Gut Endotoxin Leading to a Decline IN Gonadal function (GELDING) - a novel theory for the development of late onset hypogonadism in obese men.
Gut Endotoxin Leading to a Decline IN Gonadal function (GELDING) - a novel theory for the development of late onset hypogonadism in obese men.
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DOI：
10.1186/s12610-016-0034-7
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发表时间：
2016
影响因子：
2.4
通讯作者：
Tremellen K
中科院分区：
文献类型：
--
作者：
Tremellen K
肥胖是一个日益严重的公共健康问题，在许多西方国家，三分之二的成年人口现在要么超重，要么肥胖。男性肥胖症与晚发性性腺功能减退症有关，这是一种以血清睾酮、精子质量下降以及生育能力和生活质量下降为特征的疾病。在本文中，我们提出了一个新的理论基础的发展肥胖相关的性腺功能减退症-GELDING理论（肠道内毒素导致性腺功能下降）。几项观察性研究先前报道了肥胖相关性腺功能减退症（低睾酮）和全身炎症之间的关联。然而，我们第一次假设细菌脂多糖（LPS）从肠腔进入循环的跨粘膜通道是男性性腺功能减退症的关键炎症触发因素。据报道，肥胖和高脂肪/高热量饮食均导致肠道细菌和肠壁通透性的变化，导致细菌内毒素（脂多糖- LPS）从肠腔内进入循环（代谢性内毒素血症），在循环中其引发全身性炎症。已知内毒素通过直接抑制间质细胞类固醇生成途径和间接减少垂体LH驱动减少睾丸睾酮生成，从而也导致精子生成下降。在本文中，我们还强调了新的进化的好处的GELDING理论。众所周知，替吉奥是一种强大的免疫抑制剂，降低了男性抵抗感染的能力。因此，我们假设男性生殖轴已经进化出在感染和导致的内毒素暴露期间降低睾酮产生的能力，降低睾酮的免疫抑制作用，从而增强抵抗感染的能力。虽然这种反应在脓毒症时是适应性的，但在“非感染性”肥胖相关代谢性内毒素血症的情况下变得不适应。
Obesity is an increasing public health problem, with two-thirds of the adult population in many Western countries now being either overweight or obese. Male obesity is associated with late onset hypogonadism, a condition characterised by decreased serum testosterone, sperm quality plus diminished fertility and quality of life. In this paper we propose a novel theory underlying the development of obesity related hypogonadism- the GELDING theory (Gut Endotoxin Leading to a Decline IN Gonadal function). Several observational studies have previously reported an association between obesity related hypogonadism (low testosterone) and systemic inflammation. However, for the first time we postulate that the trans-mucosal passage of bacterial lipopolysaccharide (LPS) from the gut lumen into the circulation is a key inflammatory trigger underlying male hypogonadism. Obesity and a high fat/high calorie diet are both reported to result in changes to gut bacteria and intestinal wall permeability, leading to the passage of bacterial endotoxin (lipopolysaccharide- LPS) from within the gut lumen into the circulation (metabolic endotoxaemia), where it initiates systemic inflammation. Endotoxin is known to reduce testosterone production by the testis, both by direct inhibition of Leydig cell steroidogenic pathways and indirectly by reducing pituitary LH drive, thereby also leading to a decline in sperm production. In this paper we also highlight the novel evolutionary benefits of the GELDING theory. Testosterone is known to be a powerful immune-suppressive, decreasing a man’s ability to fight infection. Therefore we postulate that the male reproductive axis has evolved the capacity to lower testosterone production during times of infection and resulting endotoxin exposure, decreasing the immunosuppressive influence of testosterone, in turn enhancing the ability to fight infection. While this response is adaptive in times of sepsis, it becomes maladaptive in the setting of “non-infectious” obesity related metabolic endotoxaemia.