Background: There is accumulating evidence that in vitro conception in humans may be associated with adverse health outcomes later in life. It has been proposed that suboptimal early life conditions may ‘program' key endocrine systems. A disturbance of the hypothalamic-pituitary-adrenal (HPA) axis leading to alterations in cortisol secretion in the offspring may be such a mechanism. To date, no data on cortisol levels in children conceived by intracytoplasmic sperm injection (ICSI) are available in the literature. Methods: In this cross-sectional study, salivary cortisol known as a key regulator of metabolism was measured and results were compared between 201 pubertal ICSI children and 196 spontaneously conceived (SC) counterparts. Results: ICSI females had lower mean salivary cortisol levels (9.0 µg/l; 95% CI 8.1-9.9) than SC females (10.6 µg/l; 95% CI 9.7-11.5; p = 0.01). This difference remained after adjusting for current characteristics, early life factors and maternal characteristics. In ICSI males, no difference in cortisol levels was found in comparison with the SC group. Conclusion: In our study, 14-year-old female but not male ICSI teenagers were found to have lower salivary cortisol concentrations in comparison with SC peers. However, before definite conclusions can be drawn, our results should be completed by longitudinal sampling.

Keywords:
Intracytoplasmic sperm injection, Cortisol, Pubertal stage, HPA axis, Outcome
1.
Ceelen M, Ceelen M, van Weissenbruch MM, Roos JC, Vermeiden JP, van Leeuwen F, Delemarre-van de Waal H: Body composition in children and adolescents born after in vitro fertilization or spontaneous conception. J Clin Endocrinol Metab 2007;92:3417-3423.
2.
Belva F, Painter R, Bonduelle M, Roelants M, Devroey P, De Schepper J: Are ICSI adolescents at risk for increased adiposity? Hum Reprod 2012;27:257-264.
3.
Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA: Cardiometabolic differences in children born after in vitro fertilization: Follow-up study. J Clin Endocrinol Metab 2008;93:1682-1688.
4.
Sakka SD, Loutradis D, Kanaka-Gantenbein C, Margeli A, Papastamataki M, Papassotiriou I, Chrousos GP: Absence of insulin resistance and low-grade inflammation despite early metabolic syndrome manifestations in children born after in vitro fertilization. Fertil Steril 2010;94:1693-1699.
5.
Scherrer U, Rimoldi SF, Rexhaj E, Stuber T, Duplain H, Garein S, de Marchi SF, Nicod P, Germond M, Allemann Y, Sartori C: Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation 2012;125:1890-1896.
6.
Gardner DS, Jackson AA, Langley-Evans SC: The effect of prenatal diet and glucocorticoids on growth and systolic blood pressure in the rat. Proc Nutr Soc 1998;57:235-240.
7.
Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR: Glucocorticoid exposure in late gestation permanently programs rat hepatic phosophoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 1998;101:2174-2181.
8.
Reynolds RM: Corticosteroid-mediated programming and the pathogenesis of obesity and diabetes. J Steroid Biochem Mol Biol 2010;122:3-9.
9.
Hillman JB, Dorn LD, Loucks TL, Berga SL: Obesity and the hypothalamic-pituitary-adrenal axis in adolescent girls. Metabolism 2012;61:341-348.
10.
Chalew SA, Lozano RA, Armour KM, Zadik Z, Kowarski AA: Reduction of plasma cortisol levels in childhood obesity. J Pediatr 1991;119:778-780.
11.
Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JM: Cortisol effects on body mass, blood pressure and cholesterol in the general population. Hypertension 1999;33:1364-1368.
12.
Wallerius S, Rosmond R, Ljung T, Holm G, Bjorntop P: Rise in morning saliva cortisol is associated with abdominal obesity in men: a preliminary report. J Endocrinol Invest 2003;26:616-619.
13.
Ranjit N, Young EA, Raghunathan TE, Kaplan GA: Modeling cortisol rhythms in a population-based study. Psychoneuroendocrinology 2005;30:615-624.
14.
Boyne MS, Woollard A, Phillips DI, Taylor-Bryan C, Bennett FI, Osmond C, Thomas TY, Wilks RJ, Forrester TE: The association of hypothalamic-pituitary-adrenal axis activity and blood pressure in an Afro-Caribbean population. Psychoneuroendocrinology 2009;34:736-742.
15.
Belva F, Henriet S, Liebaers I, Van Steirteghem A, Celestin-Westreich S, Bonduelle M: Medical outcome of 8-year-old singleton ICSI children (born >or=32 weeks' gestation) and a spontaneously conceived comparison group. Hum Reprod 2007;22:506-15.
16.
Belva F, Roelants M, De Schepper J, Roseboom TJ, Bonduelle M, Devroey P Painter RC: Blood pressure in ICSI conceived adolescents. Hum Reprod 2012;27:3100-3108.
17.
Belva F, Roelants M, Painter RC, Bonduelle M, Devroey P, De Schepper J: Pubertal development in ICSI children. Hum Reprod 2012;27:1156-1161.
18.
Tornhage DJ: Salivary cortisol for assessment of hypothalamic-pituitary-adrenal axis function. Neuroimmunomodulation 2009;16:284-289.
19.
Tanner JM. Growth and endocrinology in the adolescent. Endocrine and genetic diseases of childhood, Ed L Gardner-Saunders, 1969, Philadelphia, USA.
20.
Rodriguez G, Moreno LA, Blay MG, Blay VA, Fleta J, Sarria A, Bueno M, the AVENA-Zaragoza Study group: Body fat measurement in adolescents: comparison of skinfold thickness equations with dual-energy X-ray absorptiometry. Eur J Clin Nutr 2005;59:1158-1166.
21.
De Mouzon J, Goossens V, Bhattacharya S, Castilla J, Ferraretti A, Korsak V, Kupka M, Nygren K, Andersen AN, The European IVF-Monitoring (EIM): Assisted reproductive technology in Europe, 2007:results generated from European registers by ESHRE. Hum Reprod 2012;27:954-966.
22.
Strain GW, Zumoff B; Kream J, Strain JJ, Levin J, Fukushima D: Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism 1982;31:209-2012.
23.
Reynolds RM, Syddall HE, Walker BR, Wood PJ, Phillips DIW: Predicting cardiovascular risk factors from plasma cortisol measured during oral glucose tolerance tests. Metabolism 2003;52:524-527.
24.
Netherton C, Goodyer I, Tamplin A, Herbert J: Salivary cortisol and dehydroepiandrosterone in relation to puberty and gender. Psychoneuroendocrinology 2004;29:125-140.
25.
Lingas R, Dean F, Matthews SG: Maternal nutrient restriction (48 h) modifies brain corticosteroid receptor expression and endocrine function in the fetal guinea pig. Brain Res 1999;846:236-242.
26.
Liu L, Li A, Matthews SG: Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects. Am J Physiol Endocrinol Metab 2001;280:E729-E739.
27.
Dean F, Matthews SG: Maternal dexamethasone treatment in late gestation alters glucocorticoid and mineralocorticoid receptor mRNA in the fetal guinea pig brain. Brain Res 1999;846:253-259.
28.
Young E: Sex differences in response to exogenous corticosterone: a rat model of hypercortisolemia. Mol Psychiatry 1996;1:313-319.
29.
Stroud LR, Papandonatos GD, Williamson DE, Dahl RE: Sex differences in cortisol response to corticotropin releasing hormone challenge over puberty: Pittsburgh Pediatric Neurobehavioral Studies. Psychoneuroendocrinology 2011;36:1226-1238.
30.
Jonetz-Mentzel L, Wiedemann G: Establishment of reference ranges for cortisol in neonates, infants, children and adolescents. Eur J Clin Chem Clin Biochem 1993;31:525-529.
31.
Rosmalen JG, Oldehinkel AJ, Ormel J, de Winter AF, Buitelaar JK, Verhulst FC: Determinants of salivary cortisol levels in 10-12 year old children; a population-based study of individual differences. Psychoneuroendocrinology 2005;30:483-495.
32.
Knutsson U, Dahlgren J, Marcus C, Rosberg S, Bronnegard M, Stierna P, Albertsson-Wikland K: Circadian cortisol rhythms in healthy boys and girls: relationship with age, growth, body composition and pubertal development. J Clin Endocrinol Metab 1997;82:536-540.
33.
Barat P, Gayard-Cros M, Andrew R, Corcuff JB, Jouret B, Barthe N, Perez P, Germain C, Tauber M, Walker BR, Mormede P, Duclos M: Truncal distribution of fat mass, metabolic profile and hypothalamic-pituitary adrenal axis activity in prepubertal obese children. J Pediatr 2007;150:535-539.
34.
Kiess W, Meidert A, Dressendorfer RA, Schriever K, Kessler U, Konig A, Schwarz HP, Strasburger CJ: Salivary cortisol levels throughout childhood and adolescence: relation with age, pubertal stage and weight. Pediatr Res 1995;37:502-506.
35.
Tornhage CJ: Reference values for morning salivary cortisol concentrations in healthy school-aged children. J Pediatr Endocrinol Metab 2002;15:197-204.
36.
Koupil I, Mann V, Leon DA, Lundberg U, Byberg L, Vagero D: Morning cortisol does not mediate the association of size at birth with blood pressure in children born from full-term pregnancies. Clin Endocrionol (Oxf) 2005;62:661-666.
37.
Martinez-Aguayo A, Aglony M, Bancalari R, Avalos C, Bolte L, Garcia H, Loureiro C, Carvajal C, Campino C, Inostroza A, Fardella C: Birth weight is inversely associated with blood pressure and serum aldosterone and cortisol levels in children. Clinical Endocrinology 2012;76:713-718.
38.
Scheer FA, Buijs RM: Light affects morning salivary cortisol in humans. J Clin Endocrinol Metab 1999;84:3395-3398.
39.
Goldman-Mellor S, Hamer M, Steptoe A: Early-life stress and recurrent psychological distress over the lifecourse predict divergent cortisol reactivity patterns in adulthood. Psychoneuroendocrinology 2012;37:1755-1768.
40.
Winter C, Belva F, Nekkebroeck J, Bonduelle M: Do ICSI adolescents encounter psychological problems? Hum Reprod 2011;26 S1:i265 (P-373).
41.
Kirschbaum C, Hellhammer DH: Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology 1994;19:313-333.
© 2013 S. Karger AG, Basel
2013
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.