According to the traditional model, steroid hormones bind to intracellular receptors and subsequently modulate transcription and protein synthesis, thus triggering genomic events finally responsible for delayed effects. Based upon similarities in molecular structure, specific receptors for steroids, vitamin D3 derivatives, thyroid hormone, retinoids, and a variety of orphan receptors are considered to represent a superfamily of steroid receptors. In addition, very rapid effects of steroids mainly affecting intracellular signaling have been widely recognized that are clearly incompatible with the genomic model. These rapid, nongenomic steroid actions are likely to be transmitted via specific membrane receptors. Evidence for nongenomic steroid effects and distinct receptors involved is presented for all steroid groups including related compounds like vitamin D3 and thyroid hormones. The physiological and clinical relevance of these rapid effects is still largely unclear, but their existence in vivo has been clearly shown in various settings including human studies. Drugs that specifically affect nongenomic steroid action may find applications in various clinical areas such as cardiovascular and central nervous disorders, electrolyte homeostasis, and infertility. In addition to a short description of genomic steroid action, this review pays particular attention to the current knowledge and important results on the mechanisms of nongenomic steroid action. The modes of action are discussed in relation to their potential physiological or pathophysiological relevance and with regard to a cross-talk between genomic and nongenomic responses.

Multiple Actions of Steroid Hormones—A Focus on Rapid, Nongenomic Effects

The neurobiology and control of anxious states

Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives

Losel, Ralf M., Elisabeth Falkenstein, Martin Feuring, Armin Schultz, Hanns-Christian Tillmann, Karin Rossol-Haseroth, and Martin Wehling. Nongenomic Steroid Action: Controversies, Questions, and A...

Nongenomic Steroid Action: Controversies, Questions, and Answers

The hormone progesterone is readily converted to 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) in the brains of males and females In the brain, 3alpha,5alpha-THP acts like a sedative, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (gamma-aminobutyric acid), the brain's major inhibitory neurotransmitter Symptoms of premenstrual syndrome (PMS), such as anxiety and seizure susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3alpha,5alpha-THP in the brain Abrupt discontinuation of use of sedatives such as benzodiazepines and ethanol can also produce PMS-like withdrawal symptoms Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription Specifically, this effect was due to reduced levels of 3alpha,5alpha-THP which enhance transcription of the gene encoding the alpha4 subunit of the GABA(A) receptor We also find that increased susceptibility to seizure after progesferone withdrawal is due to a sixfold decrease in the decay time for GABA currents and consequent decreased inhibitory function Blockade of the alpha4 gene transcript prevents these withdrawal properties PMS symptoms may therefore be attributable, in part, to alterations in expression of GABA(A) receptor subunits as a result of progesterone withdrawal

GABA A receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid

Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor

Treatment with an anabolic-androgenic steroid affects anxiety-related behavior and alters the sensitivity of cortical GABAA receptors in the rat.

The effect of ovarian steroid hormones on the behavioral and neurochemical sensitivity of the gamma-aminobutyric acid (GABA)-benzodiazepine (BZD) receptor chloride ion channel complex was studied. Locomotor activity and behavior in the elevated plus maze were examined in female rats of various ovarian states as was the efficacy and potency of GABA-stimulated chloride uptake in cortical synaptoneurosomes from proestrous and ovariectomized rats. A significant increase in the exploration of the open arms of the plus maze was observed in lactating females, in relation to diestrous, proestrous, ovariectomized, and pregnant females. The anxiolytic effect of diazepam (DZ) was decreased in ovariectomized females, in relation to proestrus females. Although 1.0 mg/kg DZ in proestrous females resulted in significant anxiolytic activity, this dose was ineffective in ovariectomized females but was reinstated by injection of estradiol benzoate and progesterone. A reduced efficacy of GABA-stimulated chloride ion transport in cortical synaptoneurosomes from ovariectomized females, in relation to that from proestrous females, was observed. Furthermore, the facilitative effect of DZ on the potency of GABA-stimulated chloride ion influx that was observed in cortical synaptoneurosomes from proestrous females was absent in synaptoneurosomes from ovariectomized females. These results are discussed in terms of the effect of ovarian steroids and reduced metabolites on GABA-BZD receptor-mediated functions.

Ovarian endocrine status modulates the anxiolytic potency of diazepam and the efficacy of gamma-aminobutyric acid-benzodiazepine receptor-mediated chloride ion transport.

Robert J. Hilvers

Papers

Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor

Treatment with an anabolic-androgenic steroid affects anxiety-related behavior and alters the sensitivity of cortical GABAA receptors in the rat.

Ovarian endocrine status modulates the anxiolytic potency of diazepam and the efficacy of gamma-aminobutyric acid-benzodiazepine receptor-mediated chloride ion transport.

Chronic anabolic-androgenic steroid treatment affects brain gabaa receptor-gated chloride ion transport