Predictors of Steroid Hormone Concentrations in Early Pregnancy: Results from a Multi-Center Cohort

Abstract

Objectives To identify factors predicting maternal sex steroid hormone concentrations in early pregnancy. Methods The Infant Development and the Environment Study recruited healthy pregnant women from academic medical centers in four US cities. Gold standard liquid chromatography–tandem mass spectrometry was used to measure maternal sex steroids concentrations (total testosterone [TT], free testosterone [FT], estrone [E1], estradiol [E2], and estriol [E3] concentrations) in serum samples from 548 women carrying singletons (median = 11.7 weeks gestation). Women completed questionnaires on demographic and lifestyle characteristics. Results In multivariable linear regression analyses, hormone concentrations varied in relation to maternal age, body mass index (BMI), race, and parity. Older mothers had significantly lower levels of most hormones; for every year increase in maternal age, there was a 1–2% decrease in E1, E2, TT, and FT. By contrast, each unit increase in maternal BMI was associated 1–2% lower estrogen (E1, E2, E3) levels, but 1–2% higher androgen (TT, FT) concentrations. Hormone concentrations were 4–18% lower among parous women, and for each year elapsed since last birth, TT and FT were 1–2% higher (no difference in estrogens). Androgen concentrations were 18–30% higher among Black women compared to women of other races. Fetal sex, maternal stress, and lifestyle factors (including alcohol and tobacco use) were not related to maternal steroid concentrations. Conclusions for Practice Maternal demographic factors predict sex steroid hormone concentrations during pregnancy, which is important given increasing evidence that the prenatal endocrine environment shapes future risk of chronic disease for both mother and offspring.

This is a preview of subscription content, log in to check access.

References

  1. Anderson, W. F., Pfeiffer, R. M., Wohlfahrt, J., et al. (2017). Associations of parity-related reproductive histories with ER+/− and HER2+/− receptor-specific breast cancer aetiology. International Journal of Epidemiology, 46(1), 86–95. https://doi.org/10.1093/ije/dyw286.

    PubMed  Article  Google Scholar 

  2. Arslan, A. A., Zeleniuch-Jacquotte, A., Lukanova, A., et al. (2006). Effects of parity on pregnancy hormonal profiles across ethnic groups with a diverse incidence of breast cancer. Cancer Epidemiology and Prevention Biomarkers, 15(11), 2123–2130. https://doi.org/10.1158/1055-9965.epi-06-0470.

    CAS  Article  Google Scholar 

  3. Bammann, B. L., Coulam, C. B., & Jiang, N. S. (1980). Total and free testosterone during pregnancy. American Journal of Obstetrics & Gynecology, 137(3), 293–298.

    CAS  Article  Google Scholar 

  4. Barbieri, R. L., Makris, A., Randall, R. W., et al. (1986). Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. Journal of Clinical Endocrinology and Metabolism, 62(5), 904–910. https://doi.org/10.1210/jcem-62-5-904.

    PubMed  CAS  Article  Google Scholar 

  5. Barbieri, R. L., Sluss, P. M., Powers, R. D., et al. (2005). Association of body mass index, age, and cigarette smoking with serum testosterone levels in cycling women undergoing in vitro fertilization. Fertility and Sterility, 83(2), 302–308. https://doi.org/10.1016/j.fertnstert.2004.07.956.

    PubMed  Article  Google Scholar 

  6. Barkai G, Goldman B, Ries L, et al. (1996). Effect of gravidity on maternal serum markers for Down’s syndrome. Prenatal Diagnosis, 16(4), 319–322. https://doi.org/10.1002/(sici)1097-0223(199604)16:4%3C319::aid-pd859%3E3.0.co;2-u

    PubMed  CAS  Article  Google Scholar 

  7. Barrett, E., Parlett, L. E., Sathyanarayana, S., et al. (2015) Prenatal life events stress modifies associations between phthalate exposure and male reproductive development. (In preparation).

  8. Barrett, E. S., Parlett, L. E., Windham, G. C., et al. (2014). Differences in ovarian hormones in relation to parity and time since last birth. Fertility and Sterility, 101(6), 1773–1780 e1. https://doi.org/10.1016/j.fertnstert.2014.02.047.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  9. Barrett, E. S., Sathyanarayana, S., Janssen, S., et al. (2014). Environmental health attitudes and behaviors: Findings from a large pregnancy cohort study. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 176, 119–125. https://doi.org/10.1016/j.ejogrb.2014.02.029.

    PubMed  PubMed Central  Article  Google Scholar 

  10. Bremme, K., Lagerstrom, M., Andersson, O., et al. (1990). Influences of maternal smoking and fetal sex on maternal serum oestriol, prolactin, hCG, and hPI levels. Archives of Gynecology and Obstetrics, 247(2), 95–103.

    PubMed  CAS  Article  Google Scholar 

  11. Caanen, M. R., Kuijper, E. A., Hompes, P. G., et al. (2016). Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome. European Journal of Endocrinology, 174(1), 25–32. https://doi.org/10.1530/eje-15-0699.

    PubMed  CAS  Article  Google Scholar 

  12. CDC. (2016). Health, United States, 2016 with chartbook on long-term trends in health: National Center for Health Statistics.

  13. Chen, T., Lundin, E., Grankvist, K., et al. (2010). Maternal hormones during early pregnancy: A cross-sectional study. Cancer Causes and Control, 21(5), 719–727. https://doi.org/10.1007/s10552-009-9500-2.

    PubMed  CAS  Article  Google Scholar 

  14. Chen, T., Surcel, H. M., Lundin, E., et al. (2011). Circulating sex steroids during pregnancy and maternal risk of non-epithelial ovarian cancer. Cancer Epidemiology and Prevention Biomarkers, 20(2), 324–336. https://doi.org/10.1158/1055-9965.epi-10-0857.

    CAS  Article  Google Scholar 

  15. Danforth, D. N. (2013). Disparities in breast cancer outcomes between Caucasian and African American women: A model for describing the relationship of biological and nonbiological factors. Breast Cancer Research: BCR, 15(3), 208. https://doi.org/10.1186/bcr3429.

    PubMed  Article  Google Scholar 

  16. de Graaf, I. M., Cuckle, H. S., Pajkrt, E., et al. (2000). Co-variables in first trimester maternal serum screening. Prenatal Diagnosis, 20(3), 186–189.

    PubMed  Article  Google Scholar 

  17. Freeman, E. W., Sammel, M. D., Gracia, C. R., et al. (2005). Follicular phase hormone levels and menstrual bleeding status in the approach to menopause. Fertility and Sterility, 83(2), 383–392. https://doi.org/10.1016/j.fertnstert.2004.06.066.

    PubMed  CAS  Article  Google Scholar 

  18. French, D. (2016). Advances in bioanalytical techniques to measure steroid hormones in serum. Bioanalysis, 8(11), 1203–1219. https://doi.org/10.4155/bio-2015-0025.

    PubMed  CAS  Article  Google Scholar 

  19. Haavaldsen, C., Fedorcsak, P., Tanbo, T., et al. (2014). Maternal age and serum concentration of human chorionic gonadotropin in early pregnancy. Acta obstetricia et gynecologica Scandinavica, 93(12), 1290–1294. https://doi.org/10.1111/aogs.12471.

    PubMed  CAS  Article  Google Scholar 

  20. Haddow, J. E., Palomaki, G. E., & Knight, G. J. (1995). Effect of parity on human chorionic gonadotrophin levels and Down’s syndrome screening. Journal of Medical Screening, 2(1), 28–30. https://doi.org/10.1177/096914139500200108.

    PubMed  CAS  Article  Google Scholar 

  21. Henderson, B. E., Bernstein, L., Ross, R. K., et al. (1988). The early in utero oestrogen and testosterone environment of blacks and whites: Potential effects on male offspring. British Journal of Cancer, 57(2), 216–218.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  22. Jarvela, I. Y., Zackova, T., Laitinen, P., et al. (2012). Effect of parity and fetal sex on placental and luteal hormones during early first trimester. Prenatal Diagnosis, 32(2), 160–167. https://doi.org/10.1002/pd.2921.

    PubMed  CAS  Article  Google Scholar 

  23. Kallak, T. K., Hellgren, C., Skalkidou, A., et al. (2017). Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain. European Journal of Endocrinology, 177(4), 379–388. https://doi.org/10.1530/eje-17-0207.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  24. Keelan, J. A., Mattes, E., Tan, H., et al. (2012). Androgen concentrations in umbilical cord blood and their association with maternal, fetal and obstetric factors. PLoS ONE, 7(8), e42827. https://doi.org/10.1371/journal.pone.0042827.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  25. Kragie, L. (2002). Aromatase in primate pregnancy: A review. Endocrine Research, 28(3), 121–128.

    PubMed  CAS  Article  Google Scholar 

  26. Krasowski, M. D., Drees, D., Morris, C. S., et al. (2014). Cross-reactivity of steroid hormone immunoassays: Clinical significance and two-dimensional molecular similarity prediction. BMC Clinical Pathology, 14, 33. https://doi.org/10.1186/1472-6890-14-33.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  27. Kunovac-Kallak, T., Hellgren, C., Skalkidou, A., et al. (2017). Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain. European Journal of Endocrinology. https://doi.org/10.1530/eje-17-0207.

    Article  Google Scholar 

  28. Lagerstrom, M., Bremme, K., & Eneroth, P. (1990). Maternal serum levels of estriol, prolactin, human placental lactogen and chorionic gonadotrophin related to fetal sex in normal and abnormal pregnancies. Gynecologic and Obstetric Investigation, 30(4), 198–203.

    PubMed  CAS  Article  Google Scholar 

  29. Lagiou, P., Samoli, E., Hsieh, C. C., et al. (2014). Maternal and cord blood hormones in relation to birth size. European Journal of Epidemiology, 29(5), 343–351. https://doi.org/10.1007/s10654-014-9914-3.

    PubMed  CAS  Article  Google Scholar 

  30. Manson, J. M., Sammel, M. D., Freeman, E. W., et al. (2001). Racial differences in sex hormone levels in women approaching the transition to menopause. Fertility and Sterility, 75(2), 297–304.

    PubMed  CAS  Article  Google Scholar 

  31. McCartney, C. R., Blank, S. K., Prendergast, K. A., et al. (2007). Obesity and sex steroid changes across puberty: Evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. Journal of Clinical Endocrinology and Metabolism, 92(2), 430–436. https://doi.org/10.1210/jc.2006-2002.

    PubMed  CAS  Article  Google Scholar 

  32. McGinley, K. F., Tay, K. J., & Moul, J. W. (2016). Prostate cancer in men of African origin. Nature reviews. Urology, 13(2), 99–107. https://doi.org/10.1038/nrurol.2015.298.

    PubMed  CAS  Article  Google Scholar 

  33. McGlynn, K. A., Devesa, S. S., Graubard, B. I., et al. (2005). Increasing incidence of testicular germ cell tumors among black men in the United States. Journal of Clinical Oncology, 23(24), 5757–5761. https://doi.org/10.1200/jco.2005.08.227.

    PubMed  Article  Google Scholar 

  34. Mendes, P. H., Martelli, D. R., de Melo Costa, S., et al. (2016). Comparison of digit ratio (2D:4D) between Brazilian men with and without prostate cancer. Prostate Cancer and Prostatic Diseases, 19(1), 107–110. https://doi.org/10.1038/pcan.2015.62.

    PubMed  CAS  Article  Google Scholar 

  35. Mendiola, J., Sanchez-Ferrer, M. L., Jimenez-Velazquez, R., et al. (2016). Endometriomas and deep infiltrating endometriosis in adulthood are strongly associated with anogenital distance, a biomarker for prenatal hormonal environment. Human Reproduction. https://doi.org/10.1093/humrep/dew163.

    PubMed  Article  Google Scholar 

  36. Mendiola, J., Stahlhut, R. W., Jorgensen, N., et al. (2011). Shorter anogenital distance predicts poorer semen quality in young men in Rochester, New York. Environmental Health Perspectives, 119(7), 958–963. https://doi.org/10.1289/ehp.1103421.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Middle, J. G. (2007). Dehydroepiandrostenedione sulphate interferes in many direct immunoassays for testosterone. Annals of Clinical Biochemistry, 44(Pt 2), 173–177. https://doi.org/10.1258/000456307780118082.

    PubMed  CAS  Article  Google Scholar 

  38. Mooney, R. A., Arvan, D. A., Saller, D. N. Jr., et al. (1995). Decreased maternal serum hCG levels with increasing gravidity and parity. Obstetrics & Gynecology, 86(6), 900–905.

    CAS  Article  Google Scholar 

  39. Musey, V. C., Collins, D. C., Brogan, D. R., et al. (1987). Long term effects of a first pregnancy on the hormonal environment: Estrogens and androgens. Journal of Clinical Endocrinology and Metabolism, 64(1), 111–118.

    PubMed  CAS  Article  Google Scholar 

  40. O’Leary, P., Boyne, P., Flett, P., et al. (1991). Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clinical Chemistry, 37(5), 667–672.

    PubMed  Google Scholar 

  41. Poretsky, L., Cataldo, N. A., Rosenwaks, Z., et al. (1999). The insulin-related ovarian regulatory system in health and disease. Endocrine Reviews, 20(4), 535–582. https://doi.org/10.1210/edrv.20.4.0374.

    PubMed  CAS  Article  Google Scholar 

  42. Qoubaitary, A., Meriggiola, C., Ng, C. M., et al. (2006). Pharmacokinetics of testosterone undecanoate injected alone or in combination with norethisterone enanthate in healthy men. Journal of Andrology, 27(6), 853–867. https://doi.org/10.2164/jandrol.106.000281.

    PubMed  CAS  Article  Google Scholar 

  43. Rasmussen, E. L., Hannibal, C. G., Dehlendorff, C., et al. (2017). Parity, infertility, oral contraceptives, and hormone replacement therapy and the risk of ovarian serous borderline tumors: A nationwide case–control study. Gynecologic Oncology, 144(3), 571–576. https://doi.org/10.1016/j.ygyno.2017.01.002.

    PubMed  Article  Google Scholar 

  44. Rosner, W., Auchus, R. J., Azziz, R., et al. (2007). Position statement: utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society position statement. Journal of Clinical Endocrinology and Metabolism, 92(2), 405–413. https://doi.org/10.1210/jc.2006-1864.

    PubMed  CAS  Article  Google Scholar 

  45. Salazar-Martinez, E., Lazcano-Ponce, E. C., Gonzalez Lira-Lira, G., et al. (1999). Reproductive factors of ovarian and endometrial cancer risk in a high fertility population in Mexico. Cancer Research, 59(15), 3658–3662.

    PubMed  CAS  Google Scholar 

  46. Sathyanarayana, S., Barrett, E., Butts, S., et al. (2014). Phthalate exposure and reproductive hormone concentrations in pregnancy. Reproduction, 147(4), 401–409. https://doi.org/10.1530/rep-13-0415.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  47. Sathyanarayana, S., Butts, S., Wang, C., et al. (2017). Early prenatal phthalate exposure, sex steroid hormones, and birth outcomes. Journal of Clinical Endocrinology and Metabolism, 102(6), 1870–1878. https://doi.org/10.1210/jc.2016-3837.

    PubMed  Article  Google Scholar 

  48. Schock, H., Zeleniuch-Jacquotte, A., Lundin, E., et al. (2016). Hormone concentrations throughout uncomplicated pregnancies: A longitudinal study. BMC Pregnancy and Childbirth., 16(1), 146. https://doi.org/10.1186/s12884-016-0937-5.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  49. Schooling, C. M., Houghton, L. C., & Terry, M. B. (2016). Potential intervention targets in utero and early life for prevention of hormone related cancers. Pediatrics, 138(Suppl 1), S22–Ss33. https://doi.org/10.1542/peds.2015-4268E.

    PubMed  Article  Google Scholar 

  50. Steier, J. A., Ulstein, M., & Myking, O. L. (2002). Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex. Obstetrics and Gynecology, 100(3), 552–556.

    PubMed  CAS  Google Scholar 

  51. Tejada, F., Cremades, A., Monserrat, F., et al. (1998). Interference of the antihormone RU486 in the determination of testosterone and estradiol by enzyme-immunoassay. Clinica Chimica Acta, 275(1), 63–69.

    Article  Google Scholar 

  52. Toriola, A. T., Vaarasmaki, M., Lehtinen, M., et al. (2011). Determinants of maternal sex steroids during the first half of pregnancy. Obstetrics and Gynecology, 118(5), 1029–1036. https://doi.org/10.1097/AOG.0b013e3182342b7f.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  53. Troisi, R., Hoover, R. N., Thadhani, R., et al. (2008). Maternal, prenatal and perinatal characteristics and first trimester maternal serum hormone concentrations. British Journal of Cancer., 99(7), 1161–1164. https://doi.org/10.1038/sj.bjc.6604639.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

  54. Troisi, R., Potischman, N., Roberts, J., et al. (2003). Associations of maternal and umbilical cord hormone concentrations with maternal, gestational and neonatal factors (United States). Cancer Causes and Control, 14(4), 347–355.

    PubMed  Article  Google Scholar 

  55. van de Beek, C., Thijssen, J. H., Cohen-Kettenis, P. T., et al. (2004). Relationships between sex hormones assessed in amniotic fluid, and maternal and umbilical cord serum: What is the best source of information to investigate the effects of fetal hormonal exposure? Hormones and Behavior, 46(5), 663–669. https://doi.org/10.1016/j.yhbeh.2004.06.010.

    PubMed  CAS  Article  PubMed Central  Google Scholar 

  56. Wald NJ, Watt HC. (1996). Serum markers for Down’s syndrome in relation to number of previous births and maternal age. Prenatal Diagnosis, 16(8), 699–703. https://doi.org/10.1002/(sici)1097-0223(199608)16:8%3C699::aid-pd919%3E3.0.co;2-p

    PubMed  CAS  Article  Google Scholar 

  57. Wu, Y., Zhong, G., Chen, S., et al. (2017). Polycystic ovary syndrome is associated with anogenital distance, a marker of prenatal androgen exposure. Human Reproduction, 32(4), 937–943. https://doi.org/10.1093/humrep/dex042.

    PubMed  CAS  Article  Google Scholar 

  58. Zhang, Y., Graubard, B. I., Klebanoff, M. A., et al. (2005). Maternal hormone levels among populations at high and low risk of testicular germ cell cancer. British Journal of Cancer, 92(9), 1787–1793. https://doi.org/10.1038/sj.bjc.6602545.

    PubMed  PubMed Central  CAS  Article  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge the contributions of the TIDES Study Team: Coordinating Center: Fan Liu, Erica Scher; UCSF: Marina Stasenko, Erin Ayash, Melissa Schirmer, Jason Farrell, Mari-Paule Thiet, Laurence Baskin; UMN: Heather L. Gray, Chelsea Georgesen, Brooke J. Rody, Carrie A. Terrell, Kapilmeet Kaur; URMC: Erin Brantley, Heather Fiore, Lynda Kochman, Lauren Parlett, Jessica Marino, William Hulbert, Robert Mevorach, Eva Pressman; UW/SCH: Kristy Ivicek, Bobbie Salveson, Garry Alcedo and the families who participated in the study. We thank the TIDES families for their participation and the residents at URMC and UCSF who assisted with birth exams. This analysis was supported by the following NIH Grants: R21ES023883, R01ES016863, R01ES06863-02S4. Additional support for the current analyses was provided by: T32ES007271, P30ES001247, P30ES005002, and UL1TR000124.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Emily S. Barrett.

Ethics declarations

Ethical Statement

TIDES was approved by institutional review boards at all participating institutions, and all subjects signed informed consent prior to starting any study activities.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 15 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Barrett, E.S., Mbowe, O., Thurston, S.W. et al. Predictors of Steroid Hormone Concentrations in Early Pregnancy: Results from a Multi-Center Cohort. Matern Child Health J 23, 397–407 (2019). https://doi.org/10.1007/s10995-018-02705-0

Download citation

Keywords

  • Pregnancy
  • Androgens
  • Estrogens
  • Fetal origins
  • Steroid hormones