Cardiovascular effects of testosterone

Human observational studies have uncovered no association between high testosterone levels and coronary artery disease. Testosterone has been shown to dilate the coronary arteries both in vitro and in vivo. Some studies have demonstrated that testosterone can be considered to have a positive effect on reducing cardiovascular risk factors; for example, inverse relationships have been shown between testosterone levels and BMI, waist circumference, and waist-to-hip ratio, as well as levels of serum leptin, LDL cholesterol, triglycerides and fibrinogen.

Low testosterone is associated with dyslipidemia, hypertension, obesity and diabetes, all of which increase the risk of cardiovascular disease and are features of the metabolic syndrome.6

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Studies indicate that low testosterone levels are associated with atherosclerosis in all major vessels. Animal experiments have shown that testosterone inhibits plaque development in rabbits and rodents fed a high-fat diet.7

Diabetes, metabolic syndrome, and obesity

Low testosterone is associated with type 2 diabetes. A man with diabetes is approximately twice as likely to be hypogonadal than a man without diabetes.8 Low testosterone concentrations predict the development of type 2 diabetes: Data from the National Health and Nutrition Examination Survey (NHANES) III survey indicated that men with the lowest levels of free testosterone were four times as likely to have diabetes as those with the highest levels.9

Evidence suggests a direct bidirectional and physiologic link between hypogonadism and metabolic syndrome in males. Data show that there is improvement in the symptoms of patients with metabolic syndrome who receive testosterone replacement therapy.10

Hyperinsulinemia and obesity may inhibit testicular testosterone production.11 Testosterone replacement therapy in hypogonadal men improves lean body mass and reduces fat mass, and may improve some symptoms of metabolic syndrome and type 2 diabetes.12

Bone density

Testosterone levels also affect bone density. Osteopenia, osteoporosis and fracture prevalence rates are greater in hypogonadal men.13 A positive direct relationship between serum testosterone and bone mineral density increments was seen in a 36-month study.14

The prevalence of osteoporosis is estimated to be 18% in men, but 30% of all fractures occur in men with low testosterone. With age, men experience a gradual decline in testosterone production and bone density. The rate of trabecular bone loss in the lumbar spine in men older than age 50 years with low testosterone is double the rate of loss in men younger than age 50 years.15

Erectile dysfunction and decreased libido

As men get older, there is a natural decline in testosterone and thus a corresponding decline in libido. Testosterone is essential for the regulation of erectile physiology by multiple mechanisms.16 In one study, after four testosterone injection intervals, the percentage of patients with “low” or “very low” levels of sexual desire/libido decreased from 64% at baseline to 10%; moderate, severe, or extremely severe erectile dysfunction decreased from 67% to 19%.17

Testosterone regulates nerve structure and function in areas of the spinal cord that are involved in erections. The hormone is critical for the maturation and maintenance of terminal axon density and neuropeptide expression in the vas deferens. Acting peripherally to the spinal cord, testosterone enhances the erectile response of the cavernous nerve. Testosterone also regulates nitric oxide synthase expression and activity in the corpus cavernosum. It may restore erectile function in men with diabetes.16

There is growing evidence that testosterone has profound effects on penile tissues involved in the mechanism of erection and that testosterone deficiency impairs the anatomical and physiologic/biochemical substrate of erectile capacity. These effects have been shown to be reversible on androgen treatment. Treatment with transdermal testosterone resulted in improved tumescence and rigidity of nocturnal erections, spontaneous erections, and sexually related erections in men with androgen deficiency.18

Effects on mental function

Low testosterone levels have an effect on cognition in men. Higher bioavailable testosterone levels are associated with better performance in cognitive tests. Often men with low testosterone complain of mental “fogginess” or forgetfulness. As testosterone levels normalize with replacement therapy, this decline in mental function reverses.

In the Veterans Affairs Puget Sound Health Care System cohort study, 278 hypogonadal men (total testosterone level ≤200 ng/dL) aged 45 years and older without previous depressive diagnosis showed an approximate fourfold increase in risk of incident depression during the two-year follow-up. Veterans with low testosterone developed depression over time. Men with depression who received testosterone therapy had improved scores on depression scales.19

In a randomized, placebo-controlled, double-blind, phase III trial, 184 men suffering from metabolic syndrome and hypogonadism were treated for 30 weeks with either parenteral testosterone undecanoate (1,000 mg intramuscularly) or placebo. Depression was assessed at baseline and at 18 and 30 weeks using the Beck Depression Inventory. At baseline, depression significantly correlated with the total testosterone level. Over time, a significant improvement in depression was seen in the testosterone undecanoate group (mean difference after 30 weeks: −2.5 points). Effects were strongest in men with the lowest baseline total testosterone (<222 ng/dL).20

Chronic opioid use

Long-acting opioid analgesics suppress the hypothalamic-pituitary-gonadal axis in men, thus producing symptomatic androgen deficiency and an increased risk of osteoporosis. The high prevalence of opioid-induced hypogonadism in both sexes is not widely recognized.21

Opioids, both endogenous and exogenous, modulate gonadal function primarily by acting on opioid receptors in the hypothalamus. This action leads to the decreased release or disruption to the normal pulsatility of GnRH secretion, resulting in a reduction of the release of LH and FSH from the pituitary gland, and of testosterone or estradiol from the gonads.22