- Open Access
Gut Endotoxin Leading to a Decline IN Gonadal function (GELDING) - a novel theory for the development of late onset hypogonadism in obese men
© The Author(s). 2016
- Received: 17 March 2016
- Accepted: 24 May 2016
- Published: 22 June 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.
L’obésité est un problème de santé publique en expansion ; les deux-tiers de la population adulte de nombreux Pays de l’Ouest sont actuellement soit en surpoids, soit obèses. L’obésité masculine est associée à l’hypogonadisme de survenue tardive, une situation caractérisée par un taux abaissé de testostérone, une qualité spermatique réduite ainsi qu’une diminution de la fertilité et de la qualité de vie. Dans le présent article, nous proposons une nouvelle théorie sous-tendant le développement de l’hypogonadisme lié à l’obésité – la théorie GELDING (Gut Endotoxin Leading to a Decline IN Gonadal function ; Endotoxines intestinales donnant lieu à un déclin de la fonction gonadique).
Plusieurs études observationnelles ont précédemment rapporté une association entre hypogonadisme (testostérone basse) lié à l’obésité et inflammation systémique. Toutefois, nous postulons pour la première fois que le passage trans-muqueuse de lypopolysaccharides bactériens (LPS) de la lumière intestinale dans la circulation constitue un élément inflammatoire clé déclencheur de l’hypogonadisme masculin. L’obésité et une alimentation riche en graisse/riche en calories sont toutes deux signalées pour induire des modifications des bactéries intestinales et de la perméabilité de la paroi intestinale, conduisant au passage d’endotoxines bactériennes (lipopolysaccharide- LPS) de l’intérieur de la lumière intestinale dans la circulation (endotoxémie métabolique) où elles initient une inflammation systémique. Les endotoxines sont connues pour réduire la production de testostérone par les testicules, à la fois par inhibition directe des voies de la stéroïdogenèse des cellules de Leydig et indirectement par la réduction du pic de LH hypophysaire, ce qui conduit aussi à une réduction de la production de spermatozoïdes.
Dans le présent article, nous avons aussi mis en relief nouveaux bénéfices évolutionnaires de la théorie GELDING. La testostérone est connue pour être un puissant immunosuppresseur qui diminue la capacité d’un homme à combattre l’infection. Par conséquent, nous postulons que l’axe reproducteur masculin a élaboré la capacité à diminuer la production de testostérone pendant les périodes d’infection et d’exposition aux endotoxines qui en résulte, ce qui réduit ainsi l’influence immunosuppressive de la testostérone, et en retour augmente la capacité de combattre l’infection. Alors que cette réponse est adaptée en période de sepsis, elle devient inadaptée dans le cadre de l’endotoxémie métabolique ‘non infectieuse’ liée à l’obésité.
- Male hypogonadism
- Lipopolysaccharide (LPS)
- Intestinal microbiome
- Hypogonadisme masculin
- Lipopolysaccharide (LPS)
- Microbiome intestinal
Obesity and its impact on male reproductive health
Obesity has become an increasing public health concern over the last few decades, primarily due to an increase in the availability of calorie dense processed food and the adoption of a sedentary lifestyle. A recent review of body mass index (BMI) changes in 199 countries reported that 20 % of the world population have a BMI above the ideal range (25 kg/m2), with a total of 205 million men being obese (BMI ≥ 30 kg/m2) . In developed countries such as the United States of America, one-third of the population are known to be overweight and a further third is obese . As obesity is a known risk factor for the development of significant general health concerns such as diabetes, cardiovascular disease, osteoarthritis, poor mental health and early death , this increase in obesity is of major public health concern.
In the last decade increasing evidence has also emerged linking obesity with impaired male reproductive health, producing so called late-onset male hypogonadism . Obesity related hypogonadism is characterised by low serum testosterone levels and associated symptoms such as poor libido, erectile dysfunction, depression, lack of motivation, lethargy; as well as somatic symptoms such as muscle weakness, aches and pains . These symptoms can have a major impact on men’s quality of life, especially when they affect relatively young men in their 30’s and 40’s. Furthermore, as testosterone is known to maintain muscle, obesity related hypogonadism produces a decline in muscle mass and therefore basal metabolic rate, meaning that these men burn fewer calories at rest and exercise, predisposing them to gaining further fat - a detrimental positive feedback loop.
Obesity has also been linked with impaired sperm production and function. Recent meta-analyses have linked obesity with a significant increased risk of low sperm count, motility and morphology, plus an increase in sperm DNA fragmentation, resulting in a decline in fertility potential [4, 5]. This decline in sperm quality with increasing BMI may help explain the gradual decrease in the general population’s sperm quality, particularly sperm count, which has been observed to coincide with the increasing trend in obesity over the last few decades [6, 7].
Given the very significant reproductive and general health concerns related to obesity, new approaches to managing this growing epidemic need to be found. While improving diet and increasing exercise are known to reverse weight gain and normalise reproductive hormones [8–10], very few patients are capable of adhering to these lifestyle changes over the long term, resulting in no long term improvements in body composition. However, if it were possible to reverse the decline in serum testosterone associated with obesity, this would not only improve men’s reproductive function and quality of life, but also result in an increase in their lean body mass (muscle) and an increase in their basal metabolic rate , producing a sustained reduction in fat mass.
Current theories behind obesity related male hypogonadism
The current prevailing theory behind obesity related hypogonadism is that the decline in testosterone levels is due to a combination of reduced pituitary LH drive (central hypogonadism) and a direct impairment of testicular function (peripheral hypogonadism) [3, 6]. Adipose tissue contains abundant aromatase activity, an enzyme responsible for the conversion of testosterone to estrogen, with 80 % of male estrogen being derived from the action of aromatase . Therefore, an increase in adipose tissue aromatase results in an increase in the conversion of testosterone to estrogen, reducing serum testosterone levels. Furthermore, estrogen has a “negative feedback” influence on the hypothalamic pituitary (HP) axis resulting in a decrease in anterior pituitary LH pulse frequency and amplitude [3, 6]. Since LH is the prime stimulus for increasing testicular Leydig cell production of testosterone, this estrogen related reduction in LH drive further produces a drop in testosterone production. Blocking aromatase action with letrazole (an aromatase inhibitor) has been reported to result in an increase in LH and testosterone concentration in obese men .
White adipose tissue is a major endocrine organ that secretes over 30 biologically active peptides and proteins such as leptin and immunomodulatory cytokines such as TNFα and IL-6 . Under lean conditions leptin increases LH and FSH release by a direct stimulatory effect on the anterior pituitary, and via increasing hypothalamic GnRH pulsatility . However, in obesity leptin levels significantly increase which then results in a functional state of leptin resistance, with impaired leptin action and a resultant decline in HP axis function. Similarly, the pro-inflammatory adipocytokines TNFα and IL-6 have also been reported to impair HP axis function and subsequent testosterone production [6, 15]. Therefore, increased production of estrogen by aromatase, combined with the direct inhibition of the HP axis by leptin and adipose derived inflammatory cytokines, results in a central hypogonadal state.
There is also abundant evidence linking obesity with a direct impairment of testicular function. INSL3, a hormone produced by the Leydig cells independent of pituitary LH drive, has been reported to be negatively associated with BMI, providing evidence for obesity directly impairing Leydig cell function independent of the HP axis . Similarly, levels of inhibin B  and AMH , both products of the Sertoli cells of the testis, have been reported to decline with increasing BMI, which suggest that obesity also directly impairs Sertoli cell function. Again leptin may play a key role in obesity related testicular dysfunction as leptin has been shown to inhibit the Leydig cell’s production of testosterone [14, 19].
Obesity is known to be characterised in an increase in the production of reactive oxygen species (ROS) and associated oxidative stress, both systemically  and within sperm themselves . It is also well established that oxidative stress can impair sperm production and function , and there is evidence linking oxidative stress with impaired Leydig cell function [22, 23]. Therefore testicular oxidative stress is also likely to play a significant role in obesity related male hypogonadism.
Finally, morbid obesity is associated with the enveloping of the scrotal contents in pelvic fat tissue, which impedes heat transfer compared to the lean scenario where the testis hang free of the body within the scrotum, maintaining a temperature 2 °C below core body temperature. This adipose related “heating” of the testicles is likely to significantly impair sperm production, since spermatogenesis is optimally performed at 35 °C .
The evolutionary advantages associated with GELDING theory of endotoxin suppression of testicular function
In today’s environment of abundant high-calorie food and a resulting epidemic of obesity, it would appear that the GELDING concept of inflammatory mediated suppression of testicular function is maladaptive; with the resulting decline in testosterone production leading to a reduction in lean muscle mass and further predisposing to adiposity. However, outside of the context of the modern industrialised society, we believe that inflammatory suppression of testicular function may actually be an adaptive response, helping protect men from sepsis and preventing them from passing on their genes in times of sickness.
Testosterone, immune responses and the immune-competence handicap
Testosterone is known to exert a suppressive effect on both humoral and cellular immune responses, and therefore appears to provide a natural anti-inflammatory advantage to men outside times of infection. Testosterone is reported to dampen the immuno-stimulatory activity of monocytes, macrophages, NK cells, T lymphocytes, as well as reducing antibody production by B lymphocytes . As a result, autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, systemic sclerosis and myasthenia gravis are all significantly less common in men than women . Conversely, men with androgen deficiency are at increased risk of autoimmune disease; with Sjogren syndrome, rheumatoid arthritis, autoimmune hypothroidism and SLE all being more common in hypogonadal men with Klinefelter’s Syndrome than their androgen replete counterparts . Interestingly, many Klinefelter’s Syndrome patients with SLE experience a significant decline in their lupus activity once they commence androgen replacement therapy , highlighting the potent immune-suppressive actions of testosterone.
While testosterone may provide men with an autoimmune advantage, it also limits their capacity to fight infections, thereby resulting in increased rates of infectious morbidity and mortality compared to women [74, 75]. Folstad and Karter  were first to propose the concept of male “immunocompetence handicap”; a situation where males are required to balance the competing demands of high testosterone production for optimal reproductive performance (sperm production, development of male secondary sexual characteristics attractive to females and the maintenance of assertive territorial behaviour conducive to successful mating), with this “cost” of high testosterone being diminished immune capacity and susceptibility to infection. For example, dominant “alpha” male reindeers, baboons and chimpanzees, known to possess both the highest levels of testosterone and reproductive performance, also have been reported to have the greatest parasitic infective load compared with non-dominant or castrated males [76–78]. Interestingly, castration of dominant males has the ability to reduce their susceptibility to these types of parasitic infections , while experimental treatment with high dose testosterone increases the intensity of parasitic infection and resultant mortality [80, 81].
What constitutes the optimal adaptive balance between high testosterone levels and reproductive performance, versus lower testosterone levels and resistance to infection, depends on the longevity of the animal and its social behaviour. Australian marsupials such as the dasyurid (quoll) have evolved a semelparious, or so called “big-bang” suicidal reproductive behaviour, where a male engages in a single frenzied mating season in their entire life fuelled by high testosterone levels, but then dies shortly after mating from infection brought about by a total collapse in their immune system [82–84]. In an environment with limited food resources, and where the male plays no active role in the upkeep of his progeny, this type of semelparous reproductive strategy may actually be adaptive since it enables him to pass on his genes, while not competing for limited resources with his offspring. However, the optimal balance between high testosterone and reproductive performance and immunity is likely to be very different for humans. Firstly, men are expected to play an active role in supporting their children over a number of years, with the death of a father having a major detrimental effect on their children’s welfare. As such, high immune competence and longevity are of paramount importance to men and their families. Secondly, for most part humans reproduce in a monogamous setting, where males do not need to compete with other males for an opportunity to “mate”, unlike the animal world where males require high testosterone to develop body strength and aggressive behaviour in order to defend their territory and attract a female mate. Therefore, the human male only requires sufficient testosterone to maintain normal spermatogenesis, but not supra-physiological levels that will unnecessarily suppress his immune system and potentially compromise his survival.
The ability for an infection to reduce testosterone production, thereby removing this hormonal brake on infection fighting capacity, is supported by the available literature. Several animal studies using experimental administration of endotoxin (LPS) as a surrogate for sepsis has shown that endotoxin initiated inflammation is a powerful inhibitor of testosterone production [52–57]. Similar studies in men have reported that endotoxin does suppress the production of the adrenal androgen DHEA , although no study to date has reported the effect of experimental administration of endotoxin on testosterone levels. However, a prospective study of 28 men has reported a significant reduction in serum testosterone and an elevation in estrogen during times of severe sepsis , a pattern identical to what we have proposed to occur in obese males as a result of metabolic endotoxaemia. While the magnitude of endotoxaemia in sepsis is approximately 10-50 fold higher than that seen in obesity , we still believe that it is reasonable to conclude that chronic exposure to low grade endotoxinaemia may interfere with testosterone production, in support of the GELDING theory.
Testosterone, infection and “reproductive fitness”
Male fertility has been shown to transiently decline during times of infection, with a significant reduction in sperm count, motility, morphology and DNA integrity [87–90], plus a reduction in sperm fertilising capacity all being reported . Previously it has been postulated that these reductions in sperm quality were due to an elevation in core body temperature (fever) that commonly occurs during infection, since spermatogenesis is optimal at 35 °C . However, chronic low grade infections with Hepatitis B and HIV have also been reported to cause a reduction in sperm quality, without any change in body temperature [92, 93]. Interestingly, around 25 % of young to middle-aged men chronically infected with HIV have hypogonadism and androgen deficiency , with the reduction in their sperm quality being directly proportional to the severity of their infectious load (CD4+ count) . As such, it appears highly probable that chronic infection and its associated inflammatory response are capable of impairing testicular function and producing a drop in sperm quality and testosterone production. While we acknowledge that viral and parasitic infections do not result in exposure of the host to LPS, an immune stimulant exclusively found in gram negative bacteria, these observations do support the GELDING hypothesis as they provide evidence that an inflammatory stimulus (viral, parasitic or bacterial exposure) can result in impaired testicular function.
From an evolutionary perspective, it is obvious that a male who is unhealthy due to infection should ideally not be capable of siring offspring. Firstly, sickness may signify a poor genetic endowment (propensity to illness), a characteristic that is best not passed on to the next generation. Secondly, since infection has been linked with a reduction in sperm DNA integrity [88, 90], and poor sperm DNA quality has been linked with an increased risk of miscarriage and illness in the resultant offspring , a block in the capacity of unhealthy males to reproduce makes perfect evolutionary “Darwinian” sense. The decline in sperm quality with infection provides the ideal biological roadblock preventing such conceptions.
A second roadblock to unhealthy males reproducing is the observed reduction in libido and social withdrawal. The experimental replication of infection through administration of endotoxin (LPS) to men has been reported to produce depression, anxiety, fatigue and a sense of social disconnection , so called “sickness behaviour”. Of course all of these psychological symptoms are likely to significantly reduce the probability of a sexual encounter and successful reproduction. While no study to date has directly analysed the link between the administration of endotoxin to men, the onset of sickness behaviour and changes in serum testosterone, it is highly probable that these symptoms are at least in part due to an acute suppression in testosterone production. Firstly, the sickness behaviours associated with experimental administration of endotoxin (decreased mood, fatigue, social disconnection, anhedonia) very closely resemble the psychological symptoms associated with androgen deficiency [3, 96]. Secondly, animal models of sickness behaviour using experimental administration of endotoxin report that male behaviour can be normalised by co-administration of testosterone therapy , highlighting the role of androgen deficiency in endotoxin mediated sickness behaviours. In the setting of infection, a decline in activity and social interest is adaptive since it allows the body to rest and recover, while also reducing the chance of spreading the infection to others. However, in the setting of obesity related metabolic endotoxaemia the chronic adoption of sickness behaviour (altered mood, poor motivation, and social isolation) is clearly maladaptive. As such, more research is needed to investigate the potential links between obesity, metabolic endotoxaemia, and impaired testicular function plus potential treatments for this significant malady.
While we acknowledge that currently there is no human data directly linking endotoxin exposure to impaired testicular function, we still believe that there is considerable circumstantial evidence supporting such a theory. Firstly, 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, 43–46]. 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 [51–57]. 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 , as anticipated by the GELDING theory. Furthermore, multiple large observational studies have now linked increased levels of inflammation (raised CRP and WCC) with lower serum testosterone [25–28].
The 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. 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 , raising exciting therapeutic potential for older men.
Finally, the GELDING theory poses the interesting and important evolutionary concept that endotoxin related suppression of testicular function may originally have been an adaptive response in times of sepsis (removing testosterone mediated immunosuppression, preventing sick males reproducing). However, such a response in today’s world of food abundance is now more commonly maladaptive, where “non-infectious” metabolic endotoxaemia related androgen deficiency significantly reduces obese men’s fertility and quality of life.
AMH, antimullerian hormone; BMI, body mass index; CFU, colony forming units; CRP, C-reactive protein; DHEA, dehydroepiandrosterone; DNA, deoxyribonucleic acid; GELDING, gut endotoxin leading to a decline in gonadal function; HIV, human immunodeficiency virus; HP, hypothalamic-pituitary; IL-1, interleukin 1; IL-6, interleukin 6; INSL3, insulin like growth factor 3; LBP, lipopolysaccharide binding protein; LH, luteinizing hormone; LPS, lipopolysaccharide; ROS, reactive oxygen species; SCFA, short chain fatty acids; SLE, systemic lupus erythematous; StAR, steroidogenic acute regulatory protein; TLR4, toll-like receptor 4; TNFa, tumour necrosis factor alpha; WCC, white cell count
No funding was required to conduct this review.
Availability of data and materials
This paper contains no primary data for future analysis and therefore no data sharing is possible.
Kelton Tremellen holds stock in the publically listed reproductive medicine service Monash IVF, and has a financial interest in the male fertility nutraceutical Menevit (Bayer Consumer Care, Australia).
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