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The Relationship between Testosterone Deficiency Syndrome (TDS), Obesity of young men and Male Infertility


Semir A. S. Al Samarrai

 

Abstract

There is clear evidence that advancing age is associated with a decline in the production of several hormones. The relationship of Clinical Male Infertility and Testosterone Deficiency Syndromes (TDS) is highly prevalent in obese men. Associated symptoms may significantly impair the quality of life and may affect the function of multiple organ systems especially the external male genital organ (testicle,penis) by adult men as well as by young men with obesity specifically those with waist circumference >94cm due to increased abdominal visceral fat.

Keywords: Testosterone Deficiency Syndrome (TDS), Obesity, Visceral Fat, Inflammatory Cytokines.

The Relationship between Testosterone Deficiency Syndrome (TDS), Obesity of young men and Male Infertility

According to the recommendation of the International Society of Andrology (ISA), the International Society for the Study of Aging Male (ISSAM) and the European Association of Urology (EAU), and the American Society of Andrology (ASA), testosterone deficiency syndrome (TDS) is defined as a clinical and biochemical syndrome associated with advancing age and that s characterized by erectile dysfunction, low libido, increased fat mass specially the visceral fat (abdominal fat), decreased muscle mass, loss of concentration, depression, and decreased bone mineral density and by deficiency in serum testosterone levels as well as male infertility. 

There is a general agreement that total testosterone levels >12 nmol/L do not require testosterone substitution. Similarly, based on data from younger men, there is consensus that serum total testosterone level <8 nmol/L require substitution [1, 2]. 

Testosterone deficiency is currently underdiagnosed, may result in reduced quality of life, and can adversely affect the function of multiple organ systems.

The overall prevalence of TDS varies from 6% to 9.5% in community-dwelling men aged 40-70 years and rises to 15-30% in diabetic or obese men [3,4].

Demographic data clearly demonstrate the increasing percentage of older men with (TDS), supporting the concept that serum testosterone levels decline gradually and progressively with age.

There are a significant percentage of men aged > 60 years with testosterone levels below the lower limits for young adult men.

Male patients aged 50-86 yrs., demonstrate the prevalence of psychosomatic symptoms and metabolic risk factors accumulate with decreasing testosterone levels (<15 nmol/L), [5] and men aged 40-79 yrs. demonstrate the age-dependent decline of testosterone levels, which is augmented by high body fat and underlying medical conditions [6].

Low serum testosterone level (<8.7 nmol/L) appear to be associated with increase mortality in male age >40 years [7]. 

Hypogonadism in Males (HIM) study, among men aged at least 45 yrs (defined as total testosterone <10.5 nmol/L) was estimated to be 38.7% [8], by these hypogonadonal men occurred significantly more frequently the obesity, diabetes, hypertension, rheumatoid arthritis and osteoporosis.

During an average follow-up of 11.8 years, by older men independent of multiple risk factors and preexisting health conditions Laughlin et al [9] demonstrated, that these older men with total testosterone levels <8.4 nmol/l had a 40% increased risk of death. compared with men with higher testosterone levels >12.9 nmol/l.

The metabolic syndrome (Table 1) [10] is a cluster of comorbidities and is associated with an increased cardiovascular risk. It is often found in viscerally obese patients, and insulin resistance plays a key role in its pathogenesis. Several new features, including increased inflammatory mediators, have been added to the definitions of metabolic syndromes over time and are probably related to both insulin resistance and obesity.

Evidence suggests that many components of the metabolic syndrome such as insulin resistance and obesity are also present in hypogonadal men. A study conducted in Norway showed that low total testosterone levels in men are associated with a higher waist circumference despite relatively low overall obesity [11]. Consequently, waist circumference might be a first indication of low testosterone levels in men. All of these observations are in agreement with the emerging role of low levels of testosterone in metabolic syndromes symptoms and insulin resistance [12]. (Table 1)

Morever, Singh et al [13] observed that testosterone induces myogenesis and inhibits adipogenesis in mouse pluripotent stem cells, providing an explanation for the reciprocal effect of testosterone on muscle and fat in men. Thus, there seem to be vicious circles in the relationships among testosterone, visceral fat, inflammation, and insulin resistance (Fig 1) 


Table 1- Profile of man with metabolic symptoms and testosterone deficiency symptoms.

A waist circumference > 94 cm
Raised triglycerides levels > 150 mg/dl Reduced HDL cholesterol < 40 mg/dl
Raised blood pressure (Systolic >130 mmHg and diastolic > 85 mmHg)
Raised fasting plasma glucose > 100 mg/dl

HDL= High-density lipoprotein. 

Many age-related clinical features, including erectile dysfunction, are closely associated with testosterone deficiency [14]. Because many men are reluctant to discuss erectile dysfunction with their Urologist and Andrologist, the condition remains underdiagnosed. Approximately 70% of erectile dysfunction cases have organic origins with major risk factors being diabetes, hypercholesterolemia, smoking and hypertension.

A close relationship has been demonstrated between testosterone and erectile dysfunction. Many studies have confirmed that testosterone is important in modulation the regulation of erectile dysfunction [15-19]. 

The physiological hypothalamic-hypophyseal regulation of the human testis are controlled by stimulating and inhibiting influence of neurotransmitters GnRH promotes the production and release of the Gonadotropin, LH and FSH in the hypophysis. Figure 1.

Changes in the mood are not an inevitable consequence of ageing, but large numbers of the elderly are affected by mood changes particularly depression, and there is a plausible and recognized link between the effects of testosterone on central androgen receptors and modulation of serotoninergic and dopaminergic pathways important in mood and depression [20,21,22]. 

The “psychiatric” symptoms of hypogonadism, which can be considered to include low libido, fatigue, loss of confidence, and irritability, overlap considerably with those of clinical depression [21,22].

Cognitive function comprises multiple domains such as memory, language, and mathematical skills, spatial ability, and judgment, memory is perhaps the most common cognitive function known to decline with age, with sever memory impairment thought to effect around 4% of adults in their late 60’s, with the incidence rising to around 35% in population aged > 85 years [23].

It is known that testosterone and other sex hormones play a role throughout life in cognitive function [24].

There is some evidence that higher levels of bioavailable testosterone are associated with better cognitive function in older men. [20,25,26].

Leptin, the adipocyte hormone, influence the secretion of GnRH from the hypothalamus. This is probably indirectly mediated via the neuropeptide Y transmitter (NPY). Leptin is produced in the adipose tissue by adipocytes and signals fat mass to the hypothalamus via specific leptin receptors, essentially to influence eating behavior and intake of nourishment.

The parallels between the consequences of frank hypogonadism due to known hypothalamus-pituitary or testicular disease and the consequences of normal aging in men suggest that the fall n testosterone with increasing age might contribute, at least in part, to the consequences of aging in men. These consequences include decreases in bone density, muscle mass and strength, physical function, energy, and sexual function, and an increase in heart disease. 
In the patient with oligospermia or azoospermia and low testosterone. (Total and free) and LH, a diagnosis of hypogonadotropic hypogonadism should be entertained. [27,28]. 
Obesity in males, particularly abdominal obesity is associated with reduced levels of SHBG and testosterone level [29]. There is a negative correlation between body mass index and SHBG levels.

Hyperinsulinemia associated with obesity is believed to be an important component if this relationship [27,28]. In moderately obese individuals, the bioavailable testosterone and LH levels are in are in the normal range; in severly obese men, however, total and free testosterone are reduced, as are LH levels and LH plus amptitude: [30]. The reduced LH and FHS level in obese men have been attributed to the impact of the elevated estrogen concentrations or an alteration in the testosterone: estradiol ratio on the hypothalamic-pituitary axis [31,32]. The change in the ratio of free testosterone to estradiol exceeds increased metabolic clearance of testosterone resulting from reduced SHBG and augmented aromatization to estradiol in adipose tissue. 

In addition to diminished LH levels, Leydig cell function might also be suppressed as a result of increased circulating levels of leptin in massively obese subjects. [33].

Furthermore, obesity is also associated with slight hypercortisonemia, which may affect gonadotropin secretion and contribute to the metabolic disturbance (e.g. hyperinsulinemia) that results in reduced-hepatic SHBG production [28]. 
Spermatogenesis may be hindered by exposure to chemothereapeutic agents, radiation,toxic agents,and occupational exposures to gonadotoxins. Prolonged periods of azoospermia or severe oligospermia may result. While sterility appears permanent, spermatogenesis may spontaneously recover years later when the surviving reserved stem cells (type A spermatogonia). Suddenly reinitiate the proliferative and differentiative events required for spermatogenensis.

Meistrich et al. proposed that endocrine manipulation can both minimize testicular damage during treatment and optimize the recovery of spermatogenesis after toxic exposure. 

Hypogonadism is more common in men, presenting with infertility, but the opportunity to make the diagnosis occur when they present to fertility clinics when the opportunity must be taken to assist these men through: (i) counseling the couple about the condition, (ii) achieving full masculinization with testosterone replacement, (iii) managing all other health issues more prevalent in men (obesity, osteoporosis, thyroid dysfunction, dyslipidemia, erectile dysfunction, lower urinary tract infections, chronic prostatitis, chronic epididymitis, chronic vasculitis), (iv) realistically presenting fertility options through hormonal replacement, spermiogenesis, hormonal stimulation, laparoscopic varicocelectomy bilateral and antioxidant treatment [34,35]. 

Men with spermatogenic failure (idiopathic or following testicular damage uncommonly have clinical testosterone deficiency. More after, they have a mildly raised LH combined with low-normal serum testosterone representing compensated Leydig cell failure.

In case of primary testicular failure (Khlinefelter’s syndrome), testosterone replacement will reduce FSH LH levels, thereby impairing FSH/LH residual spermatogenensis (if any) and reduce the prospects of successful diagnostics and treatment. [35]. 

In conclusion, that by aging men as well as by young men with obesity specifically those with waist circumference > 94 cm due to increased abdominal visceral fat may impair the quality of life and may effect the function of multiple organ systems specifically the reproductive and sexual organs of male, which may lead to the Testosterone Deficiency Syndrome (TDS), with erectile dysfunction and male infertility. 

References


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Correspondence

Prof. Dr. SAMIR AHMED SALIM AL SAMARRAI, Professor Doctor of Medicine - Urosurgery, Andrology, and Male Infertility; Dubai Healthcare City, Dubai, United Arab Emirates.

Mailing Address: Dubai Healthcare City, Bldg.No.64, Al Razi Bldg., Block D, 2nd Floor, Dubai, United Arab Emirates, PO Box 15376 Email:fmcalsam@emirates.net.ae

 

Correspondence:
Prof. Dr. SEMIR AHMED SALIM AL SAMARRAI
Professor Doctor of Medicine-Urosurgery, Andrology, and Male Infertility
Dubai Healthcare City, Dubai, United Arab Emirates.
Mailing Address: Dubai Healthcare City, Bldg. No. 64, Al Razi building, Block D,
2nd floor, Dubai, United Arab Emirates, PO box 13576
Email: fmcalsam@emirates.net.ae