The Relationship between Testosterone Deficiency Syndrome (TDS), Obesity of young men and Male Infertility
Semir A. S. Al Samarrai
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),  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 .
Low serum testosterone level (<8.7 nmol/L) appear to be associated with increase mortality in male age >40 years .
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% , 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  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)  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 . 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 . (Table 1)
Morever, Singh et al  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 . 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 .
It is known that testosterone and other sex hormones play a role throughout life in cognitive function .
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 . 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: . 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. .
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 .
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. .
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.
 Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55:121-30.
 Morales A, Schulman CC, Tostain J, Wu FCW. Testosterone deficiency syndrome (TDS) needs to be named appropriately-the importance of accurate terminology. Eur Urol 2006;50:407-9.
 Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 2007;92:4241-7.
 Tostain JL, Blanc F. Testosterone deficiency: a common, unrecognized syndrome. Nat Clin Pract Urol 2008;388-96.
 Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006; 91:4335-43.
 Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Med 2008;93:2737-45.
 Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch intern Med 2006;166:1660-5.
 Mulligan T, Frick MF, Zuraq QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60:762-9.
 Laughlin GA, Barret-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68-75.
 IDF worldwide definition of the metabolic syndrome. International diabetes Federation Web site. http://www.idf.org/metabolic_syndrom.
 Svartberg J, von Muhlen D, Sundsfjord J, Jorde R. Waist circumference and testosterone levels in community dwelling men. The Tromso study. Eur J Epidemiol 2004;190:657-63.
 Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic Syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006;24:3979-83.
 Singh R, Atraza JN, Taylor WE, Gonzales-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;144:5081-8.
 Köhler, TS, Kim J, Feia K, et al. Prevalence of androgen deficiency in men with erectile dysfunction. Urology 2008;71:693-7.
 Yassin AA, Saad F. Testosterone and erectile dysfunction. J Androl 2008;29:593-604.
 Saad F, Grahl AS, Aversa A, et al. Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction. BJU Int 2007;99:988-92.
 Foresta C, Caretta N, Rossato M, Garolla A, Ferlin A. Role of androgens in erectile function. J Urol 2004;171:2358-62, quiz 2435.
 Greco EA, Spera G, Aversa A. Combining testosterone and PDE5 inhibitors in erectile dysfunction: basic rationale and clinical evidences. Eur Urol 2006;50:940-7.
 Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol 2007;52:54-70.
 Liverman CT, Blazer DG, editors. Testosterone and Aging: Clinical Research Directions. Washington, DC, USA: National Academies Press; 2004.
 Seidman SN. Testosterone deficiency and mood in aging men: pathogenic and therapeutic interactions. World J Biol Psychiatry 2003;4:14-20
 Seidman SN. The aging male: androgens, erectile dysfunction, and depression. J Clin Psychiatry 2003; 64(Suppl 10):31-7.
 Federal interagency Forum on Aging-Related Statistics. Older Americans 2004: Key Indicators of Well-Being. Federal Interagency Forum on Aging-Related Statistics, Washington,DC: U.S. Government Printing Office. November 2004. Available at www.agingstats.gov.
 Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci 2002;57:M76-99.
 Barret-Connor E, Goodman-Gruen D, Patay B. Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 1999;84:3681-5.
 Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc 2002;50:707-12.
 Vermeulen A, Kaufman JM, Giagulli VA. Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging and obese males. J Clin Endocrinol Metab 81:1821-1826, 1996.
 Hautanen a. Synthesis and regulation of sex hormone-binding globulin in obesity. Int J Obes Relat Metab Disord 24(Suppl 2):S64-S70, 2000.
 Couillard C, Gagnon J, Bergeron J, et al. Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone concentrations in men: the HERITAGE Family Study. J Clin Endocrinol Metab 85:1026-1031, 2000.
 Giagulli VA, Kaufman JM, Vermeulen A. Pathogenensis pf the decreased androgen levels in obese men. J Clin Endocrinol Metab 79:997-1000,1994.
 Strain GW, Zummoff B, Kream J, et al. Sex difference in the influence of obesity on the 24hr mean plasma concentration of cortisol. Metabolism 31:209-2121,1982.
 Jarow JP, Kirkland J, Koritnik DR, Cefalu WT. effect of obesity and fertility status on sex steroid levels in men. Urology 42:171-174,1993.
 Lima N, Cavaliere H, Knobel M, et al. Decreased androgen levels in massively obese men may be associated with impaired function of the gonadostat. Int J Obes Relat Metab Disord 24:1433-1437,2000.
 A. Bojesen, S. Juul, C.H. Gravholt, Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study, J. Clin. Endocrinol. Metab. 88 (2003) 622-626.
 S.J. Howell, et al., Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy, Clin. Endocrinol (Oxf.) 55 (2001) 315-324.
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:firstname.lastname@example.org
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