Iwasa Takeshi, Matsuzaki Toshiya, Tungalagsuvd Altankhuu, Munkhzaya Munkhsaikhan, Kawami Takako, Niki Hirobumi, Kato Takeshi, Kuwahara Akira, Uemura Hirokazu, Yasui Toshiyuki, Irahara Minoru
Department of Obstetrics and Gynecology, The University of Tokushima Graduate School, Institute of Health Biosciences, 3-18-15 Kuramoto-Cho, Tokushima 770-8503, Japan.
Department of Obstetrics and Gynecology, The University of Tokushima Graduate School, Institute of Health Biosciences, 3-18-15 Kuramoto-Cho, Tokushima 770-8503, Japan.
Horm Behav. 2014 Jul;66(2):309-16. doi: 10.1016/j.yhbeh.2014.06.007. Epub 2014 Jun 19.
Reproductive function is suppressed by several types of stress. Hypothalamic kisspeptin, which is a product of the Kiss1 gene, and GnIH/RFRP have pivotal roles in the regulation of GnRH and gonadotropins through their receptors Kiss1r and GPR147 in many species. However, alterations of these factors under stress conditions have not been fully evaluated. This study investigated the mechanisms of immune stress-induced reproductive dysfunction, especially focusing on the changes of Kiss1 and RFRP gene expression. Serum LH levels and hypothalamic Kiss1 and GnRH mRNA levels were decreased, while hypothalamic RFRP and GPR147 mRNA levels were increased by administration of a high dose of LPS (5mg/kg) in both ovariectomized and gonadal intact female rats. In this condition, Kiss1 and/or RFRP mRNA levels were positively and negatively correlated with GnRH expression, respectively. In contrast, hypothalamic Kiss1, RFRP, and GPR147 mRNA levels were not changed by administration of a moderate dose of LPS (500μg/kg) in ovariectomized rats. Rats with high-dose LPS injection showed more prolonged fever responses and severe anorexia compared with rats with moderate-dose LPS injection, indicating that more energy was used for the immune response in the former. These results suggest that the underlying mechanisms of dysfunction of gonadotropin secretion are changed according to the severity of immune stress, and that changes of some reserved factors, such as kisspeptin and RFRP, begin to participate in the suppression of GnRH and gonadotropin in severe conditions. As reproduction needs a large amount of energy, dysfunction of gonadotropin secretion under immune stress may be a biophylatic mechanism by which more energy is saved for the immune response.
多种类型的应激会抑制生殖功能。下丘脑的 kisspeptin 是 Kiss1 基因的产物，在许多物种中，GnIH/RFRP 通过其受体 Kiss1r 和 GPR147 在 GnRH 和促性腺激素的调节中起关键作用。然而，应激条件下这些因子的变化尚未得到充分评估。本研究调查了免疫应激诱导生殖功能障碍的机制，尤其关注 Kiss1 和 RFRP 基因表达的变化。在去卵巢和性腺完整的雌性大鼠中，高剂量注射脂多糖（5mg/kg）会导致血清 LH 水平以及下丘脑 Kiss1 和 GnRH mRNA 水平降低，而下丘脑 RFRP 和 GPR147 mRNA 水平升高。在此条件下，Kiss1 和/或 RFRP mRNA 水平分别与 GnRH 表达呈正相关和负相关。相比之下，在去卵巢大鼠中注射中等剂量脂多糖（500μg/kg），下丘脑 Kiss1、RFRP 和 GPR147 mRNA 水平未发生变化。与注射中等剂量脂多糖的大鼠相比，注射高剂量脂多糖的大鼠发热反应持续时间更长且厌食更严重，这表明前者将更多能量用于免疫反应。这些结果表明，促性腺激素分泌功能障碍的潜在机制会根据免疫应激的严重程度而改变，并且在严重情况下，一些储备因子如 kisspeptin 和 RFRP 的变化开始参与对 GnRH 和促性腺激素的抑制。由于生殖需要大量能量，免疫应激下促性腺激素分泌功能障碍可能是一种生物保护机制，通过这种机制可以为免疫反应节省更多能量。
