Neuroactive steroids and stress axis regulation: Pregnancy and beyond

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 160; pp. 160 - 168
• Main Author: Brunton, Paula J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2016
• Subjects: 5α-Reductase; Animals; Brain - metabolism; Brain - physiology; Corticotropin-releasing hormone; Female; GABAA receptors; Humans; Hypothalamo-Hypophyseal System - physiology; Neurotransmitter Agents - metabolism; Paraventricular nucleus; Pituitary-Adrenal System - physiology; Pregnancy; Pregnanolone - metabolism; Progesterone; Stress, Physiological; Testosterone; Testosterone; Paraventricular nucleus; Progesterone; 5α-Reductase; Corticotropin-releasing hormone; GABAA receptors; GABA(A) receptors
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2015.08.003

•Neuroactive steroids modulate hypothalamo–pituitary–adrenal (HPA) axis activity.•In pregnancy, allopregnanolone restrains neuroendocrine responses to stress.•Prenatal stress results in HPA axis dysregulation in the offspring.•Prenatal stress exposure reduces the brain’s capacity for neurosteroidogenesis.•Neuroactive steroids can reverse the detrimental effects of prenatal stress. The hypothalamo–pituitary–adrenal (HPA) axis plays a critical role in regulating responses to stress and long term dysregulation of the HPA axis is associated with higher rates of mood disorders. There are circumstances where the HPA axis is more or less responsive to stress. For example, during late pregnancy ACTH and corticosterone responses to stress are markedly suppressed, whereas in offspring born to mothers that experienced repeated stress during pregnancy, the HPA axis is hyper-responsive to stress. Neuroactive steroids such as allopregnanolone, tetrahydrodeoxycorticosterone (THDOC) and androstanediol can modulate HPA axis activity and concentrations of some neuroactive steroids in the brain are altered during pregnancy and following stress. Thus, here altered neurosteroidogenesis is proposed as a mechanism that could underpin the dynamic changes in HPA axis regulation typically observed in late pregnant and in prenatally stressed individuals. In support of this hypothesis, evidence in rats demonstrates that elevated levels of allopregnanolone in pregnancy induce a central inhibitory opioid mechanism that serves to minimize stress-induced HPA axis activity. Conversely, in prenatally stressed rodents, where HPA axis stress responses are enhanced, evidence indicates the capacity of the brain for neurosteroidogenesis is reduced. Understanding the mechanisms involved in adaptations in HPA axis regulation may provide insights for manipulating stress sensitivity and for developing therapies for stress-related disorders in humans.