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Laboratory of Reproductive Science Graduate School of Bioagricultural Sciences Nagoya University Nagoya 464-8601, Japan
Address all correspondence and requests for reprints to: Kei-ichiro Maeda or Hiroko Tsukamura, Laboratory of Reproductive Science, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan. E-mail: keimaeda{at}agr.nagoya-u.ac.jp or htsukamu{at}agr.nagoya-u.ac.jp.
An increase in glucocorticoid secretion is one of the most common responses during stress and has often been used as a reliable marker for the strength of stressors. How much do we know about the physiological significance of increased glucocorticoid secretion during stress? Glucocorticoids stimulate gluconeogenesis and provide energy for fight or flight to an individual facing a crisis. Glucocorticoid feedback action on the brain also suppresses overactivity of the hypothalamo-pituitary-adrenal (HPA) axis. In addition, glucocorticoid secretion is also believed to contribute to the stress-induced gonadal suppression during stress by central actions on the pituitary or hypothalamus. Acute or chronic administration of glucocorticoids is known to suppress the activity of the hypothalamo-pituitary-gonadal (HPG) axis. This seems to be a logical effect, because suppression of reproduction would give higher priority to individual survival rather than the maintenance of species.
An article by Matsuwaki et al. (1), appearing in this issue of Endocrinology, opposes the notion that glucocorticoids play an inhibitory role on the reproductive axis, specifically during stress. This research group led by Masugi Nishihara from the University of Tokyo claims that glucocorticoids are protective rather than inhibitory to gonadotropin secretion during stress, through a specific mechanism that involves prostaglandin (PG) synthesis in the brain (Fig. 1
). Previous reports from this group were the first to indicate that glucocorticoids counteract the inhibitory effect of infectious stress on LH secretion (2, 3), and the present report provides a more detailed brain mechanism that is involved in the protective role of glucocorticoids on gonadotropin secretion during stress. It may surprise most readers that adrenalectomy causes more profound suppression of LH secretion during stress and that glucocorticoid replacement restores LH secretion, because glucocorticoid administration has been shown to suppress LH secretion.
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Inhibitory effects of glucocorticoids on gonadotropin secretion have been well documented in a variety of species, ranging from rodents to ruminants and primates, including humans. Chronic or acute glucocorticoid treatment is reported to suppress LH secretion in normal (nonstressed) animals or subjects (12, 13, 14). Thus, exogenous glucocorticoids injected into normal subjects do inhibit LH secretion. The importance of the current report by Matsuwaki et al. is that it elucidates the role of endogenous glucocorticoids released in response to stimuli induced by stressors. The investigators found that glucocorticoids are protective of rather than inhibitory to LH secretion under stressful conditions. Their findings imply that there may be substantial differences in the observed actions of exogenous glucocorticoids administered into normal (nonstressed) subjects and endogenous glucocorticoids released in stressed subjects. Previous reports by the same authors showed that glucocorticoids counteract the suppressive effects of TNF-
, which mimics the infectious stress, on both the pulsatile (2) and surge (3) secretion of LH in rats. In support of their findings, two other recently published reports have demonstrated that endogenous glucocorticoids did not mediate endotoxin-induced inhibition of pulsatile LH secretion in rats (15) and sheep (16). They show that lipopolysaccharide suppresses LH pulses even in adrenalectomized rats and in sheep treated with metyrapone, a glucocorticoid synthesis inhibitor.
What is the mechanism by which glucocorticoids block the LH suppression under stress? Do glucocorticoids protect against stress-induced GnRH/LH suppression simply by suppressing CRH release? Or is there another mediator(s) common to multiple stressors? Matsuwaki et al. have partly answered these questions by showing that PGs are promising candidates for stress-induced mediators that inhibit LH secretion (Fig. 1
). It is widely accepted that the action of infectious stress is mediated by cytokines such as TNF- (17) and IL-1 (18) produced by immune cells. The cytokine action is further mediated by PGs produced in the brain, causing a variety of pathophysiological reactions to infectious stress. Recent studies demonstrated that hypoglycemic (19) and restraint stresses (20) are also capable of stimulating PG synthesis in the brain. Matsuwaki et al. showed that indomethacin, a PG-synthesis inhibitor, counteracted the inhibitory effect on LH pulses of all stressors tested, including hypoglycemia. Interestingly, all of the stressors employed in their studies stimulated the expression of brain cyclooxygenase-2, an inducible PG-synthesis enzyme (Fig. 1). Thus, PGs released in the brain may be a common mediator accounting for suppressed gonadal axis activity as well as the various neurological and behavioral changes that occur under multiple types of stress. Additional studies are definitely needed to clarify the point.
Finally, the new study by Matsuwaki et al. provides intriguing clues for reconsidering the physiological role of the HPA axis in regulating the activity of the HPG axis under stress conditions. Their study followed a simple but orthodox endocrinological method to unravel a complex web of neuroendocrine network, which would never have been elucidated simply by exhaustive approaches.
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Footnotes |
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Abbreviations: HPA, Hypothalamo-pituitary-adrenal; HPG, hypothalamo-pituitary-gonadal; PG, prostaglandin.
Received December 1, 2005.
Accepted for publication December 8, 2005.
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on the surge of luteinizing hormone secretion in rats. J Endocrinol 181:509–513[Abstract]-induced decrease in luteinizing hormone secretion in the ovariectomized rhesus monkey. Endocrinology 131:153–158[Abstract] mediates endotoxin induced suppression of gonadotropin-releasing hormone pulse generator activity in the rat. Endocr J 44:141–148[Medline]
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