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Fetal sex-related dysregulation in testosterone production and their receptor expression in the human placenta with preeclampsia

Journal of Perinatology volume 32, pages 328–335 (2012)Cite this article

Abstract

Objective:

To determine the effects of fetal sex on aromatase and androgen receptor (AR) expression in the placenta of normal and preeclamptic pregnancies.

Study Design:

Placentae from preeclamptic (five female and six male fetuses) and healthy pregnancies (seven female and seven male fetuses) were examined by immunofluorescence, western blotting and quantitative reverse transcriptase PCR.

Result:

Placental AR levels were significantly higher (P<0.05) in placentae of both male and female fetuses compared with their respective sexes in normal pregnancies. The placental aromatase levels varied depending on fetal sex. If the fetus was female, aromatase levels were substantially higher (P<0.05) in preeclamptic than in normal placentae. If the fetus was male, the aromatase levels were significantly lower (P<0.05) in preeclamptic than in normal placentae. Placental aromatase levels were significantly higher (P<0.05) in male- than in female-bearing normal placentae.

Conclusion:

Dysregulation in androgen production and signaling in preeclamptic placentae may contribute to placental abnormalities, increasing the frequency of maternal–fetal complications associated with preeclampsia.

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References

  1. Gude NM, Roberts CT, Kalionis B, King RG . Growth and function of the normal human placenta. Thromb Res 2004; 114: 397–407.

    Article  CAS  Google Scholar 

  2. Lei ZM, Rao CV . Endocrinology of trophoblastic tissue. In: Kenneth L, Becker (eds) Principles and practice of endocrinology and metabolism. 3rd edn. Lippincott Williams & Wilkins: Philadelphia, 2001; 180–186.

    Google Scholar 

  3. Report of the national high blood pressure education program working group on high blood pressure in pregnancy. Am J Obstet Gynecol 2000; 183: S1–S22.

  4. Sibai BM, Caritis S, Hauth J . What we have learned about preeclampsia. Semin Perinatol 2003; 27: 239–246.

    Article  Google Scholar 

  5. Geelhoed JJ, Fraser A, Tilling K, Benfield L, Davey SG, Sattar N et al. Preeclampsia and gestational hypertension are associated with childhood blood pressure independently of family adiposity measures: the Avon Longitudinal Study of Parents and Children. Circulation 2010; 122: 1192–1199.

    Article  Google Scholar 

  6. Jayet PY, Rimoldi SF, Stuber T, Salmon CS, Hutter D, Rexhaj E et al. Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia. Circulation 2010; 122: 488–494.

    Article  Google Scholar 

  7. Luft FC . Pre-eclampsia and the maternal cardiovascular risk. Nephrol Dial Transplant 2003; 18: 860–861.

    Article  Google Scholar 

  8. Laivuori H, Kaaja R, Rutanen EM, Viinikka L, Ylikorkala O . Evidence of high circulating testosterone in women with prior preeclampsia. J Clin Endocrinol Metab 1998; 83: 344–347.

    CAS  PubMed  Google Scholar 

  9. Redman CW . Current topic: pre-eclampsia and the placenta. Placenta 1991; 12: 301–308.

    Article  CAS  Google Scholar 

  10. Zhong Y, Tuuli M, Odibo AO . First-trimester assessment of placenta function and the prediction of preeclampsia and intrauterine growth restriction. Prenat Diagn 2010; 30: 293–308.

    PubMed  Google Scholar 

  11. Roberts CT . IFPA Award in placentology lecture: complicated interactions between genes and the environment in placentation, pregnancy outcome and long term health. Placenta 2010; 31: S47–S53.

    Article  Google Scholar 

  12. Foidart JM, Schaaps JP, Chantraine F, Munaut C, Lorquet S . Dysregulation of anti-angiogenic agents (sFlt-1, PLGF, and sEndoglin) in preeclampsia--a step forward but not the definitive answer. J Reprod Immunol 2009; 82: 106–111.

    Article  CAS  Google Scholar 

  13. Furuya M, Ishida J, Aoki I, Fukamizu A . Pathophysiology of placentation abnormalities in pregnancy-induced hypertension. Vasc Health Risk Manag 2008; 4: 1301–1313.

    Article  Google Scholar 

  14. Laivuori H, Kaaja R, Rutanen EM, Viinikka L, Ylikorkala O . Evidence of high circulating testosterone in women with prior preeclampsia. J Clin Endocrinol Metab 1998; 83: 344–347.

    CAS  PubMed  Google Scholar 

  15. Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG . Androgens in preeclampsia. Am J Obstet Gynecol 1999; 180: 60–63.

    Article  CAS  Google Scholar 

  16. Salamalekis E, Bakas P, Vitoratos N, Eleptheriadis M, Creatsas G . Androgen levels in the third trimester of pregnancy in patients with preeclampsia. Eur J Obstet Gynecol Reprod Biol 2006; 126: 16–19.

    Article  CAS  Google Scholar 

  17. Ghorashi V, Sheikhvatan M . The relationship between serum concentration of free testosterone and pre-eclampsia. Endokrynol Pol 2008; 59: 390–392.

    PubMed  Google Scholar 

  18. Serin IS, Kula M, Basbug M, Unluhizarci K, Gucer S, Tayyar M . Androgen levels of preeclamptic patients in the third trimester of pregnancy and six weeks after delivery. Acta Obstet Gynecol Scand 2001; 80: 1009–1013.

    Article  CAS  Google Scholar 

  19. Carlsen SM, Romundstad P, Jacobsen G . Early second-trimester maternal hyperandrogenemia and subsequent preeclampsia: a prospective study. Acta Obstet Gynecol Scand 2005; 84: 117–121.

    Article  Google Scholar 

  20. Baksu A, Gurarslan H, Goker N . Androgen levels in pre-eclamptic pregnant women. Int J Gynaecol Obstet 2004; 84: 247–248.

    Article  CAS  Google Scholar 

  21. Steier JA, Ulstein M, Myking OL . Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex. Obstet Gynecol 2002; 100: 552–556.

    CAS  PubMed  Google Scholar 

  22. Hsu TY, Lan KC, Tsai CC, Ou CY, Cheng BH, Tsai MY et al. Expression of androgen receptor in human placentas from normal and preeclamptic pregnancies. Taiwan J Obstet Gynecol 2009; 48: 262–267.

    Article  Google Scholar 

  23. Gerulewicz-Vannini D, Camero Y, Salas J, Hernandez-Andrade E . High plasmatic androgen levels in women affected with pregnancy-induced hypertension. Rev Invest Clin 2006; 58: 228–233.

    CAS  PubMed  Google Scholar 

  24. Atamer Y, Erden AC, Demir B, Kocyigit Y, Atamer A . The relationship between plasma levels of leptin and androgen in healthy and preeclamptic pregnant women. Acta Obstet Gynecol Scand 2004; 83: 425–430.

    Article  Google Scholar 

  25. Troisi R, Potischman N, Roberts JM, Ness R, Crombleholme W, Lykins D et al. Maternal serum oestrogen and androgen concentrations in preeclamptic and uncomplicated pregnancies. Int J Epidemiol 2003; 32: 455–460.

    Article  Google Scholar 

  26. Dokras A, Spaczynski RZ, Behrman HR, Duleba AJ . Testosterone levels in pregnant women correlate with the insulin response during the glucose tolerance test. Fertil Steril 2003; 79: 492–497.

    Article  Google Scholar 

  27. Steier JA, Ulstein M, Myking OL . Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex. Obstet Gynecol 2002; 100: 552–556.

    CAS  PubMed  Google Scholar 

  28. Nestler JE . Modulation of aromatase and P450 cholesterol side-chain cleavage enzyme activities of human placental cytotrophoblasts by insulin and insulin-like growth factor I. Endocrinology 1987; 121: 1845–1852.

    Article  CAS  Google Scholar 

  29. Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG . Androgens in preeclampsia. Am J Obstet Gynecol 1999; 180: 60–63.

    Article  CAS  Google Scholar 

  30. Christensen A . Hormone and enzyme assays in pregnancy. I. Studies on the placental and the tissue cystine-aminopeptidase activity in peripheral plasma from non-pregnant and pregnant women, and in plasma from the umbilical cord. Acta Endocrinol (Copenh) 1974; 76: 189–200.

    Article  CAS  Google Scholar 

  31. Takeyama J, Sasano H, Suzuki T, Iinuma K, Nagura H, Andersson S . 17Beta-hydroxysteroid dehydrogenase types 1 and 2 in human placenta: an immunohistochemical study with correlation to placental development. J Clin Endocrinol Metab 1998; 83: 3710–3715.

    CAS  PubMed  Google Scholar 

  32. Mason JI, Ushijima K, Doody KM, Nagai K, Naville D, Head JR et al. Regulation of expression of the 3 beta-hydroxysteroid dehydrogenases of human placenta and fetal adrenal. J Steroid Biochem Mol Biol 1993; 47: 151–159.

    Article  CAS  Google Scholar 

  33. Gant NF, Hutchinson HT, Siiteri PK, MacDonald PC . Study of the metabolic clearance rate of dehydroisoandrosterone sulfate in pregnancy. Am J Obstet Gynecol 1971; 111: 555–563.

    Article  CAS  Google Scholar 

  34. Buster JE, Chang RJ, Preston DL, Elashoff RM, Cousins LM, Abraham GE et al. Interrelationships of circulating maternal steroid concentrations in third trimester pregnancies. II. C18 and C19 steroids: estradiol, estriol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, delta 5-androstenediol, delta 4-androstenedione, testosterone, and dihydrotestosterone. J Clin Endocrinol Metab 1979; 48: 139–142.

    Article  CAS  Google Scholar 

  35. Steier JA, Ulstein M, Myking OL . Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex. Obstet Gynecol 2002; 100: 552–556.

    CAS  PubMed  Google Scholar 

  36. Vlkova B, Vavrova S, Szemes T, Minarik G, Turna J, Celec P . Testosterone and estradiol in maternal plasma and their relation to fetal sex. Prenat Diagn 2010; 30: 806–807.

    Article  Google Scholar 

  37. Zhu SJ, Li Y, Li H, Wang YL, Xiao ZJ, Vihko P et al. Retinoic acids promote the action of aromatase and 17beta- type 1 on the biosynthesis of 17beta-estradiol in placental cells. J Endocrinol 2002; 172: 31–43.

    Article  CAS  Google Scholar 

  38. Diaz L, Noyola-Martinez N, Barrera D, Hernandez G, Avila E, Halhali A et al. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J Reprod Immunol 2009; 81: 17–24.

    Article  CAS  Google Scholar 

  39. Milczarek R, Sokolowska E, Hallmann A, Kaletha K, Klimek JN . NADPH- and iron-dependent lipid peroxidation inhibit aromatase activity in human placental microsomes. J Steroid Biochem Mol Biol 2008; 110: 230–235.

    Article  CAS  Google Scholar 

  40. Zhang C, Williams MA, Sanchez SE, King IB, Ware-Jauregui S, Larrabure G et al. Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and normotensive pregnant women. Am J Epidemiol 2001; 153: 572–580.

    Article  CAS  Google Scholar 

  41. Williams MA, Woelk GB, King IB, Jenkins L, Mahomed K . Plasma carotenoids, retinol, tocopherols, and lipoproteins in preeclamptic and normotensive pregnant Zimbabwean women. Am J Hypertens 2003; 16: 665–672.

    Article  CAS  Google Scholar 

  42. Cackovic M, Buhimschi CS, Zhao G, Funai EF, Norwitz ER, Kuczynski E et al. Fractional excretion of tumor necrosis factor-alpha in women with severe preeclampsia. Obstet Gynecol 2008; 112: 93–100.

    Article  CAS  Google Scholar 

  43. Kaur G, Mishra S, Sehgal A, Prasad R . Alterations in lipid peroxidation and antioxidant status in pregnancy with preeclampsia. Mol Cell Biochem 2008; 313: 37–44.

    Article  CAS  Google Scholar 

  44. Jiang B, Kamat A, Mendelson CR . Hypoxia prevents induction of aromatase expression in human trophoblast cells in culture: potential inhibitory role of the hypoxia-inducible transcription factor Mash-2 (mammalian achaete-scute homologous protein-2). Mol Endocrinol 2000; 14: 1661–1673.

    Article  CAS  Google Scholar 

  45. Clifton VL . Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 2010; 31: S33–S39.

    Article  Google Scholar 

  46. Hodyl NA, Wyper H, Osei-Kumah A, Scott N, Murphy VE, Gibson P et al. Sex-specific associations between cortisol and birth weight in pregnancies complicated by asthma are not due to differential glucocorticoid receptor expression. Thorax 2010; 65: 677–683.

    Article  Google Scholar 

  47. Clifton VL, Hodyl NA, Murphy VE, Giles WB, Baxter RC, Smith R . Effect of maternal asthma, inhaled glucocorticoids and cigarette use during pregnancy on the newborn insulin-like growth factor axis. Growth Horm IGF Res 2010; 20: 39–48.

    Article  CAS  Google Scholar 

  48. Scott NM, Hodyl NA, Murphy VE, Osei-Kumah A, Wyper H, Hodgson DM et al. Placental cytokine expression covaries with maternal asthma severity and fetal sex. J Immunol 2009; 182: 1411–1420.

    Article  CAS  Google Scholar 

  49. Engel PJ, Smith R, Brinsmead MW, Bowe SJ, Clifton VL . Male sex and pre-existing diabetes are independent risk factors for stillbirth. Aust NZJ Obstet Gynaecol 2008; 48: 375–383.

    Article  Google Scholar 

  50. Macaulay JO, Warne GL, Krozowski ZS . Human placenta contains a high affinity R1881 binding site that is not the androgen receptor. J Steroid Biochem 1988; 29: 497–503.

    Article  CAS  Google Scholar 

  51. Horie K, Takakura K, Imai K, Liao S, Mori T . Immunohistochemical localization of androgen receptor in the human endometrium, decidua, placenta and pathological conditions of the endometrium. Hum Reprod 1992; 7: 1461–1466.

    Article  CAS  Google Scholar 

  52. Iwamura M, Abrahamsson PA, Benning CM, Cockett AT, di Sant′Agnese PA . Androgen receptor immunostaining and its tissue distribution in formalin-fixed, paraffin-embedded sections after microwave treatment. J Histochem Cytochem 1994; 42: 783–788.

    Article  CAS  Google Scholar 

  53. Chan CC, Lao TT, Ho PC, Sung EO, Cheung AN . The effect of mifepristone on the expression of steroid hormone receptors in human decidua and placenta: a randomized placebo-controlled double-blind study. J Clin Endocrinol Metab 2003; 88: 5846–5850.

    Article  CAS  Google Scholar 

  54. King AJ, Olivier NB, Mohankumar PS, Lee JS, Padmanabhan V, Fink GD . Hypertension caused by prenatal testosterone excess in female sheep. Am J Physiol Endocrinol Metab 2007; 292: E1837–E1841.

    Article  CAS  Google Scholar 

  55. Sathishkumar K, Elkins R, Yallampalli U, Yallampalli C . Elevated androgen levels during pregnancy impair fetal growth due to placental insufficiency and programs for adult hypertension in rats. Biol Reprod 2009; 83: 250 (abstract).

    Article  Google Scholar 

  56. Ortega HH, Salvetti NR, Padmanabhan V . Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance. Reproduction 2009; 137: 865–877.

    Article  CAS  Google Scholar 

  57. Demissie M, Lazic M, Foecking EM, Aird F, Dunaif A, Levine JE . Transient prenatal androgen exposure produces metabolic syndrome in adult female rats. Am J Physiol Endocrinol Metab 2008; 295: E262–E268.

    Article  CAS  Google Scholar 

  58. Veiga-Lopez A, Ye W, Phillips DJ, Herkimer C, Knight PG, Padmanabhan V . Developmental programming: deficits in reproductive hormone dynamics and ovulatory outcomes in prenatal, testosterone-treated sheep. Biol Reprod 2008; 78: 636–647.

    Article  CAS  Google Scholar 

  59. Stark MJ, Clifton VL, Wright IM . Neonates born to mothers with preeclampsia exhibit sex-specific alterations in microvascular function. Pediatr Res 2009; 65: 292–295.

    Article  Google Scholar 

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Acknowledgements

The work was financially supported in part by grants HD69750, HL58144 and HL72650 from the National Institute of Health. The content is solely the responsibility of the authors and does not necessarily represent the official view, of the NIH.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA

    K Sathishkumar, M Balakrishnan, V Chinnathambi, M Chauhan, G D V Hankins & C Yallampalli

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  1. K Sathishkumar
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Correspondence to K Sathishkumar.

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Sathishkumar, K., Balakrishnan, M., Chinnathambi, V. et al. Fetal sex-related dysregulation in testosterone production and their receptor expression in the human placenta with preeclampsia. J Perinatol 32, 328–335 (2012). https://doi.org/10.1038/jp.2011.101

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