Department of Obstetrics, Gynaecology and Reproductive Medicine, Flinders University, Adelaide, South Australia, Australia.
Basic Clin Androl. 2016 Jun 22;26:7. doi: 10.1186/s12610-016-0034-7. eCollection 2016.
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.
肥胖是一个日益严重的公共卫生问题，在许多西方国家，有三分之二的成年人超重或肥胖。男性肥胖与迟发性性腺功能减退症有关，这种病症的特征是血清睾酮水平降低、精子质量下降、生育能力和生活质量下降。在本文中，我们提出了一个新的理论，即肥胖相关性腺功能减退症的发病机制——GELDING 理论（肠道内毒素导致睾丸功能下降）。以前有几项观察性研究报告称，肥胖相关性腺功能减退症（低睾酮）与全身炎症之间存在关联。然而，我们首次推测，细菌脂多糖（LPS）从肠道腔穿过黏膜进入循环是男性性腺功能减退症的一个关键炎症触发因素。肥胖和高脂肪/高热量饮食都被报道会导致肠道细菌和肠壁通透性的改变，导致细菌内毒素（脂多糖-LPS）从肠道腔进入循环（代谢性内毒素血症），从而引发全身炎症。内毒素已知会通过直接抑制睾丸间质细胞类固醇生成途径和间接减少垂体 LH 驱动来降低睾丸睾酮的产生，从而导致精子生成减少。在本文中，我们还强调了 GELDING 理论的新进化优势。众所周知，睾酮是一种强大的免疫抑制剂，降低了男性抗感染的能力。因此，我们推测，男性生殖轴在感染和随之而来的内毒素暴露时已经进化出降低睾酮产生的能力，降低了睾酮的免疫抑制作用，反过来增强了抗感染的能力。虽然这种反应在败血症时是适应性的，但在“非感染性”肥胖相关代谢性内毒素血症的情况下，它就变得不适应了。
