Kirby Elizabeth D, Geraghty Anna C, Ubuka Takayoshi, Bentley George E, Kaufer Daniela
Helen Wills Neuroscience Institute, University of California- Berkeley, 3060 VLSB #3140, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11324-9. doi: 10.1073/pnas.0901176106. Epub 2009 Jun 18.
The subjective experience of stress leads to reproductive dysfunction in many species, including rodents and humans. Stress effects on reproduction result from multilevel interactions between the hormonal stress response system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis, and the hormonal reproductive system, i.e., the hypothalamic-pituitary-gonadal (HPG) axis. A novel negative regulator of the HPG axis known as gonadotropin-inhibitory hormone (GnIH) was recently discovered in quail, and orthologous neuropeptides known as RFamide-related peptides (RFRPs) have also been identified in rodents and primates. It is currently unknown, however, whether GnIH/RFRPs influence HPG axis activity in response to stress. We show here that both acute and chronic immobilization stress lead to an up-regulation of RFRP expression in the dorsomedial hypothalamus (DMH) of adult male rats and that this increase in RFRP is associated with inhibition of downstream HPG activity. We also show that adrenalectomy blocks the stress-induced increase in RFRP expression. Immunohistochemistry revealed that 53% of RFRP cells express receptors for glucocorticoids (GCs), indicating that adrenal GCs can mediate the stress effect through direct action on RFRP cells. It is thought that stress effects on central control of reproduction are largely mediated by direct or indirect effects on GnRH-secreting neurons. Our data show that stress-induced increases in adrenal GCs cause an increase in RFRP that contributes to hypothalamic suppression of reproductive function. This novel insight into HPA-HPG interaction provides a paradigm shift for work on stress-related reproductive dysfunction and infertility, and indicates that future work on stress and reproductive system interactions must include investigation of the role of GnIH/RFRP.
压力的主观体验会导致包括啮齿动物和人类在内的许多物种出现生殖功能障碍。压力对生殖的影响源于激素应激反应系统(即下丘脑 - 垂体 - 肾上腺(HPA)轴)与激素生殖系统(即下丘脑 - 垂体 - 性腺(HPG)轴)之间的多级相互作用。最近在鹌鹑中发现了一种名为促性腺激素抑制激素(GnIH)的HPG轴新型负调节因子,并且在啮齿动物和灵长类动物中也鉴定出了称为RF酰胺相关肽(RFRP)的直系同源神经肽。然而,目前尚不清楚GnIH / RFRP是否会响应压力影响HPG轴的活性。我们在此表明,急性和慢性固定应激都会导致成年雄性大鼠背内侧下丘脑(DMH)中RFRP表达上调,并且RFRP的这种增加与下游HPG活性的抑制有关。我们还表明,肾上腺切除术可阻断应激诱导的RFRP表达增加。免疫组织化学显示,53%的RFRP细胞表达糖皮质激素(GCs)受体,这表明肾上腺GCs可通过对RFRP细胞的直接作用介导应激效应。据认为,压力对生殖中枢控制的影响很大程度上是通过对促性腺激素释放激素(GnRH)分泌神经元的直接或间接作用介导的。我们的数据表明,应激诱导的肾上腺GCs增加会导致RFRP增加,从而导致下丘脑对生殖功能的抑制。这种对HPA - HPG相互作用的新见解为与压力相关的生殖功能障碍和不孕症的研究提供了范式转变,并表明未来关于压力与生殖系统相互作用的研究必须包括对GnIH / RFRP作用的研究。