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https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16317058<\/a><\/p>\n\n\n\n http:\/\/haidut.me\/?p=441<\/a><\/p>\n\n\n\n \u041e\u0441\u0432\u0435\u043d \u0442\u043e\u0432\u0430 \u0438\u043c\u0430 \u0434\u0430\u043d\u043d\u0438, \u0447\u0435 \u0445\u0438\u043f\u043e\u0433\u043e\u043d\u0430\u0434\u0438\u0437\u043c\u044a\u0442 \u0434\u043e\u043f\u044a\u043b\u043d\u0438\u0442\u0435\u043b\u043d\u043e \u0438\u0437\u043e\u0441\u0442\u0440\u044f \u0447\u0440\u0435\u0432\u043d\u0430\u0442\u0430 \u043f\u0440\u043e\u043f\u0443\u0441\u043a\u043b\u0438\u0432\u043e\u0441\u0442 \u0438 \u0432\u044a\u0437\u043f\u0430\u043b\u0435\u043d\u0438\u0435\u0442\u043e \u0438 \u043f\u0440\u0438 \u0442\u0430\u043a\u0438\u0432\u0430 \u0443\u0441\u043b\u043e\u0432\u0438\u044f \u0434\u043e\u0440\u0438 „\u043d\u043e\u0440\u043c\u0430\u043b\u043d\u0430\u0442\u0430“ \/ „\u0434\u043e\u0431\u0440\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u0430\u0442\u0430“ \u0447\u0440\u0435\u0432\u043d\u0430 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\u0432\u0441\u044a\u0449\u043d\u043e\u0441\u0442 \u043d\u044f\u043c\u0430 \u0442\u0430\u043a\u043e\u0432\u0430 \u043d\u0435\u0449\u043e \u043a\u0430\u0442\u043e „\u0434\u043e\u0431\u0440\u043e\u043a\u0430\u0447\u0435\u0441\u0442\u0432\u0435\u043d\u0430“ \u0438\u043b\u0438 „\u043f\u043e\u043b\u0435\u0437\u043d\u0430“ \u0447\u0440\u0435\u0432\u043d\u0430 \u0444\u043b\u043e\u0440\u0430, \u043f\u0440\u0438 \u0443\u0441\u043b\u043e\u0432\u0438\u0435 \u0447\u0435 \u0431\u0430\u043a\u0442\u0435\u0440\u0438\u0430\u043b\u043d\u0438\u0442\u0435 \u0432\u0438\u0434\u043e\u0432\u0435, \u043a\u043e\u0438\u0442\u043e \u044f \u0441\u044a\u0441\u0442\u0430\u0432\u043b\u044f\u0432\u0430\u0442, \u0441\u0430 \u0441\u043f\u043e\u0441\u043e\u0431\u043d\u0438 \u0434\u0430 \u043f\u0440\u043e\u0438\u0437\u0432\u0435\u0436\u0434\u0430\u0442 \u0435\u043d\u0434\u043e\u0442\u043e\u043a\u0441\u0438\u043d.<\/p>\n\n\n\n https:\/\/www.jci.org\/articles\/view\/87430<\/a><\/p>\n\n\n\n \u041f\u043e 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\u0441\u0442\u0435\u0440\u043e\u0438\u0434\u0438 \u0431\u043b\u043e\u043a\u0438\u0440\u0430\u0442 \u0432\u044a\u0437\u043f\u0430\u043b\u0438\u0442\u0435\u043b\u043d\u0438\u0442\u0435 \u0435\u0444\u0435\u043a\u0442\u0438 \u043d\u0430 \u0435\u043d\u0434\u043e\u0442\u043e\u043a\u0441\u0438\u043d\u0430, \u0438\u0437\u0433\u043b\u0435\u0436\u0434\u0430 \u0434\u043e\u0441\u0442\u0430 \u0435\u0441\u0442\u0435\u0441\u0442\u0432\u0435\u043d\u043e \u0434\u0430 \u0441\u0435 \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430 \u043a\u043e\u043c\u0431\u0438\u043d\u0430\u0446\u0438\u044f \u043e\u0442 \u0442\u0435\u0437\u0438 \u0441\u0442\u0435\u0440\u043e\u0438\u0434\u0438 \u0437\u0430 \u0441\u0438\u043d\u0435\u0440\u0433\u0438\u0447\u043d\u0438 \u0440\u0435\u0437\u0443\u043b\u0442\u0430\u0442\u0438. \u0410\u043a\u043e \u0441\u0435 \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u0442 \u0430\u043d\u0434\u0440\u043e\u0433\u0435\u043d\u0438, \u0441\u043c\u044f\u0442\u0430\u043c, \u0447\u0435 \u0431\u0438 \u0431\u0438\u043b\u043e \u043f\u043e-\u0431\u0435\u0437\u043e\u043f\u0430\u0441\u043d\u043e \u0434\u0430 \u0441\u0435 \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u0442 \u043d\u0435\u0430\u0440\u043e\u043c\u0430\u0442\u043e\u0437\u043d\u0438 \u0432\u0438\u0434\u043e\u0432\u0435 \u043a\u0430\u0442\u043e DHT \u0438\u043b\u0438 \u043d\u0435\u0433\u043e\u0432\u0438 \u043f\u0440\u043e\u0438\u0437\u0432\u043e\u0434\u043d\u0438 \u043a\u0430\u0442\u043e \u0434\u0440\u043e\u0441\u0442\u0430\u043d\u043e\u043b\u043e\u043d, \u043f\u0440\u043e\u0432\u0438\u0440\u043e\u043d, \u0441\u0442\u0435\u043d\u0431\u043e\u043b\u043e\u043d \u0438 \u0434\u0440. \u0410\u0440\u043e\u043c\u0430\u0442\u0438\u0437\u0438\u0440\u0430\u0449\u0438\u0442\u0435 \u0441\u0435 \u0430\u043d\u0434\u0440\u043e\u0433\u0435\u043d\u0438 \u043b\u0435\u0441\u043d\u043e \u0441\u0435 \u043f\u0440\u0435\u0432\u0440\u044a\u0449\u0430\u0442 \u0432 \u0435\u0441\u0442\u0440\u043e\u0433\u0435\u043d \u0432 \u0441\u0440\u0435\u0434\u0430 \u0441 \u0432\u0438\u0441\u043e\u043a\u043e \u0441\u044a\u0434\u044a\u0440\u0436\u0430\u043d\u0438\u0435 \u043d\u0430 \u0435\u043d\u0434\u043e\u0442\u043e\u043a\u0441\u0438\u043d\u0438. \u0415\u0441\u0442\u0440\u043e\u0433\u0435\u043d\u044a\u0442 \u0435 \u0438\u0437\u0432\u0435\u0441\u0442\u0435\u043d \u0438\u043d\u0434\u0443\u043a\u0442\u043e\u0440 \u043d\u0430 \u0447\u0440\u0435\u0432\u043d\u0430\u0442\u0430 \u043f\u0440\u043e\u043f\u0443\u0441\u043a\u043b\u0438\u0432\u043e\u0441\u0442, \u043a\u0430\u043a\u0442\u043e \u0438 \u0438\u043d\u0434\u0443\u043a\u0442\u043e\u0440 \u043d\u0430 \u0432\u044a\u0437\u043f\u0430\u043b\u0438\u0442\u0435\u043b\u043d\u0438 \u043f\u044a\u0442\u0438\u0449\u0430, \u0442\u0430\u043a\u0430 \u0447\u0435 \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u043d\u0435\u0442\u043e \u043d\u0430 \u0430\u0440\u043e\u043c\u0430\u0442\u0430\u0437\u0435\u043d \u0430\u043d\u0434\u0440\u043e\u0433\u0435\u043d \u043a\u0430\u0442\u043e \u0422 \u043c\u043e\u0436\u0435 \u0434\u0430 \u0432\u043b\u043e\u0448\u0438 \u043c\u043d\u043e\u0433\u043e \u0441\u0438\u0442\u0443\u0430\u0446\u0438\u044f\u0442\u0430. \u0412 \u043a\u043e\u043c\u0431\u0438\u043d\u0430\u0446\u0438\u044f \u0441 \u043f\u0440\u043e\u0433\u0435\u0441\u0442\u0435\u0440\u043e\u043d \u0443\u043f\u043e\u0442\u0440\u0435\u0431\u0430\u0442\u0430 \u043d\u0430 \u0422 \u0432\u0435\u0440\u043e\u044f\u0442\u043d\u043e \u0435 \u043f\u043e-\u043c\u0430\u043b\u043a\u043e \u043e\u043f\u0430\u0441\u043d\u0430, \u043e\u0442\u043a\u043e\u043b\u043a\u043e\u0442\u043e \u0438\u0437\u043f\u043e\u043b\u0437\u0432\u0430\u043d\u0435\u0442\u043e \u043c\u0443 \u0441\u0430\u043c\u043e\u0441\u0442\u043e\u044f\u0442\u0435\u043b\u043d\u043e, \u043f\u043e\u0440\u0430\u0434\u0438 \u0438\u043d\u0445\u0438\u0431\u0438\u0440\u0430\u0449\u0438\u0442\u0435 \u0430\u0440\u043e\u043c\u0430\u0442\u0430\u0437\u0430\u0442\u0430 \u0441\u0432\u043e\u0439\u0441\u0442\u0432\u0430 \u043d\u0430 \u043f\u0440\u043e\u0433\u0435\u0441\u0442\u0435\u0440\u043e\u043d\u0430. \u0412\u044a\u043f\u0440\u0435\u043a\u0438 \u0442\u043e\u0432\u0430, \u0430\u043a\u043e \u0441\u0430 \u043d\u0430\u043b\u0438\u0446\u0435 \u043f\u043e-\u0431\u0435\u0437\u043e\u043f\u0430\u0441\u043d\u0438 \u0432\u0430\u0440\u0438\u0430\u043d\u0442\u0438 (\u043a\u0430\u0442\u043e \u043d\u0430\u043f\u0440\u0438\u043c\u0435\u0440 \u0441\u0435\u043c\u0435\u0439\u0441\u0442\u0432\u043e\u0442\u043e \u043d\u0430 DHT \u0441\u0442\u0435\u0440\u043e\u0438\u0434\u0438\u0442\u0435), \u0442\u043e\u0433\u0430\u0432\u0430 \u0418\u041c\u041e \u043d\u044f\u043c\u0430 \u043f\u0440\u0438\u0447\u0438\u043d\u0430 \u0434\u0430 \u0441\u0435 \u043f\u043e\u0435\u043c\u0430 \u0440\u0438\u0441\u043a \u0441 \u0430\u0440\u043e\u043c\u0430\u0442\u0430\u0437\u043d\u0438 \u0441\u0442\u0435\u0440\u043e\u0438\u0434\u0438.<\/p>\n\n\n\n https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/31689143<\/a><\/p>\n\n\n\n \u201c\u2026DHT levels in serum did not differ between the groups, but DHT levels in the liver and seminal vesicles were increased in GF (germ-free, no endotoxin) compared to CONV-R mice<\/strong> (figure 8a). T levels in serum did not differ between the groups and T levels in liver were increased in GF compared to CONV-R mice<\/strong> (figure 8b) while A-dione values did not differ between the groups in serum or the evaluated extra intestinal tissues (figure 8c). GF males had larger testes than CONV-R males<\/strong> (table 4).\u201d<\/p>\n\n\n\n https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC5899218<\/a><\/p>\n\n\n\n https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4918028<\/a><\/p>\n\n\n\n \u201c\u2026The central key to the GELDING theory of male hypogonadism is that activation of the immune system by an obesity related trigger is then capable of impairing testicular function<\/strong>. Several large epidemiological studies have already reported an association between male obesity, markers of inflammation such as CRP and white cell count (WCC), and a reduction in serum testosterone<\/strong> [25<\/a>\u201328<\/a>]. As testosterone is known to be immune-suppressive [29<\/a>, 30<\/a>], this association between obesity related inflammation and lower levels of serum testosterone has previously been suggested to be caused by a reduction in testosterone\u2019s immune-suppressive action [26<\/a>]. However, observational studies are incapable of proving cause and effect, nor the mechanistic direction of such associations. Therefore we contend that the reduction in testosterone\u2019s immune-suppressive effect is not the underlying cause of increased inflammation seen in obese men, but rather the reverse<\/strong>. Specifically, obesity triggers an inflammatory response that in turn impairs testicular function<\/strong>, and that this results in both a reduction in testosterone production and impaired spermatogenesis<\/strong>.\u201d<\/p>\n\n\n\n \u201c\u2026Obesity, and a diet high in fat or calories that is typically consumed by obese individuals, has been reported to cause a breakdown in the normal mucosal barrier function, leading to the passage of gut bacteria into the systemic circulation, initiating a chronic state of inflammation<\/strong> [34<\/a>, 35<\/a>]. Gram negative bacteria, which comprise 70 % of the total bacterial load in the human gut [36<\/a>], contain a potent immune stimulant in their cell wall referred to as lipopolysaccharide (LPS) or endotoxin<\/strong>. Animal experiments and human observational studies have shown that consumption of diets containing either high fat or high number of calories leads to significant changes in gut bacterial populations and increases in the circulating levels of plasma endotoxin<\/strong> [37<\/a>, 38<\/a>], implying a breakdown in gut mucosal wall integrity<\/strong> and the passage of gram negative bacteria into the systemic circulation. Interestingly, the magnitude of this \u201cmetabolic endotoxaemia\u201d <\/strong>is reported to be more pronounced in mice placed on a high fat diet than an isocaloric high carbohydrate diet, <\/strong>suggesting that dietary fat <\/strong>is more efficient in transporting bacterial endotoxin <\/strong>from the gut lumen into the circulation,<\/strong> possibly mediated by transfer of endotoxin across the intestinal wall in lipid laden chylomicrons<\/strong> [34<\/a>, 38<\/a>]. Furthermore, a high fat diet is reported to unfavourably alter the gut microbial composition, leading to an increase in intestinal permeability due to disordered tight junction proteins (zonulin, occludin) [39<\/a>], and a reduction in the colonic mucous barrier<\/strong> [40<\/a>]. Confirming the importance of gut microbiome in facilitating endotoxaemia, the administration of antibiotics to obese mice<\/strong> or modification of their gut microbiome with prebiotic fibre, have both been reported to result in a decline in circulating plasma endotoxin<\/strong> levels [39<\/a>, 41<\/a>, 42<\/a>].\u201d<\/p>\n\n\n\n \u201c\u2026Cross-sectional studies in humans have also reported an elevation in circulating levels of endotoxin<\/strong> [38<\/a>, 43<\/a>, 44<\/a>], or indirect markers of endotoxin (LBP) exposure<\/strong> [45<\/a>, 46<\/a>], in obese individuals<\/strong>. Obesity has also been shown to be associated with changes in the human gut microbiome, with several investigators now reporting a reduction in the beneficial genus bifidobacterium<\/em> in the faecal samples of obese individuals [47<\/a>, 48<\/a>]. Since bifidobacterium<\/em> are known to metabolise dietary fibre, producing short chain fatty acids (SCFA) that \u201cfeed\u201d the host intestinal mucosa, and enhance the production of mucus and maintain tight junction barrier function [49<\/a>], it is likely that any reduction in bifidobacterium<\/em> numbers due to obesity will result in a breakdown in intestinal barrier function and endotoxaemia. Furthermore, obese men have also been shown to have a more marked post-prandial endotoxaemic and inflammatory (IL-6) response to a standard meal containing 40 gm of fat<\/strong> than their age matched lean counterparts [34<\/a>, 50<\/a>]. As such, we propose that changes in the intestinal microbiome caused by obesity, and the associated \u201cpoor diet\u201d, result in a breakdown in the mucosal barrier function of the gut (so called \u201cleaky gut\u201d), and that this results in the passage of gram negative bacteria into the circulation (metabolic endotoxaemia) which triggers a chronic state of inflammation that impairs testicular function<\/strong>.\u201d<\/p>\n\n\n\n \u201c\u2026However, studies in women have confirmed an association between endotoxaemia and a reduction in the ovaries capacity to produce the female sex steroid hormone progesterone<\/strong> [46<\/a>]. Furthermore, there is abundant animal evidence suggesting that endotoxin (LPS) does have the capacity to impair testicular function<\/strong>. Firstly, the experimental administration of LPS to rats, sheep, cattle and non-human primates has been shown to<\/strong> decrease the frequency and amplitude of LH pulses by suppressing both hypothalamic and anterior pituitary function [51<\/a>], thereby reducing the pituitary drive for Leydig cells to produce testosterone<\/strong>. Secondly, animal studies have also confirmed that Leydig cells express the TLR4 for endotoxin<\/strong> [52<\/a>], and that experimental administration of LPS directly inhibits Leydig cell production of testosterone<\/strong> [52<\/a>\u201357<\/a>]. The direct inhibition of androgen production by endotoxin is most likely mediated by a reduction in Leydig cell expression of steroidogenic acute regulatory (StAR) protein activity<\/strong> [58<\/a>], a protein that plays a key role in the initial transfer of cholesterol into mitochondria where it is later converted into testosterone.\u201d<\/p>\n\n\n\n \u201c\u2026The activation status of testicular macrophages is also likely to play a role in testosterone production. Leydig cells and macrophages are normally in close physical contact within the testicular interstitium, and under normal conditions these macrophages play a key role in Leydig cell development as they provide essential growth and differentiation factors [58<\/a>]. However, under immune-stimulatory conditions, as occurs with metabolic endotoxaemia, macrophages produce pro-inflammatory cytokines such as IL-1 and TNF\u03b1, plus reactive oxygen species (ROS), all known to reduce steroid hormone production by the adjacent Leydig cell<\/strong> [55<\/a>, 57<\/a>, 58<\/a>]. Furthermore, Leydig cells themselves have been reported to produce inflammatory cytokines (IL-1\u03b2, TNF\u03b1 and IL-6) when exposed to LPS<\/strong> [52<\/a>], which would result in a further amplification of the neighbouring macrophages state of activation. Interestingly, dampening inflammation using TNF\u03b1 blocking antibody therapy has been shown to normalise serum testosterone levels<\/strong> in spondylo-arthritis patients [59<\/a>], highlighting the potential role for inflammation in decreasing testosterone production.\u201d<\/p>\n\n\n\n \u201c\u2026Obesity related endotoxaemia is likely to impair sperm production and function<\/strong>, both directly and indirectly. Firstly, high intra-testicular levels of testosterone are required for normal sperm production. Inadequate levels of testosterone disturbs Sertoli cell function, leading to retention and phagocytosis of mature spermatids [60<\/a>] and impaired epididymal function, both potentially reducing sperm number and quality<\/strong>. Secondly, human sperm have been reported to express both the TLR4<\/strong> [61<\/a>] and the CD14 co-receptor for LPS<\/strong> [62<\/a>], as well as directly responding to LPS exposure by increasing their production of IL-6<\/strong> [63<\/a>], initiating sperm apoptosis and a decline in sperm motility<\/strong> [61<\/a>, 64<\/a>\u201366<\/a>]. Furthermore, as semen is known to contain both LPS and leukocytes<\/strong> [61<\/a>], it is not surprising that endotoxin exposure would increase seminal leukocyte reactive oxygen species (ROS) production and result in sperm oxidative damage [67<\/a>, 68<\/a>]. Seminal plasma neopterin, a marker of macrophage activation status, has been reported to be increased in obese men [69<\/a>], with seminal plasma neopterin also being positively correlate with sperm oxidative stress, DNA damage and apoptosis [69<\/a>]. This finding, together with previous publications linking impaired sperm production with an increase in testicular macrophage density [70<\/a>, 71<\/a>], all support the concept that a trigger for inflammation such as metabolic endotoxaemia has the potential to impair spermatogenesis and sperm function<\/strong>.\u201d<\/p>\n\n\n\n \u201c\u2026Firstly, obesity and a high fat diet have both been conclusively linked with changes in gut microbiota, increased intestinal permeability and the resultant leakage of bacterial endotoxin from the gut lumen into the systemic circulation (metabolic endotoxaemia) [38<\/a>, 43<\/a>\u201346<\/a>]. Secondly, animal studies have clearly shown that exposure to endotoxin does result in a reduction in testosterone production, both indirectly (impaired pituitary LH drive), and through direct inhibition of Leydig cell function<\/strong> [51<\/a>\u201357<\/a>]. While similar studies have not yet been conducted in men, it has been reported that serum testosterone levels do fall during times of infectious endotoxin exposure<\/strong> [86<\/a>], as anticipated by the GELDING theory<\/strong>. Furthermore, multiple large observational studies have now linked increased levels of inflammation (raised CRP and WCC) with lower serum testosterone [25<\/a>\u201328<\/a>].\u201d<\/p>\n\n\n\n \u201c\u2026The GELDING theory is entirely novel in that for the first time it provides a clue to what may be initiating inflammation and impairing testicular function in obese men- gut derived endotoxin. If proven correct, the GELDING theory opens up a whole new scope for treatment of the hypogonadal male through modification of his gut microbiome and intestinal permeability<\/strong>. For example, obesity related hypogonadism becomes more common with increasing age, causing significant physical and psychological impairment. However, modification of the gut microbiome using probiotics has already been reported to reverse this age-related hypogonadism in rodents [112<\/a>], raising exciting therapeutic potential for older men.\u201d<\/p>\n\n\n\n \u0418\u0437\u0442\u043e\u0447\u043d\u0438\u043a:<\/p>\n\n\n\n http:\/\/haidut.me\/?p=660<\/a><\/p>\n\n\n