Progesterone and contraceptive progestin actions on the brain: A systematic review of animal studies and comparison to human neuroimaging studies.

In this review we systematically summarize the effects of progesterone and synthetic progestins on neurogenesis, synaptogenesis, myelination and six neurotransmitter systems. Several parallels between progesterone and older generation progestin actions emerged, suggesting actions via progesterone receptors. However, existing results suggest a general lack of knowledge regarding the effects of currently used progestins in hormonal contraception regarding these cellular and molecular brain parameters. Human neuroimaging studies were reviewed with a focus on randomized placebo-controlled trials and cross-sectional studies controlling for progestin type. The prefrontal cortex, amygdala, salience network and hippocampus were identified as regions of interest for future preclinical studies. This review proposes a series of experiments to elucidate the cellular and molecular actions of contraceptive progestins in these areas and link these actions to behavioral markers of emotional and cognitive functioning. Emotional effects of contraceptive progestins appear to be related to 1) alterations in the serotonergic system, 2) direct/indirect modulations of inhibitory GABA-ergic signalling via effects on the allopregnanolone content of the brain, which differ between androgenic and anti-androgenic progestins. Cognitive effects of combined oral contraceptives appear to depend on the ethinylestradiol dose.

Diagnosis and Therapy of Iron Deficiency Anemia During Pregnancy: Recommendation of the Austrian Society for Gynecology and Obstetrics (OEGGG).

This overview analyzes the data on the controversial therapy of iron substitution during pregnancy, the diagnosis of iron deficiency anemia and the indication-related therapy, and is the first recommendation issued by the OEGGG on the appropriate therapy. The effects of anemia during pregnancy on postnatal outcomes have been intensively investigated with heterogeneous results. A final scientific conclusion with regards to the "optimal" maternal hemoglobin level is limited by the heterogeneous results of various studies, many of which were conducted in emerging nations (with different dietary habits and structural differences in the respective healthcare systems). The current literature even suggests that there may be a connection between both decreased and increased maternal serum hemoglobin concentrations and unfavorable short-term and long-term neonatal outcomes. In Austria, 67 percent of pregnant women take pharmacological supplements or use a variety of dietary supplements. Clinically, the prevalence of maternal anemia is often overestimated, leading to overtreatment of pregnant women (iron substitution without a medical indication). To obtain a differential diagnosis, a workup of the indications for treatment should be carried out prior to initiating any form of iron substitution during pregnancy. If treatment is medically indicated, oral iron substitution is usually sufficient. Because of the restricted approval and potential side effects, medical indications for intravenous iron substitution should be limited. Intravenous iron substitution without a prior detailed diagnostic workup is an off-label use and should only be used in very limited cases, and women should be advised accordingly.

Neurobiological mechanisms underlying sex-related differences in stress-related disorders: Effects of neuroactive steroids on the hippocampus.

Men and women differ in their vulnerability to a variety of stress-related illnesses, but the underlying neurobiological mechanisms are not well understood. This is likely due to a comparative dearth of neurobiological studies that assess male and female rodents at the same time, while human neuroimaging studies often don't model sex as a variable of interest. These sex differences are often attributed to the actions of sex hormones, i.e. estrogens, progestogens and androgens. In this review, we summarize the results on sex hormone actions in the hippocampus and seek to bridge the gap between animal models and findings in humans. However, while effects of sex hormones on the hippocampus are largely consistent in animals and humans, methodological differences challenge the comparability of animal and human studies on stress effects. We summarise our current understanding of the neurobiological mechanisms that underlie sex-related differences in behavior and discuss implications for stress-related illnesses.

Placental Growth Factor informed management of suspected pre-eclampsia or fetal growth restriction: The MAPPLE cohort study.

OBJECTIVES: Placental Growth Factor (PlGF) has been shown to be beneficial in diagnosing pre-eclampsia. We performed a prospective cohort study of revealed PlGF in standard clinical use in four teaching hospitals in UK, Germany, Austria and Australia. STUDY DESIGN: Clinical data from women with suspected pre-eclampsia or fetal growth restriction <35 weeks' gestation with revealed PlGF measurement were collected (MAPPLE study). MAIN OUTCOME MEASURES: Data were compared to the PELICAN study (PlGF concealed). Pre-specified outcomes were compared using standard statistical tests (median difference or Risk Ratio). The results were further categorised by PlGF concentration: i) very low (<12 pg/ml), ii) low (12-100 pg/ml), iii) normal (>100 pg/ml). RESULTS: 396 women managed with revealed PlGF (MAPPLE) were compared with 287 women with concealed PlGF (PELICAN). Revealed PlGF led to delivery 1.4 weeks earlier (-2.0 to -0.9, 34.9 weeks vs 36.7 weeks). There were no significant differences in maternal adverse outcomes (11.9% vs 10.1%, Risk Ratio (RR) 1.17, 95% CI 0.76-1.82) or caesarean sections (73.8% vs 64.5%; RR 1.14, 95% CI 1.03-1.26). Revealed PlGF led to fewer perinatal deaths (2 vs 9; RR 0.16, 95% CI 0.03-0.74) and fewer babies with birthweight <3rd centile (28.9% vs 36.1%; RR 0.80, 0.65-0.99), but with more neonatal adverse outcomes (30.4% vs 17.1%; RR 1.78, 95% CI 1.32-2.41). CONCLUSIONS: Revealed PlGF may be associated with lower perinatal mortality and birthweight <3rd centile but appears to lead to earlier delivery with more neonatal respiratory morbidity. Randomised trials with adequate power for clinical outcomes are needed. FUNDING: Financial assistance was received from Alere to support the running of the MAPPLE database. Alere had no access to the information or control over the database itself.

Gating of the neuroendocrine stress responses by stressor salience in early lactating female rats is independent of infralimbic cortex activation and plasticity.

In early lactation (EL), stressor salience modulates neuroendocrine stress responses, but it is unclear whether this persists throughout lactation and which neural structures are implicated. We hypothesized that this process is specific to EL and that the infralimbic (IL) medial prefrontal cortex (mPFC) might provide a critical link between assessment of threat and activation of the hypothalamo-pituitary-adrenal (HPA) axis in EL. We measured neuroendocrine responses and neuronal Fos induction to a salient (predator odor) or non-salient (tail pinch) psychogenic stressor in EL and late lactation (LL) females. We found that EL females exhibited a large response to predator stress only in the presence of pups, while responses to tail pinch were reduced independently of pup presence. In LL, HPA axis responses were independent of pup presence for both stressors and only responses to tail pinch were modestly reduced compared to virgins. Intracerebral injection of the local anesthetic bupivacaine (BUP) (0.75%; 0.5 µl/side) in the IL mPFC did not differentially affect neuroendocrine responses to predator odor in virgin and EL females, suggesting that lactation-induced changes in this structure might not regulate stressor salience for the HPA axis. However, the IL mPFC displayed morphological changes in lactation, with significant increases in dendritic spine numbers and density in EL compared to LL and virgin females. EL females also showed improved performance in the attention set-shifting task (AST), which could reflect early plasticity in the IL mPFC at a time when rapid adaptation of the maternal brain is necessary for pup survival.

The maternal brain under stress: Consequences for adaptive peripartum plasticity and its potential functional implications.

The peripartum period represents a time during which all mammalian species undergo substantial physiological and behavioural changes, which prepare the female for the demands of motherhood. In addition to behavioural and physiological alterations, numerous brain regions, such as the medial prefrontal cortex, olfactory bulb, medial amygdala and hippocampus are subject to substantial peripartum-associated neuronal, dendritic and synaptic plasticity. These changes, which are temporally- and spatially-distinct, are strongly influenced by gonadal and adrenal hormones, such as estrogen and cortisol/corticosterone, which undergo dramatic fluctuations across this period. In this review, we describe our current knowledge regarding these plasticity changes and describe how stress affects such normal adaptations. Finally, we discuss the mechanisms potentially underlying these neuronal, dendritic and synaptic changes and their functional relevance for the mother and her offspring.

Prenatal maternal stress predicts stress reactivity at 2½ years of age: the Iowa Flood Study.

Prenatal maternal stress (PNMS) predicts psychosocial development in offspring. It has been hypothesized that during PNMS, glucocorticoids pass the placenta, reaching the foetus, leading to a long-term reprogramming and dysregulation of the foetal hypothalamic-pituitary-adrenal (HPA) axis. However, results are inconsistent across PNMS studies. One problem may be the confounding of objective degrees of hardship due to the stressor and subjective degrees of distress in the mother. The present study investigated the association between objective and subjective PNMS due to a natural disaster, the June 2008 Iowa floods, and stress reactivity in the offspring at 2½ years of age. Women who were pregnant during the floods were recruited, on average, within three months of the floods and their stress levels assessed. Mothers and their toddlers (n = 94 dyads) participated in a brief mother-toddler separation to induce physiological stress responses in the offspring. Salivary cortisol samples were collected four times during the procedure. We computed absolute change in cortisol (baseline to 20-minute post-stressor; baseline to 45-minute post-stressor) and Area Under the Curve with respect to increase and ground (AUCi; AUCg). Objective and subjective PNMS were positively correlated with AUCi, as was timing in gestation: the later in pregnancy the exposure occurred, the greater the cortisol increase. Controlling for objective hardship and other covariates, sex-by-subjective PNMS interactions showed a significant and positive association between subjective PNMS and Absolute Increase (45 min) and AUCi in females only, with little effect in males. These results suggest that PNMS leads to long-term alterations in the functioning of the HPA axis, evident as early as 30-months of age.

The maternal brain: an organ with peripartal plasticity.

The time of pregnancy, birth, and lactation, is characterized by numerous specific alterations in several systems of the maternal body. Peripartum-associated changes in physiology and behavior, as well as their underlying molecular mechanisms, have been the focus of research since decades, but are still far from being entirely understood. Also, there is growing evidence that pregnancy and lactation are associated with a variety of alterations in neural plasticity, including adult neurogenesis, functional and structural synaptic plasticity, and dendritic remodeling in different brain regions. All of the mentioned changes are not only believed to be a prerequisite for the proper fetal and neonatal development, but moreover to be crucial for the physiological and mental health of the mother. The underlying mechanisms apparently need to be under tight control, since in cases of dysregulation, a certain percentage of women develop disorders like preeclampsia or postpartum mood and anxiety disorders during the course of pregnancy and lactation. This review describes common peripartum adaptations in physiology and behavior. Moreover, it concentrates on different forms of peripartum-associated plasticity including changes in neurogenesis and their possible underlying molecular mechanisms. Finally, consequences of malfunction in those systems are discussed.

Lactation-induced reduction in hippocampal neurogenesis is reversed by repeated stress exposure.

The peripartum period is a time of high susceptibility for mood and anxiety disorders, some of which have recently been associated with alterations in hippocampal neurogenesis. Several factors including stress, aging, and, perhaps unexpectedly, lactation have been shown to decrease hippocampal neurogenesis. Intriguingly, lactation is also a time of reduced stress responsivity suggesting that the effect of stress on neurogenic processes may differ during this period. Therefore, the aim of the present study was to assess the effect of repeated stress during lactation [2 h restraint stress from lactation day (LD) 2 to LD13] on brain weight, hippocampal volume, cell proliferation and survival, and on neuronal and astroglial differentiation. In addition to confirming the known lactation-associated decrease in cell proliferation and survival, we could reveal that stress reversed the lactation-induced decrease in cell proliferation, while it did not affect survival of newly born cells, nor the number of mature neurons , nor did it alter immature neuron production or the number of astroglial cells in lactation. Stress exposure increased relative brain weight and hippocampal volume mirroring the observed changes in neurogenesis. Interestingly, hippocampal volume and relative brain weight were lower in lactation as compared to nulliparous females under nonstressed conditions. This study assessed the effect of stress during lactation on hippocampal neurogenesis and indicates that stress interferes with important peripartum adaptations at the level of the hippocampus.

Sex-dependent regulation of hippocampal neurogenesis under basal and chronic stress conditions in rats.

Sex differences in basal as well as in stress-induced hippocampal neurogenesis processes have been reported in the literature. However, studies directly comparing sex differences on multiple neurogenesis processes under such conditions are lacking to date. Therefore, the aim of the present study was to directly compare cell proliferation and survival, neuronal and astroglial differentiation as well as stem cells quiescence in male and female Wistar rats under both basal and chronic stress conditions (12 days of 2 h restraint stress (RS)). In addition, corticosterone (CORT) levels and spatial working memory were assessed. Under baseline conditions, only the number of immature neurons within the hippocampal dentate gyrus was higher in males compared with females. In contrast, chronic stress resulted in a number of sex-specific alterations. Thus, stress exposure reduced cell proliferation in males with a concurrent increase in stem cell quiescence, while it did not alter either parameter in females but decreased cell survival. Analysis of astroglial and neuronal differentiation patterns revealed that chronic stress specifically diminished the number of mature neurons in females, with no effect in males. Despite the observed sex differences in adult hippocampal neurogenesis, spatial working memory was not altered by stress exposure in either sex. While basal CORT levels were higher, chronic stress exposure did not affect this parameter in either sex across the initial stress period. This study presents the first direct and detailed evaluation of sex-dependent and chronic stress-induced changes in adult hippocampal neurogenesis not only showing changes in cell proliferation and survival, but moreover immature neuron production, differentiation patterns, stem cell quiescence and therefore contributes to a better understanding of sex differences in neurogenesis processes.

Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats.

The c-Raf - MEK1/2 - ERK1/2 mitogen-activated protein kinase (MAPK) intracellular signalling cascade in neurons plays important roles in the control of a variety of behaviours, including social behaviours and anxiety. These roles partially overlap with those described for oxytocin (OXT), and it has been shown that OXT activates the MAPK pathway in the hypothalamus (of male), and hippocampus (of female) rats. Here, by combining behavioural (light/dark box) and biochemical analyses (western blotting), we tested two hypotheses: (i) that OXT is anxiolytic within the hypothalamus of females, and (ii) that this effect, as well as that of lactation-associated anxiolysis, depends on the recruitment of the MAPK pathway. We found that, when injected bilaterally into the hypothalamic paraventricular nucleus (PVN), OXT decreased anxiety-like behaviour in virgins, and that this effect depended on phosphorylation of MEK1/2. MAPK pathway activation in lactation was evident by high phosphorylated (p) MEK1/2 levels, and nuclear translocation of ERK1. The high pMEK1/2 levels were necessary for the anxiolytic phenotype typically observed during lactation. Interestingly, exogenous OXT in lactating rats reduced pMEK1/2 levels without a concomitant effect on anxiety, indicating that OXT receptor activation can lead to recruitment of additional intracellular pathways to modulate MEK activity. Still other pathways could include MEK, but without subsequent activation of ERK, as we did not observe any increase in OXT-induced ERK phosphorylation. Together the results demonstrate that the MAPK pathway, especially MEK1/2, is critically involved in the regulation of anxiety-like behaviour in female rats.

From stress to postpartum mood and anxiety disorders: how chronic peripartum stress can impair maternal adaptations.

The peripartum period, in all mammalian species, is characterised by numerous adaptations at neuroendocrine, molecular and behavioural levels that prepare the female for the challenges of motherhood. These changes have been well characterised and, while they are necessary to ensure the survival and nurturance of the offspring, there is growing belief that they are also required for maternal mental health. Thus, while increased calmness and attenuated stress responsivity are common characteristics of the peripartum period, it also represents a time of increased susceptibility to mood disorders. While a number of risk factors for these disorders are known, their underlying aetiology remains poorly understood, due at least in part to a lack of appropriate animal models. One translatable risk factor is stress exposure during the peripartum period. In the following review we first describe common peripartum adaptations and the impact postpartum mood disorders have on these. We then discuss the known consequences of peripartum stress exposure on such maternal adaptations that have been described in basic research.

Exposure to chronic pregnancy stress reverses peripartum-associated adaptations: implications for postpartum anxiety and mood disorders.

Maternal adaptations, such as decreased anxiety and attenuated stress responsiveness, are necessary to enable successful postnatal development of the offspring. However, there is growing evidence that they are also required to protect the mental health of the mother and that exposure to chronic stress during pregnancy may prevent such adaptations. Overcrowding stress (24 h) and restraint stress (2 × 1 h) were employed on alternate days between pregnancy d 4-16 to examine the impact of chronic pregnancy stress on relevant behavioral, neuroendocrine, and neuronal peripartum adaptations. To determine whether the chronic stress-induced alterations were specific to the peripartum period, we included virgins as controls. Validating the stress procedure, we demonstrated decreased body-weight gain and increased adrenal weight in stressed dams, relative to their nonstressed controls. Chronic stress prevented a number of peripartum adaptations, including basal plasma hypercorticosterone levels, increased oxytocin mRNA expression in the hypothalamic paraventricular nucleus, and anxiolysis. However, chronic stress did not prevent the peripartum-associated decrease in CRH mRNA expression or attenuate corticosterone response to an acute stressor, nor did it affect hypothalamic vasopressin mRNA expression. Illustrating the specificity of these stress-induced changes to the peripartum period, none of these parameters were affected in stressed virgins. Although chronic stress did not alter depression-related behavior, it reversed the response to acute imipramine treatment and increased active maternal behavior in lactation. Thus, prevention of the peripartum-associated increases in basal corticosterone and oxytocin system activity by pregnancy stress reveal two alterations that may increase the risk of postpartum psychiatric disorders, particularly anxiety.