Neonatal programming of pubertal delay: a novel neural interaction between corticotrophin-releasing hormone and kisspeptin

青春期仍然是生物学上最大的谜团之一，人们对它的触发因素知之甚少。青春期的正常年龄是女孩10.5岁，男孩11.5岁，但差异很大。公众和医学界对早熟的原因非常感兴趣，因为“激素”的早期上升与个人的实际成熟水平造成的心理和身体变化之间的不匹配造成了后果。事实上，最近的脑成像研究表明，大脑的成熟可以延续到20岁出头。改善饮食被认为是青春期开始年龄逐渐下降的基础，但儿童肥胖发病率的不断增加正在加速这一趋势。另一方面，青春期延迟可能是由许多因素造成的，包括营养不良、情感和社会剥夺，尤其是压力。青春期提前或推迟会对健康产生严重影响，并经常引起有关个人或家庭的极大焦虑。了解控制青春期时间的过程将有助于对受影响儿童的管理和治疗。正常的青春期开始于大脑中一个叫做下丘脑的小区域的激活，它开始分泌一种叫做促性腺激素释放激素（GnRH）的激素，这种激素会引发一系列激素信号，从而刺激卵巢和睾丸。来自发育中的卵巢或睾丸的激素驱动性成熟以及与青春期相关的许多其他身体和情感变化。是什么触发了大脑中GnRH系统的激活一直是个谜，直到最近才发现，人类大脑中一种特定化学受体的基因突变阻止了他们进入青春期。在动物模型中，类似的突变导致了同样的问题。这些受体被一种叫做“kisspeptin”的大脑化学物质激活。发现这种化学物质的科学家在位于美国好时的宾夕法尼亚州立医学中心工作他们给它起了这个名字，因为；好时是美国著名的巧克力工厂所在地，科学家们以这家巧克力公司标志性的迷你巧克力“吻”来命名它。尽管kisspeptin无疑是GnRH系统中最重要的激活因子，但在青春期触发kisspeptin系统的原因仍有待发现。人们日益认识到，不良的早期生活环境可能对以后的健康和疾病产生重大不利影响。例如，在人类和动物中，出生后的一段时间对细菌感染尤其危险，因为身体的免疫系统尚未发育完全。事实上，超过40%的人类新生儿死亡（全球每年约170万）是由新生儿细菌感染造成的。在出生后第一周接触细菌物质（内毒素）的动物在成年后对压力更敏感。此外，这些动物成年后表现出免疫、代谢、焦虑、记忆和认知功能的改变，这表明早期接触细菌会对许多身体功能产生长期的“编程”影响。这些和其他观察结果导致了“健康和疾病的发育起源”的观点。在使用早期生命感染压力动物模型的初步研究中，我们已经显示出青春期开始的延迟。我们还发现，kisspeptin的大脑水平永久性下降，而促肾上腺皮质激素释放激素（CRH）受体（主要的应激激素受体）的大脑水平上升。这提供了一个独特的机会，不仅发现了应激激素系统（CRH）和控制青春期时间的触发系统（kisspeptin）之间的关键相互作用，而且可能有助于未来开发出更有效的治疗青春期压力相关疾病的方法。

Puberty remains one of the biggest mysteries in biology with precious little known about what triggers it. The normal age of puberty is about 10.5 years in girls and 11.5 years in boys, but it is very variable. There is considerable public and medical interest in the causes of very early puberty because of the consequences of a mismatch between the psychological and body changes caused by the early rise in 'the hormones' and the actual level of maturity of the individual. Indeed, recent brain imaging studies have shown that brain maturation extends into the early twenties. Improved diet is thought to underlie the gradual fall in age of puberty onset, but the ever increasing incidence of childhood obesity is accelerating this trend. On the other hand, a delay in puberty can be caused by many factors, including malnutrition, emotional and social deprivation and in particular stress. Early or late onset of puberty can have serious health effects and often raises a great deal of anxiety in the individual or family concerned. Understanding the processes that control the timing of puberty will help in the management and treatment of children affected. Normal puberty starts with activation of a small area in the brain called the hypothalamus that begins to secrete a hormone called gonadotrophin-releasing hormone (GnRH), which sets in motion a cascade of hormonal signals that lead to stimulation of both the ovaries and the testes. The hormones from the developing ovaries or testes drive sexual maturation and the many other physical and emotional changes associated with adolescence. What triggers the activation of the GnRH system in the brain remained a mystery until very recently when it was discovered that a genetic mutation of a particular chemical receptor in the brain of humans stopped them from going into puberty. Similar mutations in animal models caused identical problems. These receptors are activated by a brain chemical named 'kisspeptin'. The scientists who discovered this chemical were working at the Pennsylvania State Medical Centre in Hershey USA and they gave it this name because; Hershey is the location of America's famous chocolate factory and the scientists named it after the chocolate company's signature miniature treat chocolate 'kisses'. Although, kisspeptin is undoubtedly the single most important activator of the GnRH system it now remains to be discovered what triggers the kisspeptin system at puberty. There is growing awareness that adverse early life environments can have major detrimental effects on health and disease later in life. For example, in humans and animals the immediate period after birth is especially dangerous for bacterial infection because the body's immune system is not yet fully developed. Indeed, more than 40% of all human newborn deaths (~1.7 million per year globally) are due to neonatal bacterial infection. Animals that have been exposed to bacterial substances (endotoxins) during the first week of life are more sensitive to stress when they reach adulthood. Additionally these animals display altered immune, metabolic, anxiety, memory and cognition function as adults, which show that early life exposure to bacteria can exert long-term 'programming' effects on a number of body functions. These and other observations have led to the idea of 'developmental origins of health and disease'. In pilot studies using the animal model of early life infection stress we have shown a delay in the onset of puberty. We have also shown a permanent decrease in brain levels of kisspeptin and an increase in brain levels of corticotrophin-releasing hormone (CRH) receptor, the major stress hormone receptor. This provides a unique opportunity not only to discover key interaction between the stress hormone system (CRH) and the trigger system (kisspeptin) that controls the timing of puberty, but may help future developments of more effective treatments for stress-related disorders of puberty.