Although the initially identified actions of estradiol, progesterone and testosterone are related to sexual reproductive functions, recent evidence shows that these steroid hormones modulate development, physiology and survival of nerve cells.
Furthermore, neurosteroids can be synthesized in the developing and adult nervous system.
The main focus of this review is to summarize the described effects of steroid hormones (progesterone, allopregnanolone, dehydroepiandrosterone, estradiol and androgens) on cell parameters relevant to stem cells
steroid hormones influence stem cell behavior by several mechanisms
in some instances, these hormones can substitute or modulate the action of growth factors, and also directly influence self-renewal, proliferation, differentiation or cell death of neurogenic stem cells
Progesterone potentiates GABA(A) receptor activity indirectly through its metabolites, such as allopregnanolone (ALLO).
Laboratories around the world have shown that progesterone and allopregnanolone act through numerous metabolic and physiological pathways that can affect the injury response in many different tissues and organ systems.
Furthermore, progesterone is a natural hormone, synthesized in both males and females, that can act as a pro-drug for other metabolites with their own distinct mode of action in CNS repair.
The researchers also found a relationship between this atrophy and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a complex set of interactions among three glands. The HPA axis is part of the neuroendocrine system that controls reactions to stress and regulates many physiological processes. It's thought that this dysregulation may play a role in the atrophy of the hippocampus and the development of depression.
"Depression is one of the most common symptoms in patients with multiple sclerosis," Gold said. "It impacts cognitive function, quality of life, work performance and treatment compliance. Worst of all, it's also one of the strongest predictors of suicide."
The researchers examined three sub-regions of the hippocampus region ― CA1, CA3 and the dentate gyrus area of the hippocampal region called CA23DG (CA stands for cornu ammonis). They imaged 29 patients with relapsing remitting multiple sclerosis and compared them with 20 healthy control subjects who did not have MS. They also measured participants' cortisol level three times a day; cortisol is a major stress hormone produced by the HPA axis that affects many tissues in the body, including the brain.
n addition to the difference between MS patients and healthy controls, the researchers found that the multiple sclerosis patients diagnosed with depression showed a smaller CA23DG sub-region of the hippocampus, along with excessive release of cortisol from the HPA axis.
"Interestingly, this idea of a link between excessive activity of the HPA axis and reduced brain volume in the hippocampus hasn't received a lot of attention, despite the fact that the most consistently reproduced findings in psychiatric patients with depression (but without MS) include hyperactivity of the HPA axis and smaller volumes of the hippocampus," Sicotte said.
The steroidal environment of the brain has marked consequences for both its structure and function. Social or physical stress has deleterious results on hippocampal function. This can be replicated by raising corticoids, which are also highly responsive to stress. Corticosterone, the major glucocorticoid in the rat, induces neuronal death in primary hippocampal cultures. Elevated corticoids also induce mood changes, and these are well known to be associated with stress, particularly chronic stress such as social adversity accentuated by intercurrent aversive life events. DHEA, a second adrenal steroid, has a very different developmental history, increasing rapidly during childhood, reaching a peak in youth, and declining thereafter in both blood and CSF. DHEA, in contrast to corticoids, has brain protective actions. It reduces the neurotoxic actions of glutamate analogues (such as NMDA) as well as those of corticoids. Evidence from several sources suggests that DHEA can act as an antiglucocorticoid. DHEA levels are reduced in major depressive disorders in both adolescents and adults, and a raised cortisol/DHEA ratio (together with intercurrent life events) predicts delayed recovery. DHEA may have a role in the treatment of depression. Together, these findings suggest that altered steroidal environment, whether induced by stress or aging, can have appreciable results on the cellular structure of the brain as well as on its function, although links between the two sets of findings are still tentative.
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