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Frontiers in Biology

Front. Biol.    2018, Vol. 13 Issue (5) : 315-326
Androgen and estrogen receptors in placental physiology and dysfunction
Erin S McWhorter, Jennifer E Russ, Quinton A Winger, Gerrit J Bouma()
Department of Biomedical Sciences, Animal Reproduction and Biotechnology Laboratory, Colorado State University. 1683 Campus delivery, Fort Collins, CO 80523-1683, USA
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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     
Corresponding Author(s): Gerrit J Bouma   
Online First Date: 29 September 2018    Issue Date: 25 October 2018
 Cite this article:   
Erin S McWhorter,Jennifer E Russ,Quinton A Winger, et al. Androgen and estrogen receptors in placental physiology and dysfunction[J]. Front. Biol., 2018, 13(5): 315-326.
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Erin S McWhorter
Jennifer E Russ
Quinton A Winger
Gerrit J Bouma
Fig.1  Trophoblast cell differentiation in the human placenta. Proliferating progenitor cytotrophoblast cells differentiate and give rise to extravillous trophoblast (EVT) and multinucleated syncytiotrophoblast (ST). Extravillous trophoblast cells invade maternal interstitial uterine tissue as well as spiral arteries and are important for uterine artery remodeling necessary for increased blood flow to the placenta. Syncytiotrophoblast cells fuse and form a multinucleated syncytium and are critical for nutrient and gas exchange as well as hormone production and secretion.
Location Receptor
Differentiating cytotrophoblast ++ — +
CT — + ++ — +
ST ++ +
EVT NA — + ++
Tab.1  Localization of ESRs and AR in human trophoblast cells
Fig.2  Proposed roles of estrogen (ESR) and androgen receptor (AR) in differentiating trophoblast cells. Solid arrows indicate reported functions, according to the literature. Dashed arrows indicate proposed functions. Based on available expression and localization data we postulate that ESR1 and AR have important functions in cytotrophoblast function (proliferation) and differentiation (syncytialization), respectively. Furthermore, ESR1 expression in extravillous trophoblast cells (EVT) suggests a possible role in EVT functions such as migration and invasion.
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 pmid: 20023123
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 pmid: 15496458
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 pmid: 23606795
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 pmid: 15990167
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 pmid: 19876841
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 pmid: 28539435
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 pmid: 15059152
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 pmid: 29460303
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 pmid: 1315102
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 pmid: 19092983
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 pmid: 19502456
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 pmid: 22150464
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 pmid: 15695368
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 pmid: 18566115
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 pmid: 6321721
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 pmid: 6054057
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
pmid: 8537246
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 pmid: 15683369
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 pmid: 10882512
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 pmid: 9557857
29 CDC Preterm birth fact sheet. . 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 pmid: 10541571
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 pmid: 27037955
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 pmid: 25675430
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 pmid: 14283286
36 Enders A C (1968). Fine structure of anchoring villi of the human placenta. Am J Anat, 122(3): 419–451 pmid: 5691182
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 pmid: 28849224
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 pmid: 28808352
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
pmid: 6069273
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 pmid: 22197627
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
pmid: 18979448
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 pmid: 10816189
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 pmid: 10611265
47 Goto J, Fishman J (1977). Participation of a nonenzymatic transformation in the biosynthesis of estrogens from androgens. Science, 195(4273): 80–81 pmid: 831259
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
pmid: 20067891
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 pmid: 16306198
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
pmid: 11912350
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 pmid: 12142247
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 pmid: 17098281
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 pmid: 22698698
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 pmid: 12620937
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 pmid: 4083522
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 pmid: 14972444
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 pmid: 25947892
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 pmid: 9560344
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 pmid: 19299445
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 pmid: 12097823
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 pmid: 20922474
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 pmid: 12583598
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 pmid: 8521507
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 pmid: 9449216
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 pmid: 6947233
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
pmid: 17510501
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 pmid: 28882554
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.
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 pmid: 10617764
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
pmid: 1827758
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 pmid: 11369444
96 Padmanabhan V, Veiga-Lopez A (2014). Reproduction Symposium: developmental programming of reproductive and metabolic health. J Anim Sci, 92(8): 3199–3210 pmid: 25074449
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 pmid: 29436602
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 pmid: 16707435
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
pmid: 7671849
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 pmid: 20104425
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 pmid: 15760944
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 pmid: 21767868
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 pmid: 21812961
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 pmid: 17045112
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 pmid: 11703197
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 pmid: 8107046
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 pmid: 9875847
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 pmid: 9396883
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
pmid: 26708046
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 pmid: 8788180
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 pmid: 8980224
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
pmid: 4370479
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
pmid: 4153532
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 pmid: 6459977
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 pmid: 26848992
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 10.1016/j.preghy.2017.12.003
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 pmid: 6465051
136 Wooding F B P (1992). Current topic: the synepitheliochorial placenta of ruminants: binucleate cell fusions and hormone production. Placenta, 13(2): 101–113 pmid: 1631024
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 pmid: 8710816
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 pmid: 26226925
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 pmid: 859324
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
pmid: 11778652
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 pmid: 19284296
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 pmid: 11943725
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