Stress hypogonadism: not everything that suppresses must converge.

The rise in hypothalamic CRH, pituitary ACTH, and adrenal cortisol (in humans) or corticosterone (in rodents) is the signature neuroendocrine response to stress; indeed, some define stress functionally as anything that triggers the CRH-ACTH-cortisol response. The inputs (stressors) that trigger the stress response come from a variety of sensors monitoring defended homeostatic parameters such as blood pressure, mood, glucose levels, and inflammation, with the effect of returning them toward the desired neutral set point. Thus, cortisol/corticosterone act to raise blood sugar after insulin-induced hypoglycemia and to suppress the action of inflammatory cytokines after injection of bacterial lipopolysaccharide (LPS) to simulate infection. -Endorphin, split from hypothalamic proopiomelanocortin, from which ACTH is also cleaved, dampens the response to psychogenic stress. Initially it was believed that the pathways mediating these responses converged immediately downstream from the sensory receptors, sounding the alarms to these various types of stress. More recently, however, it has been shown that the processing of different stressors continues to follow parallel but distinct pathways through several relay points before activating CRH. Almost as universal to the neuroendocrine stress response as the rise in glucocorticoids is the central suppression of hypothalamic pulsatile GnRH and thus pulsatile gonadotropins and gonadal function. In this system, the hormonal response does not directly counter the push of the stressor away from homeostasis but serves to defer reproduction so that all available energy is prioritized to that homeostatic restoration. Here, too, the initial assumption that the pathways mediating this response converge immediately downstream from the primary sensors has given way to the realization that the mechanisms and way-stations mediating the responses to different stressors remain distinct for many further steps. In their study in this issue of Endocrinology (1), Lin et al. demonstrate that in ovariectomized rats, lesions in the central or in the medial nuclei of the amygdala have differentialeffectsonthegonadotropin-suppressiveeffectsof three different types of acute stressors: iv injections of LPS, mimicking an inflammatory or immunological stress; physical restraint, imposing a psychogenic stress; and insulin-induced hypoglycemia, a metabolic stress. Specifically, chemical lesioning of the central nucleus of the amygdala (CeA) with an excitatory neurotoxin blunted the pause in pulsatile gonadotropin secretion after LPS-induced inflammation but not after restraint or hypoglycemic stress, whereas lesions in the medial amygdala (MeA) tempered the gonadotropin suppression to restraint but not to hypoglycemia or LPS (Fig. 1) (2, 3). None of these lesions affected basal (unstressed) gonadotropin pulsatility, and in intact animals the stressors reduced gonadotropin pulse frequency but not mean LH/ FSH levels. Consistent with these results, in a separate set of experiments, theauthorsshowedthatrestraintstress in intact but not MeA-lesioned animals boosted Fos expression in glutamicaciddecarboxylase67-expressingneurons inthemedial preoptic area (MPOA) of the hypothalamus, which is rich in GnRH neurons. These Fos/ glutamic acid decarboxylase67 double-labeled neurons are most likely to secrete -aminobutyric acid and probably inhibit GnRH, whether directly or through a further link.