction.

[42]  J. Myers,et al.  The Classical Progesterone Receptor Associates with p42 MAPK and Is Involved in Phosphatidylinositol 3-Kinase Signaling inXenopus Oocytes* , 2001, The Journal of Biological Chemistry.

[43]  D. Pfaff,et al.  Early membrane estrogenic effects required for full expression of slower genomic actions in a nerve cell line , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. Edwards,et al.  Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. , 2001, Molecular cell.

[45]  B. White,et al.  Characterization of a Putative Membrane Receptor for Progesterone in Rat Granulosa Cells1 , 2001, Biology of reproduction.

[46]  K. Bland,et al.  Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. , 2000, Molecular endocrinology.

[47]  K. Ley,et al.  Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase , 2000, Nature.

[48]  F. DeMayo,et al.  Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. , 2000, Science.

[49]  Suraj,et al.  Caprine sperm acrosome reaction: promotion by progesterone and homologous zona pellucida. , 2000, Small ruminant research : the journal of the International Goat Association.

[50]  D. Wathes,et al.  Oestradiol regulation of oxytocin receptor expression in cyclic bovine endometrium. , 2000, Journal of reproduction and fertility.

[51]  J. C. Lodder,et al.  Progesterone-metabolite prevents protein kinase C-dependent modulation of γ-aminobutyric acid type A receptors in oxytocin neurons , 2000 .

[52]  B. Rueda,et al.  Decreased Progesterone Levels and Progesterone Receptor Antagonists Promote Apoptotic Cell Death in Bovine Luteal Cells1 , 2000, Biology of reproduction.

[53]  G. Gimpl,et al.  Non‐genomic effects of progesterone on the signaling function of G protein‐coupled receptors , 1999, FEBS letters.

[54]  K. Howland,et al.  Stimulation of specific binding of [3H]-progesterone to bovine luteal cell-surface membranes: specificity of digitonin , 1999, Molecular and Cellular Endocrinology.

[55]  R. Lanz,et al.  Nuclear receptor coregulators: cellular and molecular biology. , 1999, Endocrine reviews.

[56]  J. McCRACKEN,et al.  Luteolysis: a neuroendocrine-mediated event. , 1999, Physiological reviews.

[57]  G. Greene,et al.  Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. , 1999, Molecular endocrinology.

[58]  T. Bramley,et al.  Bovine ovarian non-genomic progesterone binding sites: presence in follicular and luteal cell membranes. , 1998, The Journal of endocrinology.

[59]  R. Goodman,et al.  The negative feedback actions of progesterone on gonadotropin-releasing hormone secretion are transduced by the classical progesterone receptor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[60]  A. Mcneilly,et al.  Specific non-genomic, membrane-localized binding sites for progesterone in the bovine corpus luteum. , 1998, Biology of Reproduction.

[61]  Hans H. Zingg,et al.  Inhibition of oxytocin receptor function by direct binding of progesterone , 1998, Nature.

[62]  T. Spencer,et al.  Ovine interferon tau suppresses transcription of the estrogen receptor and oxytocin receptor genes in the ovine endometrium. , 1996, Endocrinology.

[63]  T. Spencer,et al.  Temporal and spatial alterations in uterine estrogen receptor and progesterone receptor gene expression during the estrous cycle and early pregnancy in the ewe. , 1995, Biology of reproduction.

[64]  T. Spencer,et al.  Ovine interferon-tau regulates expression of endometrial receptors for estrogen and oxytocin but not progesterone. , 1995, Biology of reproduction.

[65]  K. Stevenson,et al.  Local action of trophoblast interferons in suppression of the development of oxytocin and oestradiol receptors in ovine endometrium. , 1995, Journal of reproduction and fertility.

[66]  C. Frye,et al.  Genomic and Non-genomic Actions of Progesterone in the Control of Female Hamster Sexual Behavior , 1994, Hormones and Behavior.

[67]  G. Moss,et al.  Hypothalamic and Hypophyseal Receptors for Estradiol in High and Low Sexually Performing Rams , 1993, Hormones and Behavior.

[68]  M. Lehman,et al.  Distribution of estrogen receptor-immunoreactive cells in the sheep brain. , 1993, Endocrinology.

[69]  A. Herbison,et al.  Distribution of estrogen receptor-immunoreactive cells in the preoptic area of the ewe: co-localization with glutamic acid decarboxylase but not luteinizing hormone-releasing hormone. , 1993, Neuroendocrinology.

[70]  B. Vanderhyden,et al.  A new, nongenomic estrogen action: the rapid release of intracellular calcium. , 1992, Endocrinology.

[71]  F. Bazer Mediators of Maternal Recognition of Pregnancy in Mammals 1 , 1992, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[72]  D. Brann,et al.  Inhibition of uterine contractility by progesterone and progesterone metabolites: mediation by progesterone and gamma amino butyric acidA receptor systems. , 1991, Biology of reproduction.

[73]  G. Lamming,et al.  Control of endometrial oxytocin receptor and uterine response to oxytocin by progesterone and oestradiol in the ewe. , 1990, Journal of reproduction and fertility.

[74]  M. Fields,et al.  Oxytocin and vasopressin receptors in bovine endometrium and myometrium during the estrous cycle and early pregnancy. , 1990, Endocrinology.

[75]  B. O’Malley,et al.  Steroid receptor family: structure and functions. , 1990, Endocrine reviews.

[76]  C. N. Lee,et al.  Progesterone in uterine and arterial tissue and in jugular and uterine venous plasma of sheep. , 1989, Biology of reproduction.

[77]  T. Nett,et al.  Changes in the concentration of hypothalamic and hypophyseal receptors for estradiol in pregnant and postpartum ewes. , 1986, Journal of animal science.

[78]  E. L. Sheldrick,et al.  Endocrine control of uterine oxytocin receptors in the ewe. , 1985, The Journal of endocrinology.

[79]  S. Ford,et al.  Interaction of ovarian steroids and periarterial alpha 1-adrenergic receptors in altering uterine blood flow during the estrous cycle of gilts. , 1984, American journal of obstetrics and gynecology.

[80]  T. Nett,et al.  Role of estradiol in inducing an ovulatory-like surge of luteinizing hormone in sheep. , 1984, Biology of reproduction.

[81]  R. P. Amann,et al.  Effects of season and sex on the distribution of cytosolic estrogen receptors within the brain and the anterior pituitary gland of sheep. , 1984, Biology of reproduction.

[82]  T. Nett,et al.  Expression of alpha subunit and luteinizing hormone beta genes in the ovine anterior pituitary. Estradiol suppresses accumulation of mRNAS for both alpha subunit and luteinizing hormone beta. , 1983, The Journal of biological chemistry.

[83]  Ford Sp,et al.  Role of Adrenergic Receptors in Mediating Estradiol-17β- Stimulated Increases in Uterine Blood Flow of Cows , 1983 .

[84]  M. Zelinski,et al.  Characterization of cytoplasmic progesterone receptors in the bovine endometrium during proestrus and diestrus. , 1982, Journal of animal science.

[85]  W. F. Pope,et al.  Distribution of progesterone in the uterus, broad ligament, and uterine arteries of beef cows , 1982, The Anatomical record.

[86]  A. Caraty,et al.  Characterization of cytosolic 5α-DHT and 17β-estradiol receptors in the ram hypothalamus , 1981 .

[87]  S. Ford,et al.  Blood flow to uteri of sows during the estrous cycle and early pregnancy: local effect of the conceptus on the uterine blood supply. , 1979, Biology of reproduction.

[88]  S P Ford,et al.  Uterine blood flow of cows during the oestrous cycle and early pregnancy: effect of the conceptus on the uterine blood supply. , 1979, Journal of reproduction and fertility.

[89]  J. Gorski,et al.  Effects of estrogen on primary ovine pituitary cell cultures: stimulation of prolactin secretion, synthesis, and preprolactin messenger ribonucleic acid activity. , 1979, Endocrinology.

[90]  J. Gorski,et al.  In vivo effects of estrogen on ovine pituitaries: prolactin and growth hormone biosynthesis and messenger ribonucleic acid translation. , 1979, Endocrinology.

[91]  F. Stormshak,et al.  Progesterone inhibition of estrogen receptor replenishment in ovine endometrium. , 1977, Biology of reproduction.

[92]  F. Stormshak,et al.  Nuclear and Cytoplasmic Estrogen Receptors in Ovine Endometrium During the Estrous Cycle1 , 1977 .

[93]  L. Murphy,et al.  Hormone receptor levels and hormone, RNA and protein metabolism in the genital tract during the oestrous cycle in the ewe. , 1977, Theriogenology.

[94]  R. Pietras,et al.  Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells , 1977, Nature.

[95]  S. Ford,et al.  In vitro response of ovine and bovine uterine arteries to prostaglandin F2 alpha and periarterial sympathetic nerve stimulation. , 1976, Biology of reproduction.

[96]  B. E. Senior Cytoplasmic oestradiol-binding sites and their relationship to oestradiol content in the endometrium of cattle. , 1975, Journal of reproduction and fertility.

[97]  R. Pietras,et al.  Endometrial cell calcium and oestrogen action , 1975, Nature.

[98]  C. Rosenfeld,et al.  Effect of estrogens on the uterine blood flow of oophorectomized ewes. , 1973, American journal of obstetrics and gynecology.

[99]  F. C. Greiss,et al.  Uterine vescular changes during the ovarian cycle. , 1969, American journal of obstetrics and gynecology.

[100]  B. Morris,et al.  The formation of lymph in the ovary , 1966, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[101]  H. R. Lindner,et al.  STEROIDS IN THE OVARIAN LYMPH AND BLOOD OF CONSCIOUS EWES. , 1964, The Journal of endocrinology.

[102]  F. C. Greiss,et al.  The Uterine Vascular Bed: Adrenergic Receptors , 1964, Obstetrics and gynecology.

[103]  C. Sawyer,et al.  Characteristics of behavioral and electroencephalographic after-reactions to copulation and viginal stimulation in the female rabbit. , 1959, Endocrinology.

[104]  H. Selye CORRELATIONS BETWEEN THE CHEMICAL STRUCTURE AND THE PHARMACOLOGICAL ACTIONS OF THE STEROIDS1 , 1942 .

[105]  S. Hammes,et al.  Testosterone and progesterone rapidly attenuate plasma membrane Gbetagamma-mediated signaling in Xenopus laevis oocytes by signaling through classical steroid receptors. , 2007, Molecular endocrinology.

[106]  T. Nett,et al.  A Nongenomic Action of Estradiol as the Mechanism Underlying the Acute Suppression of Secretion of Luteinizing Hormone in Ovariectomized Ewes1 , 2006, Biology of reproduction.

[107]  D. Edwards Regulation of signal transduction pathways by estrogen and progesterone. , 2005, Annual review of physiology.

[108]  K. Dunlap,et al.  Nongenomic Inhibition of Oxytocin Binding by Progesterone in the Ovine Uterus1 , 2004, Biology of reproduction.

[109]  Jing Zheng,et al.  Membrane estrogen receptor-dependent extracellular signal-regulated kinase pathway mediates acute activation of endothelial nitric oxide synthase by estrogen in uterine artery endothelial cells. , 2004, Endocrinology.

[110]  Raj Kumar,et al.  Transactivation functions of the N-terminal domains of nuclear hormone receptors: protein folding and coactivator interactions. , 2003, Molecular endocrinology.

[111]  B. White,et al.  Expression Pattern and Role of a 60-Kilodalton Progesterone Binding Protein in Regulating Granulosa Cell Apoptosis: Involvement of the Mitogen-Activated Protein Kinase Cascade1 , 2003, Biology of reproduction.

[112]  R. McPherson,et al.  Linkage of Rapid Estrogen Action to MAPK Activation by ER-Shc Association and Shc Pathway Activation , 2001 .

[113]  K. Bland,et al.  Estrogen Action Via the G Protein-Coupled Receptor , GPR 30 : Stimulation of Adenylyl Cyclase and cAMP-Mediated Attenuation of the Epidermal Growth Factor Receptor-to-MAPK Signaling Axis , 2001 .

[114]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.

[115]  P. Morgan,et al.  Autoradiographical localization of oxytocin binding sites on ovine oviduct and uterus throughout the oestrous cycle. , 1991, Reproduction, fertility, and development.

[116]  T. Parkinson,et al.  Uterine oxytocin receptors in cyclic and pregnant cows. , 1991, Journal of reproduction and fertility.

[117]  G. Niswender,et al.  Pituitary receptors for GnRH and estradiol, and pituitary content of gonadotropins in beef cows. II. Changes during the postpartum period. , 1988, Domestic animal endocrinology.

[118]  S. Ford,et al.  Control of uterine and ovarian blood flow throughout the estrous cycle and pregnancy of ewes, sows and cows. , 1982, Journal of animal science.

[119]  S. Ford,et al.  Uterine blood flow and uterine arterial, venous and luminal concentrations of oestrogens on days 11, 13 and 15 after oestrus in pregnant and non-pregnant sows. , 1982, Journal of reproduction and fertility.

[120]  S. Ford,et al.  Effects of Preimplantation Bovine and Porcine Conceptuses on Blood Flow and Steroid Content of the Uterus , 1981 .

[121]  D. McDonnell,et al.  The Estrogen Receptor ␤-isoform (er␤) of the Human Estrogen Receptor Modulates Er␣ Transcriptional Activity and Is a Key Regulator of the Cellular Response to Estrogens and Antiestrogens* , 2022 .