Androgen and estrogen receptors in placental physiology and dysfunction

Abstract

BACKGROUND: The placenta is recognized as an endocrine organ, largely due to its secretions of steroid hormones, including progesterone, androgens, and estrogens. Steroid hormones play an essential role in the progression of pregnancy, fetal development, and growth. Furthermore, steroids are necessary for establishment and maintenance of a normal pregnancy, preparing the endometrium for implantation, stimulating endometrial secretions, and regulating uterine blood flow, however the exact mechanism of sex steroid signaling through their receptors in placental function is unknown.

OBJECTIVE: In this review, we will provide an overview of the current knowledge on sex steroid receptors in normal placental development, as well as evidence of abnormal signaling associated with placental dysfunction.

METHODS: A systematic literature search was performed using the NCBI PubMed search engine, including the following key works: estrogen receptor, androgen receptor, placenta, placental development, cytotrophoblast, and differentiation.

RESULTS: Of the over 700 articles that were returned, 125 studies focused on estrogen and androgen receptors in human placenta development and function during normal and abnormal pregnancy, as well as in rodents and ruminants placentae.

CONCLUSION: Receptors for both estrogens and androgens have been localized within the mammalian placenta, but surprisingly little is known about their signaling in trophoblast cell differentiation and function. An emerging picture is developing in which estrogen receptors possibly play role in cytotrophoblast proliferation and extravillous trophoblast invasion, whereas androgen receptors are involved in syncytiotrophoblast differentiation and function.

Keywords

Placenta / ESR / AR / preeclampsia / IUGR / PCOS

References

[1] Abbas A, Gupta S (2008). The role of histone deacetylases in prostate cancer. Epigenetics, 3(6): 300–309

[2] Aberdeen G W, Baschat A A, Harman C R, Weiner C P, Langenberg P W, Pepe G J, Albrecht E D (2010). Uterine and fetal blood flow indexes and fetal growth assessment after chronic estrogen suppression in the second half of baboon pregnancy. Am J Physiol Heart Circ Physiol, 298(3): H881–H889

[3] Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, Visca P, Marino M (2005). Palmitoylation-dependent estrogen receptor α membrane localization: regulation by 17β-estradiol. Mol Biol Cell, 16(1): 231–237

[4] Açıkgöz S, Bayar U O, Can M, Güven B, Mungan G, Doğan S, Sümbüloğlu V (2013). Levels of oxidized LDL, estrogens, and progesterone in placenta tissues and serum paraoxonase activity in preeclampsia. Mediators Inflamm, 2013: 862982

[5] Albrecht E D, Bonagura T W, Burleigh D W, Enders A C, Aberdeen G W, Pepe G J (2006). Suppression of extravillous trophoblast invasion of uterine spiral arteries by estrogen during early baboon pregnancy. Placenta, 27(4-5): 483–490

[6] Albrecht E D, Pepe G J (2010). Estrogen regulation of placental angiogenesis and fetal ovarian development during primate pregnancy. Int J Dev Biol, 54(2-3): 397–408

[7] Arnal J F, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J (2017). Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev, 97(3): 1045–1087

[8] Astwood E (1938). (1038). A six-hour assay for the quantitative determination of estrogen. Endocrinology, 23(1): 25–31

[9] Atamer Y, Erden A C, Demir B, Koçyigit Y, Atamer A (2004). The relationship between plasma levels of leptin and androgen in healthy and preeclamptic pregnant women. Acta Obstet Gynecol Scand, 83(5): 425–430

[10] Bahri Khomami M, Boyle J A, Tay C T, Vanky E, Teede H J, Joham A E, Moran L J (2018). Polycystic ovary syndrome and adverse pregnancy outcomes: Current state of knowledge, challenges and potential implications for practice. Clin Endocrinol (Oxf), 88(6): 761–769; Epub ahead of print

[11] Bairagi S, Grazul-Bilska A T, Borowicz P P, Reyaz A, Valkov V, Reynolds L P (2018) Placental development during early pregnancy in sheep: Progesterone and estrogen receptor protein expression. Theriogenology, 114:1273–1284

[12] Bangsbøll S, Qvist I, Lebech P E, Lewinsky M (1992). Testicular feminization syndrome and associated gonadal tumors in Denmark. Acta Obstet Gynecol Scand, 71(1): 63–66

[13] Bartnik P, Kosinska-Kaczynska K, Kacperczyk J, Ananicz W, Sierocińska A, Wielgos M, Szymusik I (2016). Twin chorionicity and the risk of hypertensive disorders: Gestational hypertension and pre-eclampsia. Twin Res Hum Genet, 10:1–6

[14] Bazer F W, Burghardt R C, Johnson G A, Spencer T E, Wu G (2008). Interferons and progesterone for establishment and maintenance of pregnancy: interactions among novel cell signaling pathways. Reprod Biol, 8(3): 179–211

[15] Bazer F W, Spencer T E, Johnson G A, Burghardt R C, Wu G (2009). Comparative aspects of implantation. Reproduction, 138(2): 195–209

[16] Bellingham M, McKinnell C, Fowler P A, Amezaga M R, Zhang Z, Rhind S M, Cotinot C, Mandon-Pepin B, Evans N P, Sharpe R M (2012). Foetal and post-natal exposure of sheep to sewage sludge chemicals disrupts sperm production in adulthood in a subset of animals. Int J Androl, 35(3): 317–329

[17] Benirschke K, Kaufmann P (2000). Pathology of the human placenta, 4th edition. New York: Springer Biol Reprod, 83 (2010), pp. 42–51

[18] Björnström L, Sjöberg M (2005). Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol, 19(4): 833–842

[19] Bonagura T W, Pepe G J, Enders A C, Albrecht E D (2008). Suppression of extravillous trophoblast vascular endothelial growth factor expression and uterine spiral artery invasion by estrogen during early baboon pregnancy. Endocrinology, 149(10): 5078–5087

[20] Bousquet J, Lye S J, Challis J R G (1984). Comparison of leucine enkephalin and adrenocorticotrophin effects on adrenal function in fetal and adult sheep. J Reprod Fertil, 70(2): 499–506

[21] Brosens I, Robertson W B, Dixon H G (1967). The physiological response of the vessels of the placental bed to normal pregnancy. J Pathol Bacteriol, 93(2): 569–579

[22] Brosens I A (1988). The uteroplacental vessels at term: the distribution and extent of physiological changes. Trophoblast Res, 3: 61–68

[23] Brown T R (1995). Human androgen insensitivity syndrome. J Androl, 16(4): 299–303

[24] Bukovsky A, Cekanova M, Caudle M R, Wimalasena J, Foster J S, Henley D C, Elder R F (2003). Expression and localization of estrogen receptor-alpha protein in normal and abnormal term placentae and stimulation of trophoblast differentiation by estradiol. Reprod Biol Endocrinol, 1:13–29

[25] Bussolati B, Perkins J, Shams M, Rhaman M, Nijjar S, Qui Y, Kniss D, Dunk C, Yancopoulos G, Ahmed A (2000). Angiopoietin-1 and angiopoietin-2 are differentially expressed during placental development and stimulate trophoblast proliferation, migration and release of nitric oxide. J Soc Gynecol Investig, 7(Suppl): 158A

[26] Carlsen S M, Romundstad P, Jacobsen G (2005). Early second-trimester maternal hyperandrogenemia and subsequent preeclampsia: a prospective study. Acta Obstet Gynecol Scand, 84(2): 117–121

[27] Carson D D, Bagchi I, Dey S K, Enders A C, Fazleabas A T, Lessey B A, Yoshinaga K (2000). Embryo implantation. Dev Biol, 223(2): 217–237

[28] Castracane V D, Stewart D R, Gimpel T, Overstreet J W, Lasley B L (1998). Maternal serum androgens in human pregnancy: early increases within the cycle of conception. Hum Reprod, 13(2): 460–464

[29] CDC Preterm birth fact sheet. https://www.cdc.gov/reproductivehealth/maternalinfanthealth/pretermbirth.htm. Last updated 11/12/2016

[30] Chamouni A, Oury F (2014). Reciprocal interaction between bone and gonads. Arch Biochem Biophys, 561:147–153

[31] Chang C W, Wakeland A K, Parast M M (2018). Trophoblast lineage specification, differentiation and their regulation by oxygen tension. J Endocrinol, 236(1): R43–R56

[32] Chardonnens D, Cameo P, Aubert M L, Pralong F P, Islami D, Campana A, Gaillard R C, Bischof P (1999). Modulation of human cytotrophoblastic leptin secretion by interleukin-1alpha and 17beta-oestradiol and its effect on HCG secretion. Mol Hum Reprod, 5(11): 1077–1082

[33] Cheng X, Xu S, Song C, He L, Lian X, Liu Y, Wei J, Pang L, Wang S (2016). Roles of ERα during mouse trophectoderm lineage differentiation: revealed by antagonist and agonist of ERα. Dev Growth Differ, 58(3): 327–338

[34] Cleys E R, Halleran J L, Enriquez V A, da Silveira J C, West R C, Winger Q A, Anthony R V, Bruemmer J E, Clay C M, Bouma G J (2015). Androgen receptor and histone lysine demethylases in ovine placenta. PLoS One, 10(2): e0117472

[35] Enders A C (1965). A comparative study of the fine structure of the trophoblast in several hemochorial placentas. Am J Anat, 116(1): 29–67

[36] Enders A C (1968). Fine structure of anchoring villi of the human placenta. Am J Anat, 122(3): 419–451

[37] Feng X, Zhou L, Mao X, Tong C, Chen X, Zhao D, Baker P N, Xia Y, Zhang H (2017). Association of a reduction of Gprotein coupled receptor 30 expression and the pathogenesis of preeclampsia. Mol Med Rep, 16(5): 5997–6003

[38] Fornes R, Maliqueo M, Hu M, Hadi L, Jimenez-Andrade J M, Ebefors K, Nyström J, Labrie F, Jansson T, Benrick A, Stener-Victorin E (2017). The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams. Sci Rep, 7(1): 8066

[39] Fornes R, Hu M, Maliqueo M, Kokosar M, Benrick A, Carr D, Billig H, Jansson T, Manni L, Stener-Victorin E (2016). Maternal testosterone and placental function: Effect of electroacupuncture on placental expression of angiogenic markers and fetal growth. Mol Cell Endocrinol, 433:1–11

[40] Friederici H H (1967). The early response of uterine capillaries to estrogen stimulation. An electron microscopic study. Lab Invest, 17(3): 322–333

[41] Gambino Y P, Maymó J L, Pérez Pérez A, Calvo J C, Sánchez-Margalet V, Varone C L (2012). Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression. Placenta, 33(Suppl): S63–S70

[42] Gambino Y P, Maymó J L, Pérez Pérez A, Duenas J L, Sánchez-Margalet V, Calvo J C, Varone C L (2010). 17-Beta-estradiol enhances leptin expression in human placental cells through genomic and nongenomic actions. Biol Reprod, 83:1 42–51

[43] Ghorashi V, Sheikhvatan M (2008). The relationship between serum concentration of free testosterone and pre-eclampsia. Endokrynol Pol, 59(5): 390–392

[44] Gibb W, Lye S J, Challis J R G (2006). Parturition. Physiology of Reproduction. Academic Press. pp. 2925–2974

[45] Goldenberg R L, Hauth J C, Andrews W W (2000). Intrauterine infection and preterm delivery. N Engl J Med, 342(20): 1500–1507

[46] Goldman-Wohl D S, Ariel I, Greenfield C, Lavy Y, Yagel S (2000). Tie-2 and angiopoietin-2 expression at the fetal-maternal interface: a receptor ligand model for vascular remodelling. Mol Hum Reprod, 6(1): 81–87

[47] Goto J, Fishman J (1977). Participation of a nonenzymatic transformation in the biosynthesis of estrogens from androgens. Science, 195(4273): 80–81

[48] Gözükara Y M, Aytan H, Ertunc D, Tok E C, Demirtürk F, Şahin Ş, Aytan P (2015). Role of first trimester total testosterone in prediction of subsequent gestational diabetes mellitus. J Obstet Gynaecol Res, 41(2):193–8

[49] Guibourdenche J, Fournier T, Malassiné A, Evain-Brion D (2009). Development and hormonal functions of the human placenta. Folia Histochem Cytobiol, 47(5): S35–S40

[50] Hagen A S, Orbus R J, Wilkening R B, Regnault T R, Anthony R V (2005). Placental expression of angiopoietin-1, angiopoietin-2 and tie-2 during placental development in an ovine model of placental insufficiency-fetal growth restriction. Pediatr Res, 58(6): 1228–1232

[51] Hall J E (2011). Guyton and Hall Textbook of Medical Physiology.12th ed. Philadelphia, PA: Saunders/Elsevier

[52] Handelsman D J, Wartofsky L (2013). Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J Clin Endocrinol Metab, 98(10): 3971–3

[53] Hertig A, Liere P, Chabbert-Buffet N, Fort J, Pianos A, Eychenne B, Cambourg A, Schumacher M, Berkane N, Lefevre G, Uzan S, Rondeau E, Rozenberg P, Rafestin-Oblin M E (2010). Steroid profiling in preeclamptic women: evidence for aromatase deficiency. Am J Obstet Gynecol, 203(5):477.e1–9

[54] Hirano H, Imai Y, Ito H (2002). Spiral artery of placenta: development and pathology-immunohistochemical, microscopical, and electron-microscopic study. Kobe J Med Sci, 48(1-2): 13–23

[55] Hoffmann B, Schuler G (2002). The bovine placenta; a source and target of steroid hormones: observations during the second half of gestation. Domest Anim Endocrinol, 23(1-2): 309–320

[56] Horie K, Takakura K, Imai K, Liao S, Mori T (1992). Immunohistochemical localization of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium. Hum Reprod, 7(10): 1461–6

[57] Hsu T Y, Lan K C, Tsai C C, Ou C Y, Cheng B H, Tsai M Y, Kang H Y, Tung Y H, Wong Y H, Huang K E (2009). Expression of androgen receptor in human placentas from normal and preeclamptic pregnancies. Taiwan J Obstet Gynecol, 48(3): 262–267

[58] Hu R, Jin H, Zhou S, Yang P, Li X (2007). Proteomic analysis of hypoxia-induced responses in the syncytialization of human placental cell line BeWo. Placenta, 28(5-6): 399–407

[59] Hughes I A, Davies J D, Bunch T I, Pasterski V, Mastroyannopoulou K, MacDougall J (2012). Androgen insensitivity syndrome. Lancet, 380(9851): 1419–1428

[60] Jackson M R, Carney E W, Lye S J, Knox Ritchie J W (1994). Localization of two angiogenic growth factors (PDECGF and VEGF) in human placentae throughout gestation. Placenta; 15: 341–353

[61] Jahaninejad T, Ghasemi N, Kalantar S M, Sheikhha M H, Pashaiefar H (2013). StuI polymorphism on the androgen receptor gene is associated with recurrent spontaneous abortion. J Assist Reprod Genet, 30(3): 437–440

[62] Kang H Y, Cho C L, Huang K L, Wang J C, Hu Y C, Lin H K, Chang C, Huang K E (2004). Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3–E1 osteoblasts. J Bone Miner Res, 19(7): 1181–90

[63] Kaufmann P, Black S, Huppertz B (2003). Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod, 69(1): 1–7

[64] Kaufmann P, Bruns U, Leiser R, Luckhardt M, Winterhager E (1985). The fetal vascularisation of term human placental villi. II. Intermediate and terminal villi. Anat Embryol (Berl), 173(2): 203–214

[65] Kaufmann P, Castellucci M (1997). Extravillous trophoblast in the human placenta. Trophoblast Research., 10: 21–65

[66] Kaufmann P, Mayhew T M, Charnock-Jones D S (2004). Aspects of human fetoplacental vasculogenesis and angiogenesis. II. Changes during normal pregnancy. Placenta, 25(2-3): 114–126

[67] Kay, H H, Nelson, D M, Wang Y (2011). The Placenta From Development to Disease. Blackwell Publishing Ltd36–52

[68] Khatri P, Hoffmann B, Schuler G (2013). Androgen receptor is widely expressed in bovine placentomes and up-regulated during differentiation of bovine trophoblast giant cells. Placenta, 34(5): 416–423.

[69] Klinga K, Bek E, Runnebaum B (1978). Maternal peripheral testosterone levels during the first half of pregnancy. Am J Obstet Gynecol, 131(1): 60–2.

[70] Knabl J, Hiden U, Hüttenbrenner R, Riedel C, Hutter S, Kirn V, Günthner-Biller M, Desoye G, Kainer F, Jeschke U (2015). GDM alters expression of placental estrogen receptor α in a cell type and gender-specific manner. Reprod Sci, 22(12): 1488–1495

[71] Knobil E, Neill J D, eds. (1998) Placenta: Implantation and Developmental.Encyclopedia of Reproduction Academic Press: San Diego. Vol 3: 848–855

[72] Koblizek T I, Weiss C, Yancopoulos G D, Deutsch U, Risau W (1998). Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr Biol, 8(9): 529–532

[73] Koster M P, de Wilde M A, Veltman-Verhulst S M, Houben M L, Nikkels P G, van Rijn B B, Fauser B C (2015). Placental characteristics in women with polycystic ovary syndrome. Hum Reprod, 30(12): 2829–37

[74] Kumar P, Kamat A, Mendelson C R (2009). Estrogen receptor alpha (ERalpha) mediates stimulatory effects of estrogen on aromatase (CYP19) gene expression in human placenta. Mol Endocrinol, 23(6): 784–793

[75] Lash G E, Warren A Y, Underwood S, Baker P N (2003). Vascular endothelial growth factor is a chemoattractant for trophoblast cells. Placenta, 24(5): 549–556

[76] Leach L, Babawale M O, Anderson M, Lammiman M (2002). Vasculogenesis, angiogenesis and the molecular organisation of endothelial junctions in the early human placenta. J Vasc Res, 39(3): 246–259

[77] Lim J H, Kim S, Lee S W, Park S Y, Han J Y, Chung J H, Kim M Y, Yang J H, Ryu H M (2011). Association between genetic polymorphisms in androgen receptor gene and the risk of preeclampsia in Korean women. J Assist Reprod Genet, 28(1): 85–90

[78] Lodish H, Berk A, Kaiser C A, Krieger M, Scott M P, Bretscher A (2008). Molecular cell biology.6th ed. New York: W.H. Freeman and Company.

[79] Maisonpierre P C, Suri C, Jones P F, Bartunkova S, Wiegand S J, Radziejewski C, Compton D, McClain J, Aldrich T H, Papadopoulos N, Daly T J, Davis S, Sato T N, Yancopoulos G D (1997). Angiopoietin-2, a natural antagonist for TiE2 that disrupts in vivo angiogenesis. Science, 277: 55–60 15

[80] Malassiné A, Cronier L (2002). Hormones and human trophoblast differentiation: a review. Endocrine, 19(1): 3–11

[81] Maliqueo M, Echiburú B, Crisosto N (2016). Sex Steroids Modulate Uterine-Placental Vasculature: Implications for Obstetrics and Neonatal Outcomes. Front Physiol, 7: 152

[82] Mangelsdorf D J, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans R M (1995). The nuclear receptor superfamily: the second decade. Cell, 83(6): 835–839

[83] Maymo J L, Perez A P, Gambino Y, Calvo J C, Sanchez-Margalet V, Varone C L (2011). Review: leptin gene expression in the placenta–regulation of a key hormone in trophoblast proliferation and survival. Placenta, 32 Suppl 2: S146–153

[84] McRobie D J, Korzekwa K R, Glover D D, Tracy T S (1997). The effects of diabetes on placental aromatase activity. J Steroid Biochem Mol Biol, 63(1-3): 147–153

[85] Meng C X, Cheng L N, Lalitkumar P G, Zhang L, Zhang H J, Gemzell-Danielsson K (2009) Expressions of steroid receptors and Ki67 in first-trimester decidua and chorionic villi exposed to levonorgestrel used for emergency contraception. Fertil Steril; 91:1420–1423. 28.

[86] Meng Q, Shao L, Luo X, Mu Y, Xu W, Gao L, Xu H, Cui Y (2016). Expressions of VEGF-A and VEGFR-2 in placentae from GDM pregnancies. Reprod Biol Endocrinol, 14(1): 61

[87] Metzler V M, de Brot S, Robinson R S, Jeyapalan J N, Rakha E, Walton T, Gardner D S, Lund E F, Whitchurch J, Haigh D, Lochray J M, Robinson B D, Allegrucci C, Fray R G, Persson J L, Ødum N, Miftakhova R R, Rizvanov A A, Hughes I A, Tadokoro-Cuccaro R, Heery D M, Rutland C S, Mongan N P (2017). Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development. Placenta, 56: 79–85

[88] Migeon B R, Brown T R, Axelman J, Migeon C J (1981). Studies of the locus for androgen receptor: localization on the human X chromosome and evidence for homology with the Tfm locus in the mouse. Proc Natl Acad Sci USA, 78(10): 6339–6343

[89] Molvarec A, Vér A, Fekete A, Rosta K, Derzbach L, Derzsy Z, Karádi I, Rigó J Jr (2007). Association between estrogen receptor alpha (ESR1) gene polymorphisms and severe preeclampsia. Hypertens Res, 30(3): 205–211

[90] Morford J J, Wu S, Mauvais-Jarvis F (2018). The impact of androgen actions in neurons on metabolic health and disease. Mol Cell Endocrinol, 465: 92–102

[91] Morgan, T K (2016). Role of the placenta in preterm birth: A Review. Am J Perinatol, 33(3): 258–266

[92] Mouse Genome Informatics.http://www.informatics.jax.org/reference/summary?id=j:46439

[93] Niswender G D, Juengel J L, Silva P J, Rollyson M K, McIntush E W (2000). Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev, 80(1): 1–29

[94] O’Leary P, Boyne P, Flett P, Beilby J, James I (1991). Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clin Chem, 37(5): 667–672

[95] O’Neil J S, Burow M E, Green A E, McLachlan J A, Henson M C (2001). Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors alpha and beta. Mol Cell Endocrinol, 176(1-2): 67–75

[96] Padmanabhan V, Veiga-Lopez A (2014). Reproduction Symposium: developmental programming of reproductive and metabolic health. J Anim Sci, 92(8): 3199–3210

[97] Park M N, Park K H, Lee J E, Shin Y Y, An S M, Kang S S, Cho W S, An B S, Kim S C (2018). The expression and activation of sex steroid receptors in the preeclamptic placenta. Int J Mol Med, 41(5): 2943–2951

[98] Park S Y, Kim Y J, Gao A C, Mohler J L, Onate S A, Hidalgo A A, Ip C, Park E M, Yoon S Y, Park Y M (2006). Hypoxia increases androgen receptor activity in prostate cancer cells. Cancer Res, 66(10): 5121–5129

[99] Pawar S, Laws M J, Bagchi I C, Bagchi M K (2015). Uterine epithelial estrogen receptor- controls decidualization via a paracrine mechanism. Mol Endocrinol, 29(9): 1362–74

[100] Pi M, Chen L, Huang M Z, Zhu W, Ringhofer B, Luo J, Christenson L, Li B, Zhang J, Jackson P D, Faber P, Brunden K R, Harrington J J, Quarles L D (2008). GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome. PLoS ONE, 3(12): e3858

[101] Pi M, Parrill A L, Quarles L D J (2010). GPRC6A mediates the non-genomic effects of steroids. Biol Chem, 285(51): 39953–64

[102] Pi M, Wu Y, Quarles L D (2011). GPRC6A mediates responses to osteocalcin in -cells in vitro and pancreas in vivo. J Bone Miner Res, 26(7): 1680–1683

[103] Pijnenborg R, Robertson W, Brosens I, Dixon G (1981). Trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta, 32(Suppl. 2): S146–S153

[104] Poidatz D, Dos Santos E, Duval F, Moindjie H, Serazin V, Vialard F, De Mazancourt P, Dieudon M Nné (2015). Involvement of estrogen-related receptor- and mitochondrial content in intrauterine growthrestriction and preeclampsia. Fertil Steril,104(2): 483–490

[105] Quigley C A, De Bellis A, Marschke K B, el-Awady M K, Wilson E M, French F S (1995). Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev, 16(3): 271–321

[106] Ramathal C Y, Bagchi I C, Taylor R N, Bagchi M K (2010). Endometrial decidualization: of mice and men. Semin Reprod Med, 28(1): 17–26

[107] Red-Horse K, Zhou Y, Genbacev O, Prakobphol A, Foulk R, McMaster M, Fisher S J (2004). Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface. J Clin Invest, 114(6): 744–5

[108] Regnault T R, Galan H L, Parker T A, Anthony R V (2002) Placental development in normal and compromised pregnancies– a review. Placenta, S119–129

[109] Reynolds L P, Borowicz P P, Vonnahme K A, Johnson M L, Grazul-Bilska A T, Redmer D A, Caton J S (2005). Placental angiogenesis in sheep models of compromised pregnancy. J Physiol, 565(Pt 1): 43–58

[110] Reynolds L P, Haring J S, Johnson M L, Ashley R L, Redmer D A, Borowicz P P, Grazul-Bilska A T (2015). Placental development during early pregnancy in sheep: estrogen and progesterone receptor messenger RNA expression in pregnancies derived from in vivo-produced and in vitro-produced embryos. Domest Anim Endocrinol, 53: 60–69

[111] Rhind S M, Kyle C E, Kerr C, Osprey M, Zhang Z L (2011). Effect of duration of exposure to sewage sludge-treated pastures on liver tissue accumulation of persistent endocrine disrupting compounds (EDCs) in sheep. Sci Total Environ, 409(19): 3850–3856

[112] Sathishkumar K, Elkins R, Chinnathambi V, Gao H, Hankins G D V, Yallampalli C (2011). Prenatal testosterone-induced fetal growth restriction is associated with down-regulation of rat placental amino acid transport. Reprod Biol Endocrinol, 9(1): 110–122

[113] Schiessl B, Mylonas I, Kuhn C, Kunze S, Schulze S, Friese K, Jeschke U (2006). Expression of estrogen receptor-alpha, estrogen receptor-beta and placental endothelial and inducible NO synthase in intrauterine growth-restricted and normal placentals. Arch Med Res, 37(8): 967–975

[114] Schuler G, Greven H, Kowalewski MP, Döring B, Ozalp GR, Hoffmann B (2008). Placental steroids in cattle: hormones, placental growth factors or by-products of trophoblast giant cell differentiation? Exp Clin Endocrinol Diabetes,116(7): 429–436

[115] Schuler G, Teichmann U, Taubert A, Failing K, Hoffmann B (2002). Estrogen receptor beta (ERbeta) is expressed differently from ERalpha in bovine placentomes. Exp Clin Endocrinol Diabetes, 113(2): 107–114

[116] Schuler G, Wirth C, Teichmann U, Failing K, Leiser R, Thole H, Hoffmann B (2002). Occurrence of estrogen receptor alpha in bovine placentomes throughout mid and late gestation and at parturition. Biol Reprod, 66(4): 976–982

[117] Seabrook J, Cantlon J, Cooney A, McWhorter E, Fromme B, Bouma G, Anthony R, Winger Q (2013). Role of LIN28A in mouse and human trophoblast cell differentiation. Biol Reprod, 89(4): 95, 1–13

[118] Seki K, Makimura N, Mitsui C, Hirata J, Nagata I(1991). Calcium-regulating hormones and osteocalcin levels during pregnancy: a longitudinal study. Am J Obstet Gynecol, 164(5 Pt 1): 1248–1252

[119] Serin I S, Kula M, Başbuğ M, Unlühizarci K, Güçer S, Tayyar M (2001). Androgen levels of preeclamptic patients in the third trimester of pregnancy and six weeks after delivery. Acta Obstet Gynecol Scand, 80(11): 1009–1013

[120] Sharkey A M, Charnock-Jones D S, Boocock C A, Brown K D, Smith S K (1993). Expression of mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil, 99(2): 609–615

[121] Shiau A K, Barstad D, Loria P M, Cheng L, Kushner P J, Agard D A, Greene G L (1998). The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell, 95(7): 927–937

[122] Sibai B M, Ewell M, Levine R J, Klebanoff M A, Esterlitz J, Catalano P M, Goldenberg R L, Joffe G, and the The Calcium for Preeclampsia Prevention (CPEP) Study Group (1997). Risk factors associated with preeclampsia in healthy nulliparous women. Am J Obstet Gynecol, 177(5): 1003–1010

[123] Sir-Petermann T, Maliqueo M, Angel B, Lara H E, Pérez-Bravo F, Recabarren S E (2002). Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod, 17(10): 2573–2579

[124] Solomon S (1994). The placenta as an endocrine organ: steroids. In: Knobil E, Neil J D (Eds). Physiology of Reproduction, vol. II, second ed. Raven Press, New York, 863–873

[125] Srichomkwun P, Houngngam N, Pasatrat S, Tharavanij T, Wattanachanya L, Khovidhunkit W (2015). Undercarboxylated osteocalcin is associated with insulin resistance, but not adiponectin, during pregnancy. Endocrine, (Dec): 26

[126] Strauss J F 3rd, Martinez F, Kiriakidou M (1996). Placental steroid hormone synthesis: unique features and unanswered questions. Biol Reprod, 54(2): 303–311

[127] Suri C, Jones P F, Patan S, Bartunkova S, Maisonpierre P C, Davis S, Sato T N, Yancopoulos G D (1996). Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell, 87(7): 1171–1180

[128] Thompson E A Jr, Siiteri P K (1974). The involvement of human placental microsomal cytochrome P-450 in aromatization. J Biol Chem, 249(17): 5373–5378

[129] Thompson E A Jr, Siiteri P K (1974). Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J Biol Chem, 249(17): 5364–5372

[130] Thoumsin H J, Alsat E, Cedard L (1982). In vitro aromatization of androgens into estrogens in placental insufficiency. Gynecol Obstet Invest, 13(1): 37–43

[131] Tong C, Feng X, Chen J, Qi X, Zhou L, Shi S, Kc K, Stanley J L, Baker P N, Zhang H (2016). G protein-coupled receptor 30 regulates trophoblast invasion and its deficiency is associated with preeclampsia. J Hypertens, 34(4): 710–718

[132] Uzelac P S, Li X, Lin J, Neese L D, Lin L, Nakajima S T, Bohler H, Lei Z (2010). Dysregulation of leptin and testosterone production and their receptor expression in the human placenta with gestational diabetes mellitus. Placenta, 31(7): 581–588

[133] Wan J, Hu Z, Aeng K, Yin Y, Zhao M, Chen M, Chen Q (2017). The reduction in circulating levels of estrogen and progesterone in women with preeclampsia. Pregnancy Hypertens, 11: 18–25

[134] Wang C, Liu Y, Cao J M (2014). G protein-coupled receptors: extranuclear mediators for the non-genomic actions of steroids. Int J Mol Sci, 15(9): 15412–15425

[135] Wooding F B (1984). Role of binucleate cells in fetomaternal cell fusion at implantation in the sheep. Am J Anat, 170(2): 233–250

[136] Wooding F B P (1992). Current topic: the synepitheliochorial placenta of ruminants: binucleate cell fusions and hormone production. Placenta, 13(2): 101–113

[137] Wooding F B P, Morgan G, Monaghan S, Hamon M, Heap R B (1996). Functional specialization in the ruminant placenta: evidence for two populations of fetal binucleate cells of different selective synthetic capacity. Placenta, 17(1): 75–86

[138] Xu J, Li M, Zhang L, Xiong H, Lai L, Guo M, Zong T, Zhang D, Yang B, Wu L, Tang M, Kuang H, Kuang H (2015). Expression and regulation of androgen receptor in the mouse uterus during early pregnancy and decidualization. Mol Reprod Dev, 82(11): 898–906

[139] Zachariah P K, Juchau M R (1977). Inhibition of human placental mixed-function oxidations with carbon monoxide: reversal with monochromatic light. J Steroid Biochem, 8(3): 221–228

[140] Zhang E G, Smith S K, Baker P N, Charnock-Jones D S (2001). The regulation and localization of angiopoietin-1, -2, and their receptor Tie2 in normal and pathologic human placentae. Mol Med, 7(9): 624–635

[141] Zhang J, Bai H, Liu X, Fan P, Liu R, Huang Y, Wang X, He G, Liu Y, Liu B (2009). Genotype distribution of estrogen receptor alpha polymorphisms in pregnant women from healthy and preeclampsia populations and its relation to blood pressure levels. Clin Chem Lab Med, 47(4): 391–397

[142] Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, Alitalo K, Damsky C, Fisher S J (2002). Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol, 160(4): 1405–1423

RIGHTS & PERMISSIONS

2018 Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature