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Nutritional programming by glucocorticoids in breast milk: Targets, mechanisms and possible implications

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Vertical transmission of glucocorticoids via breast milk might pose a mechanism through which lactating women could prepare their infants for the postnatal environment. The primary source of breast-milk glucocorticoids is probably the systemic circulation. Research from our group showed that milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus–pituitary–adrenal axis activity, with a higher abundance of cortisone compared to cortisol. Measurement of breast-milk glucocorticoid concentrations is challenging due to possible cross-reactivity with progestagens and sex steroids, which are severely elevated during pregnancy and after parturition. This requires precise methods that are not hindered by cross reactivity, such as LC–MS/MS. There are some data suggesting that breast-milk glucocorticoids could promote intestinal maturation, either locally or after absorption into the systemic circulation. Breast-milk glucocorticoids might also have an effect on the intestinal microbiome, although this has not been studied thus far. Findings from studies investigating the systemic effects of breast-milk glucocorticoids are difficult to interpret, since none took the diurnal rhythm of glucocorticoids in breast milk into consideration, and various analytical methods were used. Nevertheless, glucocorticoids in breast milk might offer a novel potential pathway for signal transmission from mothers to their infants.

Introduction

Numerous studies suggest that adversities occurring in early life could predispose to later diseases such as cardiovascular diseases, type 2 diabetes mellitus and neuropsychiatric diseases. The mechanisms that could explain these associations relate to the concept of early-life programming, stating that insults early in life could persistently alter the body's structure and/or function. These alterations, although adaptive in nature, might become deleterious with age [1].

Glucocorticoids are known for their programming effects on metabolism and the brain [2]. The fetal cortisol hypothesis postulates that a lower activity of the placental barrier enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2 allows a larger proportion of maternal cortisol to reach the fetus, leading to permanent alterations in hypothalamus–pituitary–adrenal (HPA) axis settings, and, hence, predisposition to cardiometabolic and neuropsychiatric diseases in offspring [3].

Emerging data suggest that postnatal nutrition could play a role in early-life programming [4]. Breast feeding has been associated with improved health outcomes, including reduced risks of infections and obesity [4], [5]. Although glucocorticoids were recovered in breast milk already in the early 1970s [6], only few studies have addressed their effects in offspring. The recent discovery of a diurnal rhythm in the secretion of glucocorticoids into breast milk has opened new avenues for the study of the postnatal programming effects of maternal glucocorticoids.

Section snippets

Glucocorticoids, pregnancy and the mammary gland

Cortisol is produced by the zona fasciculata of the adrenal cortex. Its synthesis is regulated by adrenocorticotropin hormone (ACTH) from the anterior pituitary gland. The release of ACTH, in turn, is under the control of corticotropin releasing hormone (CRH) from the hypothalamus. When cortisol is present in adequate amounts, a negative feedback system operates on the pituitary gland and hypothalamus. The hypothalamus also receives input from multiple brain areas involved in the stress

Immunoassay versus LC–MS/MS

For the study of glucocorticoids in breast milk, reliable analytical methods are necessary. Steroid hormones can be measured with immunoassays or chromatography, possibly coupled to mass spectrometry. In general, immunoassays are prone to cross reactivity with compounds that share the general structure with the hormone of interest, necessitating the use of more specific analytical methods [22]. This is especially important during pregnancy and after parturition, when concentrations of steroid

Fate of breast-milk glucocorticoids in the neonatal gut

There is some evidence showing that breast-milk glucocorticoids are absorbed by the developing gut into the systemic circulation. Experiments in rats showed that milk-ingested labeled corticosterone – the principal glucocorticoid in rats – was able to cross the pups' intestinal epithelial barrier and was, subsequently, detectable in their plasma and brains [35]. Additionally, corticosterone was detectable in the serum of adrenalectomized pups fed with their own mother's milk [36]. In humans, a

Systemic effects of breast-milk glucocorticoids in offspring

Surprisingly few studies have investigated associations between breast-milk glucocorticoids and systemic effect in offspring. Here, we review the evidence from studies in both animals and man. The findings from these studies are summarized in Table 2.

Conclusions and future prospects

Given the methodological shortcomings of the studies conducted thus far, at present there is no compelling evidence for persistent effects of breast-milk glucocorticoids in offspring. Future studies should use sound methodologies to test associations between breast-milk glucocorticoids and infant developmental pathways, including frequent sampling and LC–MS/MS analysis with simultaneous measurement of cortisol and cortisone.

Recent evidence from studies in adults suggests that flattening of HPA

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

None of the authors have any conflicts of interests to declare.

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