Sex differences in early-life programming of the hypothalamic–pituitary–adrenal axis in humans suggest increased vulnerability in females: a systematic review
Open accessAbstract
Fetal glucocorticoid overexposure is a key mechanism linking early development with later-life disease. In humans, low birth weight associates with increased fasting cortisol, hypothalamic–pituitary–adrenal (HPA) axis reactivity, and with cardiovascular risk and cognitive decline. As there are sex differences in these adult diseases, we hypothesized that there may be sex differences in programming of the HPA axis in response to prenatal stressors. We conducted a systematic review following Meta-Analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analysis. We searched Embase, MEDLINE and Web of Science from inception to 31 October 2016. We included studies related to sex differences, prenatal exposures and HPA axis. We excluded studies investigating specific disease states. The 23 included studies investigated the consequences of low birth weight, preterm birth and maternal stressors of asthma, psychosocial stress and glucocorticoid medications on HPA axis outcomes of placental glucocorticoid biology and offspring HPA axis function in early life and later life. Female offspring exposed to stressors had increased HPA axis reactivity compared with males. Furthermore, the female placenta increased its permeability to maternal glucocorticoids following maternal stress with changes in the expression of 11β-hydroxysteroid dehydrogenase enzymes in response to maternal glucocorticoid exposure or asthma. Among males there was some evidence of altered diurnal cortisol secretion. We conclude that although there is some evidence of male vulnerability leading to altered diurnal cortisol secretion, the female HPA axis is more vulnerable to programming, particularly in terms of its reactivity; this suggests a mechanism underlying sex differences in later-life diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The female placenta may facilitate higher glucocorticoid exposure, as the activity of 11β-HSD1 and 11β-HSD2 responsible for cortisol metabolism was altered in the placenta of females.
“The female placenta may facilitate higher glucocorticoid exposure, as the activity of the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) responsible for cortisol metabolism was found to be altered in the placenta of females [117,119].”
From Stress and the HPA Axis: Balancing Homeostasis and Fertility. (2017) · cites this paper as [117]
Male and female offspring differ in their responses to prenatal stress.
“Furthermore, evidence suggests that male and female offspring differ in their responses to prenatal stress [117].”
From Stress and the HPA Axis: Balancing Homeostasis and Fertility. (2017) · cites this paper as [117]
Prenatal stress in humans was associated with alterations in diurnal cortisol secretion in males that were not apparent in females.
“prenatal stress in humans was associated with alterations in diurnal cortisol secretion in males that were not apparent in females 163”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [163]
Female offspring exposed to prenatal stressors had higher HPA axis reactivity than did similarly exposed males, with differences in placental expression of 11β-HSD enzymes.
“female offspring exposed to prenatal stressors had higher HPA axis reactivity than did similarly exposed males, with differences in placental expression of 11β-HSD enzymes”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [163]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Stroup, D. F. (2000) · JAMA · doi:10.1001/jama.283.15.2008 · Cited by 20,623 · see citing works
Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gotzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · BMJ · doi:10.1136/bmj.b2700 · Cited by 17,648 · see citing works
Development and validation of a questionnaire to measure asthma control
Juniper, E. F., O′byrne, P. M., Guyatt, G. H., Ferrie, P. J., & King, D. R. (1999) · European Respiratory Journal · doi:10.1034/j.1399-3003.1999.14d29.x · Cited by 2,473 · see citing works
Edwards, C. R. W., Benediktsson, R., Lindsay, R. S., & Seckl, J. R. (1993) · The Lancet · doi:10.1016/0140-6736(93)90148-a · Cited by 549 · see citing works
Reynolds, R. M. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.08.012 · Cited by 497 · see citing works
Self-citationIs there a viability–vulnerability tradeoff? Sex differences in fetal programming
Sandman, C. A., Glynn, L. M., & Davis, E. P. (2013) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2013.07.009 · Cited by 343 · see citing works
Reynolds, R. M., Walker, B. R., Syddall, H. E., Andrew, R., Wood, P. J., Whorwood, C. B., & Phillips, D. I. W. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.1.7145 · Cited by 328 · see citing works
Self-citationMaternal Asthma Is Associated with Reduced Female Fetal Growth
Murphy, V. E., Gibson, P. G., Giles, W. B., Zakár, T., Smith, R., Bisits, A. M., Kessell, C. G., & Clifton, V. L. (2003) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200303-374oc · Cited by 295 · see citing works
Reynolds, R. M. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.86.1.245 · Cited by 242 · see citing works
Self-citationJuniper, E. F., O’Byrne, P. M., Ferrie, P. J., KING, D. R., & ROBERTS, J. N. (2000) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.162.4.9912138 · Cited by 227 · see citing works
Alexander, N., Rosenlöcher, F., Stalder, T., Linke, J., Distler, W., Morgner, J., & Kirschbaum, C. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-1970 · Cited by 211 · see citing works
Stark, M. J., Wright, I. M. R., & Clifton, V. L. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00175.2009 · Cited by 161 · see citing works
Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life
Wüst, S., Entringer, S., Federenko, I. S., Schlotz, W., & Hellhammer, D. H. (2005) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2005.01.008 · Cited by 142 · see citing works
Prenatal maternal stress predicts stress reactivity at 2½ years of age: The Iowa Flood Study
Ping, E. Y., Laplante, D. P., Elgbeili, G., Hillerer, K. M., Brunet, A., O’Hara, M. W., & King, S. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.02.015 · Cited by 120 · see citing works
Sex-specific differences in placental global gene expression in pregnancies complicated by asthma
Osei-Kumah, A., Smith, R., Jurišica, I., Caniggia, I., & Clifton, V. L. (2011) · Placenta · doi:10.1016/j.placenta.2011.05.005 · Cited by 108 · see citing works
Saif, Z., Hodyl, N. A., Hobbs, E., Tuck, A., Butler, M. S., Osei-Kumah, A., & Clifton, V. L. (2014) · Placenta · doi:10.1016/j.placenta.2014.01.012 · Cited by 100 · see citing works
Ostlund, B. D., Conradt, E. D., Crowell, S. E., Tyrka, A. R., Marsit, C. J., & Lester, B. M. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00147 · Cited by 89 · see citing works
Fetal sex and prenatal betamethasone therapy
Ballard, P. L., Ballard, R. A., Granberg, J., et al. (1980) · The Journal of Pediatrics · doi:10.1016/s0022-3476(80)80204-6 · Cited by 87 · see citing works
Mericq, V, Medina, P., Kakarieka, E., Márquez, L., Johnson, M. C., & Iñiguez, G. (2009) · European Journal of Endocrinology · doi:10.1530/eje-09-0308 · Cited by 86 · see citing works
Mina, T. H., Räikkönen, K., Riley, S. C., Norman, J. E., & Reynolds, R. M. (2015) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.05.004 · Cited by 76 · see citing works
Self-citationSaif, Z., Hodyl, N. A., Stark, M. J., Fuller, P. J., Cole, T. J., Lu, N. Z., & Clifton, V. L. (2015) · Placenta · doi:10.1016/j.placenta.2015.05.001 · Cited by 71 · see citing works
Reynolds, R. M., Walker, B. R., Syddall, H. E., Andrew, R., Wood, P. J., & Phillips, D. I. W. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.01846 · Cited by 62 · see citing works
Self-citationJohnstone, J. F., Bocking, A. D., Unlugedik, E., & Challis, J. R. G. (2005) · Journal of the Society for Gynecologic Investigation · doi:10.1016/j.jsgi.2005.01.029 · Cited by 55 · see citing works
van Montfoort, N., Finken, M. J. J., le Cessie, S., et al. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.02050 · Cited by 55 · see citing works
Fall, C. H. D., Dennison, E. M., Cooper, C. C., Pringle, P. J., Kellingray, S., & Hindmarsh, P. C. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.5.8469 · Cited by 50 · see citing works
Maternal Mood and Neuroendocrine Programming: Effects of Time of Exposure and Sex
Vedhara, K., Metcalfe, C. D., Brant, H., Crown, A. L., Northstone, K., Dawe, K., Lightman, S. L., & Smith, G. D. (2012) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2012.02309.x · Cited by 48 · see citing works
de Bruijn, A. T. C. E., van Bakel, H. J. A., Wijnen, H. A. A., Pop, V. J. M., & van Baar, A. L. (2009) · Developmental Psychobiology · doi:10.1002/dev.20393 · Cited by 48 · see citing works
Hodyl, N. A., Wyper, H., Osei-Kumah, A., Scott, N. M., Murphy, V. E., Gibson, P. G., Smith, R., & Clifton, V. L. (2010) · Thorax · doi:10.1136/thx.2009.123091 · Cited by 44 · see citing works
Asthma During Pregnancy and Clinical Outcomes in Offspring: A National Cohort Study
Tegethoff, M., Olsen, J., Schaffner, E., & Meinlschmidt, G. (2013) · PEDIATRICS · doi:10.1542/peds.2012-3686 · Cited by 43 · see citing works
Effect of Low Birth Weight on Adrenal Steroids and Carbohydrate Metabolism in Early Adulthood
Szathmári, M., Vásárhelyi, B., & Tulassay, T. (2001) · Hormone Research in Paediatrics · doi:10.1159/000049991 · Cited by 38 · see citing works
Quesada, A. A., Tristão, R. M., Pratesi, R., & Wolf, O. T. (2014) · Stress · doi:10.3109/10253890.2014.949667 · Cited by 36 · see citing works
Asthma During Pregnancy and Clinical Outcomes in Offspring: A National Cohort Study
Davoodi, P., & Dolen, W. K. (2014) · PEDIATRICS · doi:10.1542/peds.2014-1817ccc · Cited by 33 · see citing works
ter Wolbeek, M., Kavelaars, A., de Vries, W. B., Tersteeg-Kamperman, M. D. J., Veen, S., Kornelisse, R. F., van Weissenbruch, M. M., Baerts, W., Liem, K. D., van Bel, F., et al. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.10.017 · Cited by 31 · see citing works
Hodyl, N. A., Stark, M. J., Butler, M. S., & Clifton, V. L. (2013) · Placenta · doi:10.1016/j.placenta.2013.01.013 · Cited by 28 · see citing works
Lee, J., Fried, R. L., Thayer, Z. M., & Kuzawa, C. W. (2014) · American Journal of Human Biology · doi:10.1002/ajhb.22569 · Cited by 25 · see citing works
Demendi, C., Börzsönyi, B., Pajor, A., et al. (2012) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2012.08.009 · Cited by 17 · see citing works
Increased Steroid Excretion in Children with Extremely Low Birth Weight at a Median Age of 9.8 years
Gohlke, B. C., Wudy, S. A., Stutte, S., et al. (2015) · Hormone Research in Paediatrics · doi:10.1159/000441031 · Cited by 12 · see citing works
Kaseva, N., Pyhälä, R., Pesonen, A., Räikkönen, K., Järvenpää, A., Andersson, S., Eriksson, J. G., Hovi, P., & Kajantie, E. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162650 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [6]6. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000; 283, 2008-2012.
Cited by
Sorted by citations
Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms
Yehuda, R., & Lehrner, A. (2018) · World Psychiatry · doi:10.1002/wps.20568 · Cited by 730 · see citing works
Stress and the HPA Axis: Balancing Homeostasis and Fertility.
Joseph, D., & Whirledge, S. (2017) · International journal of molecular sciences · doi:10.3390/ijms18102224 · Cited by 290 · see citing works
“The female placenta may facilitate higher glucocorticoid exposure, as the activity of the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) responsible for cortisol metabolism was found to be altered in the placenta of females [117,119].”
BackgroundGlucocorticoids and reproduction: Traffic control on the road to reproduction
Whirledge, S., & Cidlowski, J. A. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2017.02.005 · Cited by 178 · see citing works
Aktar, E., Qu, J., Lawrence, P. J., Tollenaar, M. S., Elzinga, B. M., & Bögels, S. M. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00391 · Cited by 140 · see citing works
Psychological correlates of COVID-19 pandemic in the Austrian population
Traunmüller, C., Stefitz, R., Gaisbachgrabner, K., & Schwerdtfeger, A. (2020) · BMC Public Health · doi:10.1186/s12889-020-09489-5 · Cited by 120 · see citing works
Endocrine insights into the pathophysiology of autism spectrum disorder
Wilson, H. A., Creighton, C., Scharfman, H., Choleris, E., & MacLusky, N. J. (2021) · The Neuroscientist · doi:10.1177/1073858420952046 · Cited by 23 · see citing works
Possamai-Della, T., Cararo, J. H., Aguiar-Geraldo, J. M., Peper-Nascimento, J., Zugno, A. I., Fries, G. R., Quevedo, J., & Valvassori, S. S. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03348-1 · Cited by 16 · see citing works
- Authors
- Carpenter, T., Grecian, S. M., & Reynolds, R. M.
- Affiliations
- The Queen's Medical Research Institute (GB)
- Corresponding author
- Reynolds, R. M.
- Venue
- Journal of Developmental Origins of Health and Disease
- Publisher
- Cambridge University Press (CUP)
- Published
- 2017-01-20
- Volume
- 8
- Issue
- 2
- Pages
- 244-255
- ISSN
- 2040-1744 (ISSN-L)
- 2040-1752
- OpenAlex
- W2574374105
- Cited by
- 191
- References
- 38
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 15 · 2023: 21 · 2022: 26 · 2021: 23 · 2020: 28 · 2019: 22 · 2018: 20 · 2017: 9
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Developmental Origins of Health and Disease (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
- Funders
- British Heart Foundation
- Tommy's
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- sex differences, hypothalamic-pituitary-adrenal axis, fetal programming, prenatal glucocorticoid exposure, low birth weight, preterm birth, maternal stress, asthma, psychosocial stress, 11β-hydroxysteroid dehydrogenase, women's vulnerability, cardiovascular risk, cognitive decline
- MeSH terms
- Cardiovascular Diseases, Female, Humans, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Pregnancy, Prenatal Exposure Delayed Effects, Stress, Physiological
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
