Excess body fat, particularly around the abdomen, is linked to lower testosterone levels. This insulin resistance doesn’t just affect blood sugar levels—it can also disrupt the normal functioning of the testes, where testosterone is produced. In men with diabetes, especially type 2 diabetes, there’s a higher chance of developing low testosterone levels.
Testosterone therapy should not be commenced for a period of three to six months in patients with a history of a cardiovascular events. The long-term impact of exogenous testosterone on spermatogenesis should be discussed with patients who are interested in future fertility. Patients with persistently high prolactin levels of unknown etiology should undergo evaluation for endocrine disorders. Guidance is also given on the management of patients with cardiovascular disease, men who are interested in preserving their fertility and men who are at risk for or have prostate cancer.
There does appear to be a trend towards lower total testosterone and a diagnosis of ED. A challenge in making the diagnosis of testosterone deficiency is that many of the symptoms reported by patients are non-specific and might be related to conditions other than low testosterone. Total testosterone  absence of signs and/or symptoms increases the likelihood of making a false diagnosis and reduces the potential benefit of testosterone therapy. Given that the direct method for free testosterone measurement is also time-consuming and labor intensive, calculation derived free testosterone measurement is more commonly used, however there is considerable variation in total testosterone assays as well as the clinical conditions that affect serum albumin and SHBG, all of which impact this measurement. The Panel recommends that clinicians use the same laboratory with the same method/instrumentation for serial total testosterone measurement. There is a great deal of variability across studies with respect to the forms of testosterone measured (total versus free), the assays utilized to measure testosterone, the time of day when the sample is obtained, and the number of testosterone measurements taken. As an example, a total testosterone value of 250 ng/dL may be considered low based on the current guideline but be marked within the normal range by the laboratory.
The general trend indicated that higher doses of testosterone were more likely to result in azoospermia than lower doses, however a dose-response effect was not consistently seen. Normal sperm production depends on a functionally intact hypothalamic-pituitary-gonadal axis with normal secretion of pituitary LH and FSH to support intratesticular testosterone production and spermatogenesis. There were inconsistently defined end points to categorize severe cardiac events, which included 'softer' endpoints (e.g., edema, tachycardia, hypertension) along with myocardial infarction and stroke.194 The statistical analysis did not account for confounding factors; the duration of follow-up varied widely, from 12 weeks to 3 years; and many of the trials were not powered to detect cardiac events as primary endpoints, rather they were catalogued as adverse outcomes. Thresholds for low testosterone were not universal. One RCT by Maggi et al. followed 715 testosterone deficient men for 12 weeks to evaluate the effects of a 2% transdermal testosterone agent on sex drive and energy. Of these, 14 biopsies (54%) revealed no cancer, and no patients required additional biopsy for clinical concerns.357
Conversely, a population-based retrospective case-control study utilizing a UK clinical database of 19,215 patients with confirmed VTE showed that there was increased risk of VTE in the first 6 months of testosterone therapy. Prostate cancer patients on testosterone therapy should have their PSA levels monitored on the same schedule as men without testosterone deficiency; however, clinicians may choose to increase the frequency of testing. Currently published studies have not demonstrated an increased risk of biochemical cancer recurrence in post-RP patients who are on testosterone therapy, nor does it define the optimal timing for commencement of testosterone therapy. At the end of the study, serum testosterone levels rose in those men receiving testosterone therapy; however, no rise in testosterone levels were seen within the prostate tissue itself. While the FDA retains a warning regarding the potential risk of prostate cancer in patients who are prescribed testosterone products ("patients treated with androgens may be at increased risk for prostate cancer"), there is accumulating evidence against a link between testosterone therapy and prostate cancer development. Given the reproductive profile of the study population, the spermatogenesis results might not be generalizable to patients with testosterone deficiency.332A study of 66 males who presented with infertility while on exogenous testosterone therapy revealed several interesting findings.333 The authors used a total motile sperm count (TMSC) of 5 million as the benchmark for spermatogenesis recovery. Another meta-analysis of RCTs performed by Cai324 concluded that testosterone therapy in diabetic men improved fasting glucose levels (mean difference -1.1 points), fasting serum insulin levels (mean difference -2.73), and HbA1c (mean difference -0.87).