Obesity is the new health concern threatening to engulf the world, well the developed world at least. While most of the world can’t find enough to eat, the rest shovel vast quantities of food into their stomachs causing, amongst other things, low testosterone or hypogonadism.
Not only are men becoming fatter they are also becoming increasingly hypogonadic and as a consequence less fertile. In this blog, we will explore the mechanism that causes gluttony to be one of the deadly sins facing men today.
Increased body fat and hypogonadism
Increased body fat is a well-known clinical feature of hypogonadism or low testosterone.[1] Studies have shown that BMI (Body mass index) and central obesity increase when testosterone levels decline.[2] The gradual decline of testosterone levels in ageing men is related to an increase in truncal obesity, that is the fat around your waist.[3]
Low testosterone and visceral fat
There are two types of fat, subcutaneous, the type just under your skin and visceral which surrounds the major organs. It was found that low testosterone levels were associated with increased visceral fat.[4] A study called the Tromso study, which looked at 1548 men aged 24-85 years, showed that a greater waist circumference was associated with low SHBG and testosterone levels.[5]
Weight loss increases testosterone levels
Studies on the effect of weight loss on testosterone are harder to find (typical!). One study that stood out found that massive weight loss of between 26 and 129kg over a period of between 5 and 39 months led to an increase in free and total testosterone.[6]
Interactions between the hypothalamic-pituitary-testicular axis and adipose tissue
Testosterone is a key hormone in the pathology of metabolic diseases such as obesity. Low testosterone levels are associated with increased fat mass (particularly central adiposity) and reduced lean mass in males. It has been found that testosterone deficiency is associated with energy imbalance, impaired glucose control, reduced insulin sensitivity and dyslipidaemia.[7]
It is also known that obesity and an increased BMI have an inverse relationship to testosterone levels. What this means is that the more obese you become the lower your testosterone levels.[8] So, a vicious cycle follows where hypogonadism leads to fat deposition while the resultant obesity further reduces testosterone levels.
Hypogonadal-Obesity Cycle
Cohen 1999[9] first proposed that during the hypogonadal state, there is a preferential deposition of abdominal adipose tissue. With the increasing fatty tissue accumulation, there is an increase in aromatase activity that is associated with a greater conversion of testosterone to oestradiol (testosterone-oestradiol shunt). This oestradiol then acts on higher brain centres to decrease the levels of LH and FSH. It’s as if the body detects the oestrogen and makes the following logical arguments:
- oestrogen comes from testosterone
- there is plenty of oestrogen
- so, there must be enough testosterone
- so, no need to send a signal to the testes to produce more testosterone.
More recently this theory has been developed to include the effects of the adipocytokines or fat messengers and became known as the Hypogonadal-Obesity-Adipocytokine Hypothesis.[10]
Hypogonadal-Obesity-Adipocytokine Hypothesis
The enzyme aromatase, which is responsible for the conversion of testosterone to oestradiol, is primarily found in fat cells or adipocytes, especially in central fat deposits. The greater the degree of obesity the higher the activity of the enzyme aromatase.
In obese men Zumoff et al 2003[11] found that testosterone levels increased with the administration of aromatase inhibitors such as anastrozole.
How clomiphene increases testosterone levels
The anti-oestrogen, clomiphene works at a higher brain level, in the hypothalamus, where it blocks oestrogen receptors causing an increase in testosterone levels. This indicates that the oestrogen, which was made from aromatised testosterone, plays an important role in negative feedback on the hypothalamic-pituitary-testicular axis.[12] (see above).
Low testosterone levels in men with type II diabetes
Hypogonadism occurs commonly in men with type 2 diabetes (T2DM) and severe obesity. Current evidence points to a decreased secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus and thereby decreased secretion of gonadotropins (LH and FSH) from the pituitary gland, to be responsible for the low testosterone levels seen in hypogonadal men.
Hyperglycaemia, inflammation, leptin and oestrogen-related feedback have been proposed to make contributions to the hypogonadotropic hypogonadism of type 2 diabetes. However, the neuroendocrine signals that link these factors with modulation of GnRH neurons have yet to be identified although the peptide kisspeptin is thought to be heavily involved.
Adipose tissue, a hormone-producing factory
Adipose tissue, or fat, is the largest endocrine (hormonal) organ in the body. Your fat produces many hormones and pro-inflammatory messengers known as cytokines. In fact, many disease states such as the metabolic syndrome and type 2 diabetes are now recognised as pro-inflammatory states. So basically, being overweight puts you in an inflammatory, pro-disease state.
Free fatty acids and NF-k?
When free fatty acids are circulating, they stimulate something called NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells, wow that’s a mouthful!) pathways which then causes the release of these messengers or cytokines such as:
- TNF a
- Interleukin 1 (IL-1)
- Interleukin 6 (IL-6)
- IL-1b
- Plasminogen activator inhibitor (PAI-1)
- Serum amyloid A
Some of the above cytokines have been found to inhibit the HPT axis.[13]
Leptin and fat
The hormone leptin is only produced in fat cells and is commonly known as the satiety hormone, it makes us feel full. This is not technically quite correct. Leptin is actually a measure of how much fat storage you have.
This is the body’s survival mechanism and again it’s that negative feedback system at work. When you lose weight and hence fat, your leptin levels fall, this is interpreted by your brain as starvation. Your brain doesn’t know the difference between a diet and famine and so to protect you it initiates a series of steps that will help to preserve this vital energy supply.
Decreased leptin levels and reduced metabolism
The decreased leptin levels will make you feel hungry, as everyone who has tried dieting will have experienced. Secondly, to preserve energy, the metabolic rate is reduced; this is why you feel sluggish when you start dieting. Your body and your subconscious mind are doing everything it can to get you back to your set weight. In the past, these actions would have made the difference between survival and extinction but in the modern world, this mechanism has become redundant.
I find it interesting that a mechanism that was designed to keep us alive is now responsible for causing many diseases of the modern world.
The modern lifestyle and infertile men
While evolution encourages us to spread our genes far and wide to ensure the propagation of the species, the modern lifestyle has turned this survival instinct on its head. Instead of young fertile, virile men expanding the gene pool we have succumbed to our gluttonous nature resulting in increasing hypogonadism and as a consequence reduced fertility.
So, maybe the Illuminati has created the epidemic of obesity as a solution for population control…maybe there’s a reason for the worldwide spread of junk food symbolised by those golden arches that have spread across the world like a virus…..time to take the tin foil hat off my head…
Obesity and reduced GnRH signals
In obesity states the increased leptin levels dampen the release of GnRH from the hypothalamus via kisspeptin (see below). Also, leptin inhibits the actions of HCG on Leydig cells.[14] This helps to explain why hypogonadotropic hypogonadism is observed in men with central obesity. Here the levels of LH are low or normal. Weight reductions have been shown to increase testosterone levels but not LH levels.[15] Piteloud et al 2005a[16] also found an impaired Leydig cell response, that is less testosterone was produced, in men with insulin resistance and obesity when gonadotropins such as HCG were externally administered.
Kisspeptin (what a nice name)
Yes, there is really something called Kisspeptin! It is rather appropriately named since it is the go-between or mediator between leptin and the fertility centres in the brain. Who said scientists didn’t have a sense of humour? There is also a Sonic the Hedgehog gene…I bet you will Google this!
Kisspeptin and the onset of puberty
Kisspeptin is responsible for the onset of puberty or sexual maturation. If the body has enough fat, the leptin starts the production of kisspeptin which then stimulates the brain’s fertility centres.[17]
Lack of menstruation in female athletes
Did you know that in some instances, it pays to have a certain amount of fat? Young women, especially athletes, due to their lack of fat may begin their periods at a later age and some may stop menstruating altogether. This comes back to the fact that fat is a method of energy storage. It’s like your savings account which can be cashed in on a rainy day.
Fat and female fertility
With regards to female fertility only when the body detects sufficient amounts of fat to sustain a pregnancy will it allow the woman to become pregnant. However, before any women reading this rush out to get their Happy Meal to prepare for a pregnancy, being too fat will also cause infertility in women. So, it is a balancing act….not too fat, not too thin….it’s a wonder that anyone becomes pregnant at all!
Kisspeptin and GnRH release from the hypothalamus
George et al 2010 found that the peptide kisspeptin is involved in the negative feedback of gonadal steroids on GnRH release from the hypothalamus.[18] Thus Kisspeptins play a central role in the modulation of GnRH secretion and thus stimulate the release of LH, FSH and testosterone (if the terminology is getting confusing have a read of the blog, “How testosterone is produced”).
Hypogonadotropic hypogonadism and kisspeptin
Inactivating mutations of the kisspeptin receptor have been shown to cause hypogonadotropic hypogonadism in men, whilst an activating mutation is associated with earlier puberty.
Animal studies have shown a link between kisspeptin expression and individual factors known to regulate GnRH secretion, such as hyperglycaemia, inflammation, leptin and oestrogen. These factors can cause a disruption in kisspeptin secretion which leads to a reduced GnRH pulse and hence reduced LH and FSH and subsequently low testosterone levels.
It’s all about kisspeptin
It has been hypothesised that this decreased endogenous kisspeptin secretion is the common central pathway that links metabolic and endocrine factors causing testosterone deficiency seen in men with obesity and type 2 diabetes.
It has been proposed that the kisspeptin system plays the starring role, bringing together a range of metabolic inputs, thus acting as the link or bridge between energy status with the hypothalamic-pituitary-gonadal axis.[19]
Stem cells and low testosterone
A persistent state of low testosterone leads to increases in fat levels. When there is a low testosterone environment this favours the differentiation of pluripotent stem cells to mature into adipocytes as opposed to myocytes.[20] So instead of forming muscle cells, in a low testosterone environment, cells are persuaded to become fat cells.
Triglycerides and low testosterone
Hypogonadism or low testosterone levels have also been shown to encourage the synthesis and storage of triglycerides in adipocytes or fat cells. It has been found that adipocytes have androgen receptors which allows testosterone to have a direct effect on fat cells.[21] It was found that on cultured adipocytes testosterone had a direct effect which implies that it can affect intracellular lipid metabolism and lipogenesis.[22] Lipolysis may also be increased by testosterone by its action on increasing the number of b-adrenergic receptors.[23]
Lipoprotein Lipase and low testosterone levels
Lipoprotein lipase is present on the outer surface of cells as well as being present in the circulation. It acts to break down circulating triglycerides into fat. Fatty acids are then taken up into the adipocytes and then converted back into triglycerides for storage. Testosterone inhibits lipoprotein lipase activity, therefore, when testosterone levels are reduced then this promotes triglyceride storage. The increased rate of fat deposition also stimulates the transformation of immature adipocytes into mature cells.
TRT or Testosterone Replacement Therapy
Testosterone substitution in men with hypogonadism is well known to improve body composition, with a decrease in fat and an increase in lean muscle mass.[24] Testosterone also decreases serum leptin, which itself is a reflection of body fat content.[25]
If you think that you have low testosterone levels, have a go at the ADAM (Androgen Deficiency in the Ageing Male) questionnaire.
If your responses to the ADAM questionnaire indicate that you could be suffering from low testosterone levels and you are unsure of what to do, give us a call. We will gladly help guide you on the best path to take to get your testosterone levels back to normal…and the best part is, it’s a FREE consultation. So, contact us today if you have any questions.
References
[1] MacDonald AA, Herbison GP, Showell M, Farquhar CM. The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Hum Reprod Update. 2010;16(3):293-311
[2] Haffner SM, Valdez RA, Stern MP, Katz MS. Obesity, body fat distribution and sex hormones in men. Int J Obes Relat Metab Disord. 1993;17(11):643-649.
[3] Khaw KT, Barrett-Connor E. Lower endogenous androgens predict central adiposity in men. Ann Epidemiol. 1992;2(5):675-682. doi:10.1016/1047-2797(92)90012-f
[4] Seidell JC, Björntorp P, Sjöström L, Kvist H, Sannerstedt R. Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism. 1990;39(9):897-901. doi:10.1016/0026-0495(90)90297-p
[5] Svartberg J, von Mühlen D, Sundsfjord J, Jorde R. Waist circumference and testosterone levels in community dwelling men. The Tromsø study. Eur J Epidemiol. 2004;19(7):657-663. doi:10.1023/b:ejep.0000036809.30558.8f
[6] Strain GW, Zumoff B, Miller LK, et al. Effect of massive weight loss on hypothalamic-pituitary-gonadal function in obese men. J Clin Endocrinol Metab. 1988;66(5):1019-1023. doi:10.1210/jcem-66-5-1019
[7] Kelly, D.M. and Jones, T.H. (2015), Testosterone and obesity. Obes Rev, 16: 581-606.
[8] Diaz-Arjonilla, M., Schwarcz, M., Swerdloff, R. et al. Obesity, low testosterone levels and erectile dysfunction. Int J Impot Res 21, 89–98 (2009).
[9] Cohen P (1999) The hypogonadal-obesity-cycle. Med Hypothesis 52:49-51
[10] Jones TH (2007) Testosterone associations with erectile dysfunction, diabetes and the metabolic syndrome. Eur Urol Suppl 6:847-857
[11] Zumoff B, Miller LK, Strain GW. Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone. Metabolism. 2003;52(9):1126-1128.l
[12] Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab. 1995;80(12):3546-3552.
[13] Jones TH, Kennedy RL. Cytokines and hypothalamic-pituitary function. Cytokine. 1993;5(6):531-538.
[14] Isidori AM, Caprio M, Strollo F, et al. Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab. 1999;84(10):3673-3680.
[15] GLADYS W. STRAIN, BARNETT ZUMOFF, LORRAINE K. MILLER, WILLIAM ROSNER, CHARLES LEVIT, MARCIA KALIN, RICHARD J. HERSHCOPF, ROBERT S. ROSENFELD, Effect of Massive Weight Loss on Hypothalamic Pituitary-Gonadal Function in Obese Men, The Journal of Clinical Endocrinology & Metabolism, Volume 66, Issue 5, 1 May 1988, Pages 1019–1023,
[16] Pitteloud, Nelly & Hardin, Megan & Dwyer, Andrew & Valassi, Elena & Yialamas, Maria & Elahi, Dariush & Hayes, Frances. (2005). Increasing Insulin Resistance Is Associated with a Decrease in Leydig Cell Testosterone Secretion in Men. The Journal of clinical endocrinology and metabolism. 90. 2636-41.
[17] Skorupskaite, K. et al., “The kisspeptin-GnrH pathway in human reproductive health and disease.” Human reproduction update (2014),20:485-500
[18] George JT, Millar RP, Anderson RA. Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes. Neuroendocrinology. 2010;91(4):302-307.
[19] George JT, Millar RP, Anderson RA. Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes. Neuroendocrinology. 2010;91(4):302-307.
[20] Singh R, Artaza JN, Taylor WE, Gonzalez-Cadavid NF, Bhasin S. Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003;144(11):5081-5088
[21] Björntorp P. The regulation of adipose tissue distribution in humans. Int J Obes Relat Metab Disord. 1996;20(4):291-302.
[22] Blouin K, Boivin A, Tchernof A. Androgens and body fat distribution. J Steroid Biochem Mol Biol. 2008;108(3-5):272-280.
[23] De Pergola, Giovanni. (2000). The adipose tissue metabolism: Role of testosterone and dehydroepiandrosterone. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 24 Suppl 2. S59-63.
[24] Christina Wang, Ronald S. Swerdloff, Ali Iranmanesh, Adrian Dobs, Peter J. Snyder, Glenn Cunningham, Alvin M. Matsumoto, Thomas Weber, Nancy Berman the Testosterone Gel Study Group, Transdermal Testosterone Gel Improves Sexual Function, Mood, Muscle Strength, and Body Composition Parameters in Hypogonadal Men, The Journal of Clinical Endocrinology & Metabolism, Volume 85, Issue 8, 1 August 2000, Pages 2839–2853
[25] Kapoor D, Clarke S, Channer KS, Jones TH (2007b) The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol 156:595-602
