The precise role of neurosteroids in cognition as well as neurological and psychiatric disorders is currently under investigation. Although data from human studies are sparse, results obtained from in vitro and in vivo experiments show promising leads for future clinical applications of neurosteroids.
In recent years, memory-enhancing properties have been attributed to pregnenolone and pregnenolone sulfate. This effect is probably related to its agonistic function at the NMDA receptor () because NMDA receptor antagonists impair acquisition and/or retention of various memory tasks in rodents (). Studies investigating the effects of intracerebroventricular administration of pregnenolone and pregnenolone sulfate on performances in avoidance tasks in mice () and rats () have so far yielded positive results. Memory-enhancing properties had previously also been described for DHEA and its sulfate in mice (). In addition, lack of progesterone in aged female rats seems to contribute steroid-mediated neuronal degeneration (), pointing toward possible application of neurosteroids in the treatment of dementia disorders.
Increased levels of progesterone are known to be associated with decreases in pain sensitivity (), but the mechanisms by which progesterone exerts its antinoceptive effects are unclear. A first description of analgesic properties of neurosteroids, for example, the progesterone metabolite pregnenolone, was given by Kavaliers and Wiebe (). A study investigating the effects of intracerebroventricularly administered neurosteroids showed that progesterone, dihydroprogesterone, pregnenolone, and THDOC decreased pain sensitivity, whereas 17-OH-pregnenolone, pregnenolone sulfate, and DHEAS did not. The speed of action and the substances involved, for example, nonsulfated steroids producing analgesic effects, suggest that pain modulation by neurosteroids occurs via agonistic GABAA receptor action ().
Stress and Seizure Disorders
Purdy et al. () have reported that allopregnanolone and allo-THDOC rise sufficiently in cerebral cortex of stressed rats to affect GABA-mediated inhibition, a mechanism that has been suggested to increase seizure thresholds (). However, the relation between elevated stress levels with consecutive changes in neurosteroid concentrations and increases in seizure thresholds remains unclear because sulfated neurosteroids, for example, pregnenolone sulfate, may conceivably cause a potent epileptogenic event (). It has been proposed that elevated CNS levels of neurosteroids, particularly pregnenolone sulfate, with antagonistic properties inhibit the action of GABA and contribute to the arousal present in the initial phase of stress; in later phases, the secretion of nonsulfated neurosteroids, for example, THDOC, induced by adrenocorticotropic hormone, might protect neurons from overstimulation through a potentiation of the inhibitory effects of GABA (). Interestingly, a recent study () proposed that allopregnanolone protects against seizure activity through inhibition of nerve cell growth because seizure activity is associated with aberrant nerve cell growth.
Pregnancy and Premenstrual Syndrome
It has long been recognized that during pregnancy the risk of developing emotional disease is decreased (). Furthermore, mood and behavioral changes typical of pregnancy, such as somnolence and the sense of well-being, may be dependent on the activation of the GABA-ergic system by steroids because circulating plasma levels of progesterone, DOC, pregnenolone, and allopregnanolone are elevated (). On the other hand, depression, anxiety, and irritability associated with the premenstrual syndrome (PMS) appear in a phase of the cycle where progesterone levels are decreasing or low (). Some claim that the symptoms can be reversed by administration of progesterone (); but most well-controlled studies did not confirm this claim (). A recent study failed to demonstrate that symptoms of PMS are associated with a simple deficiency state of either progesterone or its anxiolytic steroid metabolites (allopregnanolone or pregnenolone) in human plasma; however, no cerebrospinal fluid (CSF) values of these compounds were determined ().
THP has been shown to influence neuropeptide secretion by modulation of GABAA receptors in peptidergic nerve terminals (). GABA is a coregulator of neurohypophysial hormone secretion (), involving inhibition of corticotropin-releasing hormone (CRH) secretion (). Because centrally mediated oversecretion of CRH has been implied in the etiology of depressive illness (), the possibility is raised that neuroactive steroids could be used as potential therapeutics by modulating GABA-ergic neurohypophysial inputs (). On the other hand, considering that the GABA-ergic system appears not to be critically involved in the pathogenesis of major depression, the use of neurosteroids for the treatment of these disorders remains to be elucidated. Preliminary studies investigating CSF levels of progesterone, pregnenolone, and diazepam binding inhibitor, known to promote steroid biosynthesis (), in medication-free patients with depression compared with euthymic control subjects demonstrated significantly lower CSF concentrations of pregnenolone ().