BACKGROUND According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, environmental changes taking place during early maturational periods may alter normal development and predispose to the occurrence of diverse pathologies later in life. Indeed, adverse conditions during these critical developmental windows of high plasticity have been reported to alter the offspring developmental trajectory, causing permanent functional and structural perturbations that in the long term may enhance disease susceptibility. However, while solid evidence has documented that fluctuations in environmental factors, ranging from nutrient availability to chemicals, in early developmental stages (including the peri-conceptional period) have discernible programming effects that increase vulnerability to develop metabolic perturbations, the impact and eventual mechanisms involved, of such developmental alterations on the reproductive phenotype of offspring have received less attention. OBJECTIVE AND RATIONALE This review will summarize recent advances in basic and clinical research that support the concept of DOHaD in the context of the impact of nutritional and hormonal perturbations, occurring during the periconceptional, fetal and early postnatal stages, on different aspects of reproductive function in both sexes. Special emphasis will be given to the effects of early nutritional stress on the timing of puberty and adult gonadotropic function, and to address the underlying neuroendocrine pathways, with particular attention to involvement of the Kiss1 system in these reproductive perturbations. The implications of such phenomena in terms of reproductive medicine will also be considered. SEARCH METHODS A comprehensive MEDLINE search, using PubMed as main interface, of research articles and reviews, published mainly between 2006 and 2021, has been carried out. Search was implemented using multiple terms, focusing on clinical and preclinical data from DOHaD studies, addressing periconceptional, gestational and perinatal programming of reproduction. Selected studies addressing early programming of metabolic function have also been considered, when relevant. OUTCOMES A solid body of evidence, from clinical and preclinical studies, has documented the impact of nutritional and hormonal fluctuations during the periconceptional, prenatal and early postnatal periods on pubertal maturation, as well as adult gonadotropic function and fertility. Furthermore, exposure to environmental chemicals, such as bisphenol A, and maternal stress has been shown to negatively influence pubertal development and gonadotropic function in adulthood. The underlying neuroendocrine pathways and mechanisms involved have been also addressed, mainly by preclinical studies, which have identified an, as yet incomplete, array of molecular and neurohormonal effectors. These include, prominently, epigenetic regulatory mechanisms and the hypothalamic Kiss1 system, which likely contribute to the generation of reproductive alterations in conditions of early nutritional and/or metabolic stress. In addition to the Kiss1 system, other major hypothalamic regulators of GnRH neurosecretion, such as γ-aminobutyric acid and glutamate, may be targets of developmental programming. WIDER IMPLICATIONS This review addresses an underdeveloped area of reproductive biology and medicine that may help to improve our understanding of human reproductive disorders and stresses the importance, and eventual pathogenic impact, of early determinants of puberty, adult reproductive function and fertility.

中文翻译：

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生殖健康和生育力的早期规划：新的神经内分泌机制及其对生殖医学的影响

背景技术根据健康与疾病的发育起源（DOHaD）假说，成熟早期发生的环境变化可能会改变正常发育并导致晚年发生多种病理。事实上，据报道，在这些高可塑性的关键发育窗口期间的不利条件会改变后代的发育轨迹，导致永久性的功能和结构扰动，从长远来看可能会增加疾病的易感性。然而，虽然有确凿的证据证明，从营养物质可用性到化学物质等环境因素的波动，在早期发育阶段（包括围孕期）具有明显的编程效应，增加了代谢紊乱的脆弱性，但其影响和最终机制，这种对后代生殖表型的发育改变受到的关注较少。目的和理由本综述将总结基础和临床研究的最新进展，这些研究支持 DOHaD 概念，即围孕期、胎儿期和产后早期发生的营养和激素扰动对生殖功能不同方面的影响。两性。将特别强调早期营养应激对青春期和成人促性腺功能的影响，并解决潜在的神经内分泌途径，特别关注 Kiss1 系统在这些生殖扰动中的参与。还将考虑此类现象对生殖医学的影响。检索方法 使用 PubMed 作为主要界面，对主要在 2006 年至 2021 年期间发表的研究文章和评论进行了全面的 MEDLINE 检索。使用多个术语进行搜索，重点关注 DOHaD 研究的临床和临床前数据，解决围孕期、妊娠期和围产期的生殖规划。在相关时，还考虑了涉及代谢功能早期编程的选定研究。结果 来自临床和临床前研究的大量证据记录了围孕期、产前和产后早期营养和激素波动对青春期成熟以及成人促性腺功能和生育能力的影响。此外，接触双酚 A 等环境化学物质和母亲压力已被证明会对青春期发育和成年期促性腺功能产生负面影响。主要通过临床前研究也解决了所涉及的潜在神经内分泌途径和机制，这些研究已经确定了一系列尚未完整的分子和神经激素效应器。这些主要包括表观遗传调节机制和下丘脑 Kiss1 系统，这可能有助于在早期营养和/或代谢应激条件下产生生殖改变。除了 Kiss1 系统之外，GnRH 神经分泌的其他主要下丘脑调节因子，例如 γ-氨基丁酸和谷氨酸，可能是发育编程的目标。更广泛的影响 这篇综述涉及生殖生物学和医学的欠发达领域，可能有助于提高我们对人类生殖疾病的理解，并强调青春期早期决定因素、成人生殖功能和生育力的重要性和最终的致病影响。