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Maternal Signatures of Cortisol in First Trimester Small-for-Gestational Age

  • Maternal Fetal Medicine/Biology: Original Article
  • Published:
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Abstract

The objective of this study was to identify predictable maternal serum signatures of cortisol metabolism during the first trimester of women who are expected to deliver small-for-gestational-age (SGA) neonates. This prospective cohort study included 112 pregnant women (with and without SGA, n = 56 each). Maternal serum samples were collected at 10–14 gestational weeks to quantify the levels of cortisol and its precursors and metabolites by liquid chromatography-mass spectrometry. Increased maternal serum levels of tetrahydrocortisol (11.82 ± 8.16 ng/mL vs. 7.51 ± 2.90 ng/mL, P < 0.005) and decreased 21-deoxycortisol (2.98 ± 1.36 ng/mL vs. 4.33 ± 2.06 ng/mL, P < 0.0001) were observed in pregnant women carrying SGA fetus. In conjunction with individual steroid levels, metabolic ratios corresponding to the activity of related enzymes were calculated. In addition to increased tetrahydrocortisol/cortisol ratio (P < 0.006), the SGA group showed a significant increase in the two metabolic ratios including cortisol/11-deoxycortisol (P < 0.03) and cortisol/21-deoxycortisol (P < 0.0003). The receiver operating characteristic (ROC) curve generated in combination with three variables of 21-deoxycortisol concentration and two metabolic ratios of cortisol/21-deoxycortisol and tetrahydrocortisol/cortisol resulted in an area under the ROC curve = 0.824 (95% confidence interval, 0.713–0.918). A significant decrease in maternal serum levels of 21-deoxycortisol and an increase in two metabolic ratios of cortisol/21-deoxycortisol and tetrahydrocortisol/cortisol, indicating cortisol biosynthetic rate, represent potential biomarkers for the prediction of SGA in the first trimester.

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Availability of Data and Materials

The raw and processed data used and analyzed in the current study are available from the corresponding author.

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References

  1. Ludvigsson JF, Lu D, Hammarström L, Cnattingius S, Fang F. Small for gestational age and risk of childhood mortality: a Swedish population study. PLoS Med. 2018;15:e1002717.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sacchi C, Marino C, Nosarti C, Vieno A, Simonelli A. Association of intrauterine growth restriction and small for gestational age status with childhood cognitive outcomes: a systematic review and meta-analysis. JAMA Pediatr. 2020;174:772–81.

  3. Karagiannis G, Akolekar R, Sarquis R, Wright D, Nicolaides KH. Prediction of small-for-gestation neonates from biophysical and biochemical markers at 11–13 weeks. Fetal Diagn Ther. 2011;29:148–54.

    Article  PubMed  Google Scholar 

  4. Houk CP, Lee PA. Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes. Int J Pediatr Endcorinol. 2012;2012:11.

    Article  Google Scholar 

  5. Bronstein MD, Paraiba DB, Jallad RS. Management of pituitary tumors in pregnancy. Nat Rev Endocrinol. 2011;7:301–10.

    Article  CAS  PubMed  Google Scholar 

  6. Duthie L, Reynolds RM. Changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy and postpartum: influences on maternal and fetal outcomes. Neuroendocrinol. 2013;98:106–15.

    Article  CAS  Google Scholar 

  7. Ng PC. The fetal and neonatal hypothalamic-pituitary-adrenal axis. Arch Dis Child Fetal Neonatal Ed. 2000;82:F250–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Economides DL, Nicolaides KH, Linton EA, Perry LA, Chard T. Plasma cortisol and adrenocorticotropin in appropriate and small for gestational age fetuses. Fetal Ther. 1988;3:158–64.

    Article  CAS  PubMed  Google Scholar 

  9. Mericq V, Medina P, Kararieka E, Márquez L, Johnson MC, Iñiguez G. Differences in expression and activity of 11β-hydroxysteroid dehydrogenase type 1 and 2 in human placentas of term pregnancies according to birth weight and gender. Eur J Endocrinol. 2009;161:419–25.

    Article  CAS  PubMed  Google Scholar 

  10. Lee MM, Rajagopalan L, Berg GJ, Moshang T Jr. Serum adrenal steroid concentrations in premature infants. J Clin Endocrinol Metab. 1989;69:1133–6.

    Article  CAS  PubMed  Google Scholar 

  11. Hingre RV, Gross SJ, Hingre KS, Mayes DM, Richman RA. Adrenal steroidogenesis in very low birth weight preterm infants. J Clin Endocrinol Metab. 1994;78:266–70.

    CAS  PubMed  Google Scholar 

  12. Goedhart G, Vrijkotte TGM, Roseboom TJ, van der Wal MF, Cuijpers P, Bonsel GJ. Maternal cortisol and offspring birthweight: results from a large prospective cohort study. Psychoneuroendocrinol. 2010;35:644–52.

    Article  CAS  Google Scholar 

  13. Siemiatkowska A, Kosicka K, Szpera-Gozdziewicz A, Krzyscin M, Breborowicz G, Glowka FK. Cortisol metabolism in pregnancies with small for gestational age neonates. Sci Rep. 2019;9:17890.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol. 2004;151:U49-62.

    Article  CAS  PubMed  Google Scholar 

  15. Sennaiyan UN, Melov SJ, Arcus C, Kirby A, Alahakoon IA. Fetal adrenal gland: total gland volume and fetal zone to total gland ratio as markers for small for gestational age. Clin Ultrasound. 2020;48:377–87.

    Article  Google Scholar 

  16. Mohajeri ZF, Aalipour S, Sheikh M, Shafaat M, Hantoushzadeh S, Borna S, Khazardoost S. Ultrasound measurement of fetal adrenal gland in fetuses with intrauterine growth restriction, an early predictive method for adverse outcomes. J Matern Fetal Neonatal Med. 2019;32:1485–91.

    Article  Google Scholar 

  17. Lee C, Kim JH, Moon SJ, Shim J, Kim HI, Choi MH. Selective LC-MRM/SIM-MS based profiling of adrenal steroids reveals metabolic signatures of 17α-hydroxylase deficiency. J Steroid Biochem Mol Biol. 2020;198:105615.

    Article  CAS  PubMed  Google Scholar 

  18. Lee JK, Jang HL, Kang BH, Lee KS, Choi YS, Shim KS, et al. percentile distributions of birth weight according to gestational ages in Korea (2010–2012). J Korean Med Sci. 2016;31:939–49.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lee SH, Lee N, Hong Y, Chung BC, Choi MH. Simultaneous analysis of free and sulfated steroids by liquid chromatography/mass spectrometry with selective mass spectrometric scan modes and polarity switching. Anal Chem. 2016;88:11624–30.

    Article  CAS  PubMed  Google Scholar 

  20. Krasowski MD, Drees D, Morris CS, Maakestad J, Blau JL, Ekins S. Cross-reactivity of steroid hormone immunoassays: clinical significance and two-dimensional molecular similarity prediction. BMC Clin Pathol. 2014;14:33.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Akinloye O, Obikoya OM, Jegede AI, Oparinde DP, Arowojolu AO. Cortisol plays central role in biochemical changes during pregnancy. Int J Med Biomed Res. 2013;2:3–12.

    Article  Google Scholar 

  22. Santiago JR, Nolledo MS, Knizler W, Santiago TV. Sleep and sleep disorders in pregnancy. Ann Intern Med. 2001;134:396–408.

    Article  CAS  PubMed  Google Scholar 

  23. Nepomnaschy PA, Welch KB, McConnell DS, Low BS, Strassmann BI, England BG. Cortisol levels and very early pregnancy loss in humans. Proc Natl Acad Sci USA. 2006;103:3938–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Holmes MC, Abrahamsen CT, French KI, Peterson JM, Mullins JJ, Seckl JR. The mother of the fetus? 11β-Hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J Neurosci. 2006;26:3840–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuwabara Y, Murata T, Mizuno M, Sakamoto S. Plasma 11-deoxycortisol in normal and abnormal human pregnancy. Am J Obstet Gynecol. 1983;147:766–9.

    Article  CAS  PubMed  Google Scholar 

  26. Miller WL. Congenital adrenal hyperplasia: time to replace 17OHP with 21-deoxycortisol. Horm Res Paediatr. 2019;91:416–20.

    Article  CAS  PubMed  Google Scholar 

  27. Kamrath C, Hartmann MF, Boettcher C, Wudy SA. Reduced activity of 11β-hydroxylase accounts for elevated 17α-hydroxyprogesterone in preterms. J Pediatr. 2014;165:280–4.

    Article  CAS  PubMed  Google Scholar 

  28. Murphy VE, Clifton VL. Alterations in human placental 11β-hydroxysteroid dehydrogenase type 1 and 2 with gestational age and labour. Placenta. 2003;24:739–44.

    Article  CAS  PubMed  Google Scholar 

  29. Yang Q, Wang W, Liu C, Wang Y, Sun K. Compartmental localization of 11β-HSD 1 and 2 at the feto-maternal interface in the first trimester of human pregnancy. Placenta. 2016;46:63–71.

    Article  CAS  PubMed  Google Scholar 

  30. Aufdenblatten M, Baumann M, Raio L, Dick B, Frey BM, Schneider H, et al. Prematurity is related to high placental cortisol in preeclampsia. Pediatr Res. 2009;65:198–202.

    Article  CAS  PubMed  Google Scholar 

  31. Vayssière C, Sentilhes L, Ego A, Bernard C, Cambourieu D, Flamant C, et al. Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Ostetricians. Eur J Obstet Gynecol Reprod Biol. 2015;193:10–8.

    Article  PubMed  Google Scholar 

  32. Gaudineau A. Prevalence, risk factors, maternal and fetal morbidity and mortality of intrauterine growth restriction and small-for-gestational age. J Gyneol Obstet Biol Reprod. 2013;42:895–910.

    Article  CAS  Google Scholar 

  33. Tanner LD, Brock C, Chauhan SP. Severity of fetal growth restriction stratified according to maternal obesity. J Matern Fetal Neonatal Med. 2020; https://doi.org/10.1080/14767058.2020.1773427.

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Funding

This study was supported by a grant from the Korea Institute of Science and Technology Institutional Program (Project No. 2E30480), and the Bio & Medical Technology Development Programs (NRF-2016M3A9B6902059) through the Ministry of Science and ICT, and sponsored by the Seoul National University Hospital research fund (03–2018-0400).

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Author notes

  1. Chaelin Lee and Seung Mi Lee contributed equally to this study

Authors and Affiliations

  1. Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Korea

    Chaelin Lee, Dong Jun Byun & Man Ho Choi

  2. Department of Chemistry, Korea University, Seoul, Korea

    Chaelin Lee, Dong Jun Byun & Hugh I. Kim

  3. Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

    Seung Mi Lee, So Yeon Kim, Young Mi Jung, Chan-Wook Park & Joong Shin Park

  4. Department of Food and Animal Biotechnology, Seoul National University, Seoul, Korea

    Do Yup Lee

Authors
  1. Chaelin Lee
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  2. Seung Mi Lee
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  3. Dong Jun Byun
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  4. So Yeon Kim
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  5. Hugh I. Kim
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  7. Young Mi Jung
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  8. Chan-Wook Park
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  9. Joong Shin Park
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  10. Man Ho Choi
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Contributions

Chaelin Lee performed steroid analysis, data collection, and drafting of the manuscript. Seung Mi Lee contributed to clinical sampling and interpretation of quantitative results. Dong Jun Byun did the statistical analysis based on steroid quantities. So Yeon Kim performed the correlation of clinical parameters with steroid signatures. Hugh I Kim confirmed the mass spectrometric data in quantification. Do Yup Lee investigated the predictive biomarkers using various statistical equations. Young Mi Jung interpreted the results obtained from both lab findings and clinical observations. Chan-Wook Park was involved in manuscript editing. Joong Shin Park conceived the idea for this study. Man Ho Choi supervised the analytical platform and finalized the manuscript.

Corresponding authors

Correspondence to Joong Shin Park or Man Ho Choi.

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This study was approved by the ethics committees of Seoul National University Hospital. All participants signed an informed consent form prior to the study.

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The authors declare no competing interests.

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Lee, C., Lee, S.M., Byun, D.J. et al. Maternal Signatures of Cortisol in First Trimester Small-for-Gestational Age. Reprod. Sci. 29, 1498–1505 (2022). https://doi.org/10.1007/s43032-021-00822-w

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  • DOI: https://doi.org/10.1007/s43032-021-00822-w

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