Lowered testosterone in male obesity: mechanisms, morbidity and management. Ng Tang Fui M, Dupuis P, Grossmann M. Asian journal of andrology. 2014;16(2):223-231.

Testosterone and weight loss: the evidence. Traish AM. Current opinion in endocrinology, diabetes, and obesity. 2014;21(5):313-322.

Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Saad F, Aversa A, Isidori AM, Gooren LJ. Current diabetes reviews. 2012;8(2):131-143.

The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. Saad F, Gooren LJ. Journal of obesity. 2011;2011.

It is well documented that obesity may cause hypogonadism, and that hypogonadism may cause obesity.^1-4 This has generated debate about what condition comes first; obesity or hypogonadism? And what should be the first point of intervention?

In this editorial we summarize data from several reviews on the association of obesity and hypogonadism^1-4, and make the case that obesity and hypogonadism create a self-perpetuating vicious circle. Once a vicious circle has been established, it doesn’t matter where one intervenes; one can either treat the obese condition or treat hypogonadism first. The critical issue is to break the vicious circle as soon as possible before irreversible health damage arises.

Nevertheless, as we will explain here, treating hypogonadism first may prove more effective in that it to a large extent “automatically” takes care of the excess body fat and metabolic derangements, and also confers psychological benefits that will help obese men become more physically active. Thereby, restoring testosterone levels in hypogonadal obese men will relatively quickly break the self-perpetuating vicious circle, and transform it into a “health promoting circle.”

• Non-obese men who become obese experience a decline of testosterone levels comparable to that of 10 years of aging.
• Testosterone deficiency and obesity each contribute independently to a self-perpetuating vicious cycle. Long-term testosterone replacement therapy in men with hypogonadism improves body composition, metabolic syndrome components and quality of life, and thereby can help break the vicious cycle.
• Treatment of hypogonadism with long-term testosterone replacement therapy, with or without lifestyle modifications, effectively treats obesity by correcting testosterone deficiency; one physiological root cause of obesity.
• In contrast to the U-shaped curve for weight loss seen with traditional obesity treatments, which are characterized by weight loss and weight regain, treatment with testosterone replacement therapy results in a continuous reduction in obesity parameters (waist circumference, weight and BMI) for >5 years, or until metabolic abnormalities return to healthy ranges.
• The significant effectiveness of testosterone replacement therapy in combating obesity in hypogonadal men remains largely unknown to doctors. Educational efforts are therefore critical to bring research findings into clinical practice in order to improve patient care and health outcomes.

Obesity, classified by the American Medical Association in 2013 as a disease, is an epidemic that is rapidly spreading globally. Obesity is the most common preventable disease and the most common modifiable risk factor for several chronic diseases^5,6; it is notable that obesity is an independent risk factor for cardiovascular disease^7,8 and type 2 diabetes^9,10, as well as an independent cause of increased morbidity and mortality.⁵ With the contemporary pervasive unhealthy food habits and sedentary lifestyles, it is anticipated that the prevalence of obesity and its health consequences will continue to rise.¹¹ Over the last decade, an escalation in diabetes incidence has paralleled the rapid increase in obesity prevalence, constituting a global health crisis.¹² The concurrent occurrence of obesity and diabetes in the same individual, known as “diabesity” is also rising in prevalence at a fast pace.^13,14

A comprehensive program of lifestyle modification can produce a 7% to 10% reduction of body weight and clinically meaningful improvements in several cardiovascular risk factors, including the prevention of type 2 diabetes.¹⁵ However, long-term maintenance of lifestyle induced weight loss is notoriously difficult and fails for the large majority.¹⁶ In turn, anti-obesity drugs have limited efficacy and adverse side effects that limit their use.^5,17

Therefore, new interventions are urgently needed to combat this alarming preventable threat to society. A new line of reasoning has suggested that it is time to test hormonal theories about why people get fat.¹⁸ Testosterone is a promising candidate.

Multiple lines of evidence, from experimental to observational studies, and randomized controlled trials of both testosterone replacement therapy and testosterone deprivation, show the critical role of testosterone in regulation of body fat metabolism and body composition.^1-4

Obesity as a cause of hypogonadism - Evidence that obesity leads to low testosterone

Multiple observational studies in community-dwelling men suggest that obesity leads to decreased testosterone. Cross-sectional analyses show that obese men have lower testosterone levels than age-matched non-obese men.^19,20 In the prospective Massachusetts Male Aging Study (MMAS), non-obese men who became obese had a decline of testosterone levels comparable to that of 10 years of aging.²¹ Another prospective study confirmed that weight gain results in a proportional decrease in testosterone levels at follow-up.²² Obesity, metabolic syndrome, diabetes and dyslipidaemia have been identified as risk factors of incident hypogonadism.²³

Hypogonadism as a cause of obesity - Evidence that low testosterone leads to obesity

There is also ample evidence, both from experimental and human studies, to suggest the reverse. Lower baseline testosterone levels independently predict an increase in intra-abdominal fat after 7.5 years of follow-up.²⁴ Experimental induction of hypogonadism in healthy men aged 20-50 years, significantly increases body fat mass within 16 weeks, indicating that severe testosterone deficiency rapidly causes body fat gain.²⁵ Moreover, men with prostate cancer receiving androgen deprivation therapy show marked increases in total body fat mass and abdominal visceral fat within 6 months.²⁶

Further proof of the causal role of testosterone in the pathogenesis of obesity comes from a growing number of studies showing that testosterone replacement therapy significantly reduces several markers of obesity, (including weight, waist circumference and BMI)^27-31, total body fat mass^32-37 and intra-abdominal fat mass.^37-40

While testosterone is most known for its effect on libido and sexual function, it plays a key role in fat, carbohydrate and protein metabolism as well.^37,41-45 The exact mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. Nevertheless, data from animal, cell and clinical studies show that testosterone at the molecular level controls the expression of important regulatory proteins involved in energy and substrate metabolism.⁴¹ The cumulative effects of testosterone on these biochemical pathways would account for the overall benefits seen with testosterone replacement therapy on fat loss and body composition.

Low testosterone and obesity: a self-perpetuating vicious cycle

When taking into consideration both sides of the testosterone – obesity link, it becomes clear that a bidirectional relationship exists between testosterone and obesity, initiating and reinforcing a self-perpetuating cycle (figure 1).

On the one hand, increasing body fat suppresses the HPT (hypothalamic-pituitary-gonadal) axis by multiple mechanisms; via increased insulin resistance, metabolic syndrome and diabetes^46,47, and elevation in estradiol and cortisol levels.^48,49 Because of this, it has been suggested that obesity-induced hypogonadism should be regarded as a distinct subtype of hypogonadism.⁵⁰

On the other hand, low testosterone promotes accumulation of total and visceral fat mass, thereby inducing and/or exacerbating the gonadotropin inhibition, which will further reduce testosterone levels.^46,48,49 A recent placebo-controlled study investigated the effects of testosterone replacement therapy on obesity, HbA_1c, hypertension and dyslipidemia in hypogonadal diabetic patients.⁵¹ It was found that testosterone replacement therapy did break the metabolic vicious circle by raising testosterone levels, and it was concluded that re-instituting physiological levels of testosterone has an important role in reducing the prevalence of diabetic complications.⁵¹

Psychological effects – Adherence to lifestyle changes

Testosterone replacement therapy as an obesity treatment confers additional benefits in that it consistently improves mood and feelings of energy, and reduces fatigue^52-56; this in turn may bolster motivation to adhere to diet and exercise regimens designed to combat obesity.² This has been demonstrated in studies that added testosterone or placebo to diet and exercise recommendations or structured programs.^57,58

Because testosterone improves mitochondrial function, hypogonadism may cause mitochondrial dysfunction and thereby give rise to fatigue, which in turn negatively impacts the sense of energy and vitality, and the “pick-up-and-go” mentality.⁵⁹ Therefore, testosterone replacement therapy, by addressing a root cause of obesity, can help obese men adhere to exercise programs and thereby not only break the vicious circle, but also initiate a health promoting circle.

It is of utmost interest that in contrast to the U-shaped curve for weight loss seen with traditional obesity treatments, which are characterized by weight loss and weight regain, treatment with testosterone replacement therapy results in a continuous reduction in obesity parameters (waist circumference, weight and BMI) for >5 years, or until metabolic abnormalities return to healthy ranges.^27-31

Testosterone replacement therapy has been proposed to be a new potential obesity treatment modality in hypogonadal men with excessive body fat mass and metabolic derangements.² It should be underscored that the contribution of testosterone replacement therapy to combating obesity remains largely unknown to medical professionals.² It is therefore important to highlight the promising research on the anti-obesity effects of testosterone replacement therapy and help implement its research findings into clinical practice, for the benefit of a growing population of suffering hypogonadal obese men.