Sex differences in early-life programming of the hypothalamic–pituitary–adrenal axis in humans suggest increased vulnerability in females: a systematic review

Abstract

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 Hypothalamic-Pituitary-Adrenal Axis and the Fetus

“…Applying gene ontology analysis to the same data set revealed “cell proliferation” as the top functional network regulated by Dex in NSPCs [64]. These data are consistent with the body of literature suggesting sexual differences in response to early-life exposure to GCs and its effects on the HPA axis [66]. …”

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

“…Data supporting the role of stress and elevated glucocorticoids in fetal programming has been documented in many species and thoroughly reviewed [36–41]. Interestingly programming of the HPA axis in response to prenatal stressors demonstrates sex-specific differences [42]. A systematic review of human studies concluded that the placenta of female offspring altered permeability to maternal glucocorticoids through regulation of the 11β-HSD enzymes in response to maternal stress [42].…”

“…Interestingly programming of the HPA axis in response to prenatal stressors demonstrates sex-specific differences [42]. A systematic review of human studies concluded that the placenta of female offspring altered permeability to maternal glucocorticoids through regulation of the 11β-HSD enzymes in response to maternal stress [42]. Maternal exposure to dexamethasone in rats results in sexually dimorphic behavior in offspring, associated with structural changes to neuronal populations [43, 44].…”

Sex Differences in Vulnerability to Prenatal Stress: a Review of the Recent Literature

“…This confers lasting susceptibility to health complications in the child [2, 4, 5, 6] and potentially transgenerational risks through epigenetic programming [8, 9, 11]. There is also accumulating evidence that the child’s biological sex may modify the effect of PNMS on child health [12, 13, 14, 15]. Consequently, many scholars have underscored the need to evaluate for sex-dependent effects in PNMS programming models [12, 13, 15, 16, 17, 18].…”