Hypothalamic-pituitary-adrenal axis function during perinatal depression

Abstract

Abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis is an important pathological finding in pregnant women exhibiting major depressive disorder. They show high levels of cortisol proinflammatory cytokines, hypothalamic-pituitary peptide hormones and catecholamines, along with low dehydroepiandrosterone levels in plasma. During pregnancy, the TH2 balance together with the immune system and placental factors play crucial roles in the development of the fetal allograft to full term. These factors, when altered, may generate a persistent dysfunction of the HPA axis that may lead to an overt transfer of cortisol and toxicity to the fetus at the expense of reduced activity of placental 11β-hydroxysteroid dehydrogenase type 2. Epigenetic modifications also may contribute to the dysregulation of the HPA axis. Affective disorders in pregnant women should be taken seriously, and therapies focused on preventing the deleterious effects of stressors should be implemented to promote the welfare of both mother and baby.Keywords: brain; depression; neuroendocrine; pregnancy; stress; glucocorticoids Extensive studies have demonstrated that early life stressors produce changes in behavior and enhance the sensitivity of the stress response systems [1][2][3][4] . Although the genetic background has been implicated in the development of mood-related disorders, and genetic research has identified some chromosomal regions and genes that are involved in susceptibility to mood disorders, the etiology of anxiety and depressive disorders is still not clear in humans, particularly in women with major depressive disorder (MDD) [1] .The pathogenesis of perinatal depression is an emerging field. Although considerable progress has been made in this area in the last few years, there still remain unanswered questions and gaps in our knowledge of the underlying pathogenesis, the long-term impact of perinatal depression on the developing fetus, and the best methods for counseling pregnant women concerning the risks of untreated MDD versus the risks of psychopharmacologic treatment during pregnancy and lactation [5] . Meta-analysis studies have reported that the mean prevalence rate of prenatal depression is ~12% (this varies greatly according to location, mode of assessment, and socioeconomic conditions), and show that a large percentage of pregnant women displaying major depression remain depressed in the postpartum period and/or continuously [6,7] . Anxiety, depressive disorder, and stress during pregnancy are risk Phillipe Leff Gelman, et al. HPA axis in perinatal depression 339 factors for negative outcomes in newborns, like preterm birth or low birth weight; also, insecure attachment and impaired child development could be a consequence of mental disorders during pregnancy [6,[8][9][10] . The mechanisms by which maternal depression impacts fetal and neonatal development are currently under investigation; there is some evidence that depressive symptoms impact the infant's hypothalamic-pituitary-adrenal (HPA) axis, enhancing the ...

The Immune System and the Role of Inflammation in Perinatal Depression

“…Autocrine mediators released by trophoblast cells (TGF-b, IL-1b, TNF-a, IL-6, IL-8, IL-10, and decorin) and paracrine factors secreted by decidual cells [leukemia inhibitory factor (LIF, a member of the IL-6 protein family); IL-11, granulocyte macrophage colony-stimulating factor (GM-CSF); and macrophage colony-stimulating factor (M-CSF)], in addition to proteins such as prokineticin 1 and heparin-binding epidermal growth factor (hb-EGF), upregulate the expression and synthesis of soluble mediators, such as LIF/IL-6 [151,152], chemokines (CCL7/MIP3 and CCL4/ MIP1b), COX-2, and prostanoids (prostaglandins, prostacyclin, and thromboxane) [153], as well as serotonin (5-HT) and histamine [154][155][156], which stimulate and drive placental processes (blastocyst implantation, trophoblast proliferation, decidualization of endometrial tissue, implantation, and blood flow regulation) in a time-and space-dependent manner, facilitating the tolerance and development of the fetal ''allograft'' [157]. In addition, LIF, IL-6, and IL-11 upregulate the expression of adhesion molecules in human endometrial epithelial cells, facilitating implantation and trophoblast invasion during early gestation [152] (Fig.…”

“…Thus, based on multiple lines of evidence showing an active role of the immune system in MDD [130,131], it may be feasible to assume that TLR signaling in response to endogenous danger signals (psychological stress), activation of the NLPR3 inflammasome, and increased secretion of IL-1b and IL-18 from microglia (M1-active state phenotype) [138] or PBMCs [97] [97], in addition to the release of placental cytokines (IL-1b, TNF-a, LIF/IL-6, and IFN-c) from immune (Mus, NKs, and DCs) and nonimmune cells (decidual cells and trophoblasts) [157] during the third trimester, may contribute to triggering the changes in the prefrontal cortex, anterior cingulate, and hippocampus as well as neuroendocrine (hypothalamus, pituitary, and adrenal) and placental processes, which elicit the hallmark symptoms of depression during pregnancy [157].…”

“…In placenta: (1) expression of high levels of placental TLR4 [197] and TLR6 [195,196] in third trimester trophoblasts; (2) expression of TLR4 in macrophage-like cells (Hofbauer cells) in the term placenta [195,196]; 3increased secretion of placental (IL-1b, TNF-a, and LIF, IL-6) and peripheral cytokines (IL-2, IFN-c, and TNF-a) facilitating the release of endometrial prostaglandins (PGE2 and PGD2), chemokines (CCL7 and CCL4), and protein factors (MMPs), which promote dysregulation of the Th1/Th2 balance towards a predominant Th1 over Th2 immune response [165,[187][188][189]; and (4) effects of GCs, pro-inflammatory cytokines, anoxic conditions, and stress conditions of pregnancy such as preeclampsia on the increased CRH secretion and CRH blood levels in women delivering preterm, compared to the low hormone levels in women delivering at term [157].…”

Cortisol reactivity and depressive symptoms in pregnancy: The moderating role of perceived social support and neuroticism

“…This makes sense because the maternal HPA axis is challenged to integrate its function with the emerging placenta, a temporary endocrine organ, and has to continually adjust not only to the increasing placental CRH production as pregnancy progresses but also to the sudden absence of the placenta after delivery. For a detailed review on the interaction between the HPA axis and the endocrine placenta in the pathophysiology of perinatal depression, interested readers are referred to Gelman, Flores-Ramos, López-Martínez, Fuentes, and Grajeda (2015).…”

Implications of Polymorphisms in the CRHR1 Gene on the Hypothalamic-Pituitary-Adrenal Axis Functioning in Postpartum Depression

“…The HPA axis is under the control of negative feedback mechanisms and circadian variations in the lightdark cycle. During pregnancy, the corticotropinreleasing hormone (CRH), ordinarily produced by the paraventricular nucleus of the hypothalamus (PVN), is also produced by the placenta, leading to a significant increase in the circulating levels of CRH in the mother's blood [14]. The CRH system plays an important role in the coordination of physiological stress responses with different functions and at different brain levels [15].…”