Beyond the HPA Axis: Progesterone-Derived Neuroactive Steroids in Human Stress and Emotion

Recent scientific work has established both a theoretical basis and strong empirical evidence for a causal impact of social relationships on health. Prospective studies, which control for baseline health status, consistently show increased risk of death among persons with a low quantity, and sometimes low quality, of social relationships. Experimental and quasi-experimental studies of humans and animals also suggest that social isolation is a major risk factor for mortality from widely varying causes. The mechanisms through which social relationships affect health and the factors that promote or inhibit the development and maintenance of social relationships remain to be explored.

Marriage is the central relationship for most adults and has beneficial effects for health. At the same time, troubled marriages have negative health consequences. This review outlines the physiological pathways through which marital relationships influence health based on a stress/social support model. In addition, we review recent findings suggesting that unhappy marriages are associated with morbidity and mortality. We then turn to studies of marital interaction that include assessment of physiological pathways through which marital functioning influences health: the cardiovascular, endocrine, and immune systems. Across these studies, negative and hostile behaviors during marital conflict discussions are related to elevations in cardiovascular activity, alterations in hormones related to stress, and dysregulation of immune function. Using recent conceptualizations of the physiological impact of chronic stress, we illustrate how physiological changes associated with marital functioning in these studies have long-term implications for health outcomes. Finally, we discuss future implications of current research for understanding the relationships among marital functioning, physiology, and health.

Neuroactive steroids are natural or synthetic steroids that rapidly alter the excitability of neurons by binding to membrane-bound receptors such as those for inhibitory and (or) excitatory neurotransmitters. The best-studied neuroactive steroids are a series of sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnane steroids that include the major metabolites of progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC), respectively. These 3 alpha-hydroxysteroids do not interact with classical intracellular steroid receptors but bind stereoselectively and with high affinity to receptors for the major inhibitory neurotransmitter in brain, gamma-amino-butyric acid (GABA). Biochemical and electrophysiological studies have shown that these steroids markedly augment GABA-activated chloride ion currents in a manner similar (but not identical) to that of anesthetic barbiturates. Several steroids have also been observed to have convulsant or proconvulsant properties, including the synthetic amidine 3 alpha-hydroxy-16-imino-5 beta-17-azaandrostan-11-one (RU5135) and the natural sulfate esters of pregnenolone and dehydroepiandrosterone. Several of these have been shown to be bicuculline or picrotoxin-like GABAA receptor antagonists. Examples of steroids that alter neuronal excitability rapidly by augmenting or inhibiting excitatory amino acid receptor-mediated responses have also been reported. Recently, allopregnanolone and allotetrahydroDOC have also been measured in brain and plasma where their levels have been shown to fluctuate in response to stress and during the estrous and menstrual cycles of rats and humans, respectively. Although the major fraction of allopregnanolone in tissue, including brain, is of adrenal and/or ovarian origin, appreciable levels of allopregnanolone can still be measured in the brains of adrenalectomized and/or oophorectomized animals. Receptor-active neurosteroids may represent an important class of neuromodulators that can rapidly alter central nervous system excitability via novel nongenomic mechanisms.