Obesity and Testicular Function


Loss of libido

Erectile dysfunction

Sarcopenia

Low bone mass

Depressive thoughts

Fatigue

Loss of body hair

Hot flushes

Loss of vigour



A321264_1_En_10_Fig1_HTML.jpg


Fig. 10.1
Relationship between endocrinometabolic disturbances, obesity and testicular function




10.2 Male Obesity Secondary Hypogonadism and Associated Metabolic Disturbances


Emerging data suggest that bone mass, energy metabolism and reproduction may be coordinately regulated. There has been a growing interest towards the nonclassical effects of 25-hydroxycholecalciferol 25(OH)D (vitamin D), based on the presence of its receptors in tissues other than the bone, gut and kidneys [21]. Furthermore, several studies have suggested the involvement of vitamin D in the pathogenesis of CVD, cancer and MetS [2224]. The association of low vitamin D levels and MetS is more pronounced in overweight and obese than in normal-weight individuals [25]. A recent study confirmed the lowest vitamin D concentrations and the highest prevalence of vitamin D deficiency in T2DM patients with hypogonadism, particularly in those with SH [26]. Several mechanisms have been proposed to explain the role of vitamin D in the pathogenesis of insulin resistance, and adiponectin has been proposed as a major player with its strong association with impaired glucose tolerance, independent from adiposity [27]. Adiponectin and glucose homeostasis are both correlated to osteocalcin (OSCA) levels, an osteoblast hormone linked to vitamin D metabolism [28]. Interesting animal studies suggest that bone may be a positive regulator of male fertility and that this action may be mediated through OSCA, via binding to a specific receptor present on Leydig cells that favours T biosynthesis. OSCA-deficient mice show a decrease in testicular, epididymal and seminal vesicle weights and sperm count, and Leydig cell maturation appears to be halted in absence of OSCA [29]. Androgens favour periosteal bone formation in men and maintain trabecular bone mass and integrity by inhibiting IL6 production [30]. Also, they stimulate the proliferation of osteoblast progenitors and the differentiation of mature osteoblasts by decreasing osteoclast formation and bone resorption, via increased production of osteoprotegerin by osteoblasts [31]. The net result of these functions leads to an accrual in bone formation [32]. In agreement with animal data, our group has recently demonstrated an association between visceral fat mass, insulin sensitivity, OSCA and T levels in ageing males that are significantly correlated with skeletal health. In this view, OSCA may be considered a new important marker of metabolic and gonadic function, other than the well-established function as marker of bone remodelling [33].


10.3 Obesity or Hypogonadism: Which Comes First?


The cause–effect relationship between obesity, insulin resistance, MetS, T2DM and TDS remains unclear. Data from the Massachusetts Male Aging Study showed that lower levels of total T and SHBG were predictive of the development of the MetS, particularly in men with BMI <25 kg/m2 [34]. By contrast, other data suggests that the MetS is an independent risk factor for hypogonadism in middle-aged men, and relative T deficiency appears to be a marker, rather than the cause of MetS or T2DM in older men [35]. Recently we demonstrated that in hypogonadal men with MetS, TRT improves body composition and insulin sensitivity independently from diet and physical exercise [36]. Follow-up for 2 years in these men demonstrated also a significant reduction of cardiovascular risks (CVRs) without any serious adverse event [37]. However, it is not clear whether after TRT withdrawal there is a stabilisation of clinical patterns associated with CVR over the time and recovery from hypogonadism. We then investigated whether TRT combined with diet and physical exercise is better than diet plus physical exercise alone in achieving a reduction of CVR in a cohort of severely obese male subjects and whether T withdrawal was able to maintain outcomes evaluated. In this study, we demonstrated for the first time that TRT is beneficial on cardiac function in severely obese patients and that withdrawal is not a good prevention strategy for reducing CVR. The new protective effects of T on endothelial function and its inverse relationship with epicardial fat thickness clearly suggest that T reduction plays a critical role in the pathogenesis of cardiac dysfunction associated with obesity [38]. If male hypogonadism remains clinically unrecognised or underinvestigated, this can subsequently lead to significantly higher morbidity and mortality. Therefore, it is important that this condition is managed appropriately with TRT along with weight reduction and lifestyle changes [39]. However, encouragement of weight reduction alone (without TRT) cannot be endorsed and recommended as an effective treatment for SH and its associated sequelae, unless clear evidence is produced to demonstrate this. On the basis of our studies, we believe that TDS may be antecedent to visceral fat accumulation in ageing men, and in fact, once TRT is withdrawn, many of the advantages determined by TRT are lost in the short term thus suggesting that T decline comes first instead of being the consequence of central obesity. In conclusion, the available data suggest that hypoandrogenism may represent an early marker for glico-metabolic disturbances that may progress to MetS or T2DM and may in turn contribute to vicious cycle maintaining visceral obesity and its associated metabolic and andrologic disturbances.


10.4 Treatment of Male Obesity in the Presence of Hypogonadism


Generalized symptoms and signs of androgen deficiency vary depending on age of onset, duration and severity of the TDS. When severe obesity occurs, T serum level below 3.45 ng/mL (12 nmol/L) should be considered pathognomonic of TDS as stated by International Guidelines and clinical questionnaires [40]. The Endocrine Society Guidelines recommend measurement of T levels in men with T2DM and endorse the early prescription of TRT in hypogonadal men with ED [41] especially because of the reduced success rate of phosphodiesterase type 5 (PDE5) inhibitors. Interestingly, in obese men with ED who do not respond to treatment with PDE5 inhibitors alone, the addition of T is recommended and even makes PDE5 inhibitors redundant in a number of cases. The use of a PDE5 inhibitor before T normalisation may be recommended until time-course effects on penile erection are achieved [42] keeping in mind that its efficacy is reduced because of low T levels [43].

In men with ‘severe’ TDS (total T less than 8 nmol/l), significant improvements in ED and sexual desire are expected. In symptomatic men with ‘moderate’ TDS, men falling within the ‘grey area’ (total T between 8 and 12 nmol/l or 180 and 250 pmol/l for free T), a trial of 3–6 months is also recommended. A target level of 15–21 nmol/l for total T during TRT is suggested [44]. Recent evidence suggests that long-term T treatment of obese diabetic men with low T levels produces important clinical benefits for up to 6 years [45]; improves glycaemic control, lipid profiles and bone mineral density [46]; and may prove useful in reducing CVR. Similar results were reported in a controlled study by our group [47], suggesting that TRT therapy ameliorates MetS components, MOSH and CVR without prostate adverse events [48]. Accurate evaluation of absolute contraindications (Table 10.2) and regular follow-up is needed in patients receiving TRT, as potentially androgen-dependent adverse events may occur suddenly (Table 10.3). The primary aim of TRT is to alleviate the clinical symptoms of TDS. Careful monitoring of changes in the clinical manifestations of T deficiency should therefore be an essential part of every follow-up visit. Effects of TRT on sexual drive may already appear after 3 weeks of treatment and reach a plateau at 6 weeks. Improvements in ED and ejaculation may require up to 6 months. Effects on quality of life and also on depressive mood may become detectable within 1 month, but the maximum effect may take longer [42]. In severely obese men, TRT appears to be a promising treatment leading to persistent results on body composition and cardiac performance than lifestyle changes alone. In addition, attrition rates without T supplementation seem to be higher and lead to poor adherence to diet and physical exercise in the long term.


Table 10.2
Absolute contraindications against testosterone treatment



















Prostate cancer

PSA >4 ng/ml

Male breast cancer

Severe sleep apnoea

Male infertility

Haematocrit >50 %

Severe lower urinary tract symptoms due to benign prostatic hyperplasia



Table 10.3
Monitoring of patients receiving testosterone replacement therapy (TRT)

















The response to treatment should be assessed 3, 6 and 12 months after the onset of treatment and thereafter annually

In men with an abnormal BMD, BMD measurements should be repeated 6 and 12 months after the start of TRT and thereafter annually

Haematocrit: at 3, 6 and 12 months and thereafter annually. The testosterone dosage should be decreased or therapy discontinued if the haematocrit increases above normal levels

Healthy prostate should be assessed by digital rectal examination and PSA before the start of TRT. Follow-up by PSA at 3, 6 and 12 months and thereafter annually

Routine screening of potential cardiovascular side effects is not indicated in men receiving TRT

Men with cardiovascular co-morbidity should be assessed by a cardiologist before TRT is initiated, and there should be close cardiovascular monitoring during TRT

Jul 5, 2017 | Posted by in UROLOGY | Comments Off on Obesity and Testicular Function

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