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NavyChief

NavyChief

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Sep 26, 2013
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#13
Mental and Cognitive Health
Testosterone is also thought to play a role in modulation of both cognitive abilities and mental health. Studies have provided conflicting results in terms of the cognitive benefits of testosterone supplementation in older men. A study of 237 older men with low-normal testosterone levels randomized to receive either twice daily capsular testosterone or placebo found that the men receiving treatment had increases in lean body mass, decreases in fat, and improved insulin sensitivity. These men did not show significant improvements in cognitive abilities.55 In a randomized double-blind trial, healthy older men were given 100 mg of weekly testosterone intramuscularly or placebo for 6 weeks. The study found that the treatment group demonstrated significant short-term improvements in spatial and verbal memory.56 However, this study did not have long-term follow-up, nor did it analyze whether the effects were due to increased testosterone, increased estradiol, or both.
Testosterone has also been shown to play a role in mood and mental health. In a 2-month study of 51 hypogonadal men, subjects were withdrawn from their previous TRT for at least 6 weeks before enrollment and subsequently restarted after enrollment. Every 20 days, the subjects rated mood parameters using the Likert scale, including anger, irritability, nervousness, and energy. The study found that TRT improved positive mood parameters (energy, well-being) and decreased negative mood parameters (anger, irritability). The study also found that the largest increases in mood occurred when subjects were in the low-normal serum testosterone range.57
TRT improved positive mood parameters (energy, well-being) and decreased negative mood parameters (anger, irritability).
Risks and Side Effects
Epidemiologic data from the Framingham Heart Study showed that menopausal and postmenopausal women are at a greater risk of coronary heart disease (CHD) and mortality from CHD compared with premenopausal women and men, thought to be largely due to differences in hormonal status. Decreasing levels of estrogen in the postmenopausal period and/or an overall greater serum concentration of testosterone led to more thrombotic events.58 Matsuda and associates59 demonstrated that testosterone augments platelet responsiveness by increasing the density of receptors for the platelet metabolite thromboxane A2. These factors were implicated in thrombotic coronary events. Moreover, there were many reported cases of myocardial infarction and heart disease in men who supplemented with testosterone for hypogonadism or abused high-dose anabolic steroids for personal gain.60 These experiences and knowledge of the pathophysiology of CHD should make clinicians wary of using TRT. Nevertheless, it is important to keep in mind that testosterone used at physiologically appropriate levels may not be as risky and may benefit patients with cardiovascular disease.
Several studies challenged the preconceived notion that higher concentrations of testosterone may explain more deaths from heart disease in men versus women by showing that men with less testosterone were discovered to have more coronary artery and aortic disease.61 Remarkably, a randomized, double-blinded study from the United Kingdom found that low-dose transdermal testosterone significantly improved the electrocardiographic signs and pain perception in patients with chronic stable angina, particularly in men with lower concentration of baseline testosterone. The authors noted that estrogen levels in the men treated in the study did not change, thereby disproving the notion that aromatization of testosterone to estrogen explained the phenomenon. In addition, when men with coronary disease were given diethylstilbestrol, they had increased cardiac mortality.62 Further studies have validated findings regarding anginal pain and have shown that low testosterone levels are associated with increased incidence of metabolic syndrome, insulin resistance, peripheral artery disease, and cerebrovascular disease, even after controlling for other risk factors.63 One study using data from the Massachusetts Male Aging Study found that higher free testosterone levels were associated with ischemic heart disease mortality, whereas total testosterone and SHBG levels were not associated with mortality.64 Although our understanding of the effects of testosterone on cardiovascular health continues to evolve, a metaanalysis of studies that reviewed these types of effects cautions that large, randomized trials of men with and without existing cardiovascular disease treated with testosterone need to be performed before clinicians can be more comfortable prescribing it.65 A retrospective cohort study compared the cardiovascular safety of various forms of TRT administration in men. The study found that injections were associated with an increased risk of cardiovascular events (myocardial infarctions or unstable angina) when compared with gels. Injections were also associated with a higher rate of hospitalizations and death.66 This study did not prove causality, and highlighted the need for proper dosing of TRT for adequate symptomatic relief while mitigating adverse event risks.67 A recent randomized controlled trial found that older men with low or low-normal serum testosterone levels did not report increased quality of life when supplemented with testosterone gel for 3 years when compared with placebo. The same study also concluded that there was no difference in atherosclerosis between the groups, but noted that no conclusions regarding overall cardiovascular safety could be drawn.68
The literature on this topic has almost exclusively been focused on men; however, the need for trials in women who generally have naturally low levels of testosterone may provide greater insight into relationship between testosterone and cardiovascular health. Further, it may open the door for treatment of another patient population. Most recently, both the US Food and Drug Administration (FDA) and the European Medicines Agency advocated for restrictions on testosterone therapy usage. The FDA report states that the benefits of testosterone therapy in older patients with idiopathic hypogonadism are equivocal and need further investigation. This recommendation was primarily based on two studies, the first of which was an observational study of older men in the US Veterans Affairs system with low serum testosterone levels. The study found a 30% increased risk of stroke, myocardial infarction, and death in the patients who received testosterone replacement.69 Another observational study of men taking testosterone therapy found that men both over and under 65 with pre-existing cardiovascular disease had an increased risk of heart attack while on TRT. Men under 65 without history of cardiovascular disease, however, did not have an increased risk of heart attacks on TRT.70 These results may parallel studies with estrogen replacement in women. According to the Women’s Health Initiative study,71 women starting estrogen replacement therapy in their early 50s have a different predictive cardiac mortality rate than those starting supplements at age 63. The FDA plans to continue to evaluate the risk of stroke, heart attack, or death in these patients and encourages physicians to seriously weigh the risks and benefits of TRT prior to prescription. The Endocrine Society Clinical Guideline Practice recommends that men should be diagnosed with androgen deficiency if they present with consistent symptoms and low serum testosterone levels. Other recommendations included initiation of TRT for symptomatic relief, followed by close monitoring with a standardized plan.72
It is important to note that TRT should be administered with caution due to potential side effects outside the cardiovascular system.
It is important to note that TRT should be administered with caution due to potential side effects outside the cardiovascular system. Studies have shown that oral forms of testosterone may be associated with hepatic tumors and hepatotoxicity.73 Other effects include gynecomastia, which is caused by conversion of testosterone to estradiol in adipose tissue.74 Patients may experience infertility from the decreased production of gonadotropins secondary to increased testosterone levels, causing decreased spermatogenesis.75 Patients with azoospermia usually have a recovery of sperm count and fertility within 18 months of TRT cessation.76 Another major concern of patients eligible for TRT is the potential aggression associated with testosterone administration, especially with spikes in testosterone from monthly intramuscular injections. Though TRT may help augment mood, as previously discussed, results about changes in anger are inconsistent. A doubleblind study of testosterone in eugonadal men found no changes in anger levels with testosterone when compared with placebo.77 A placebo-controlled study looking at the effects of intramuscular testosterone on aggression in both eugonadal and hypogonadal men found no increases in aggression in the eugonadal group. Increases in hostility and verbal aggression were statistically significant in the hypogonadal group.78 These potential adverse effects should be considered and disclosed to the patient prior to initiation of TRT, and knowledge of these complications can help physicians titrate doses accordingly.
Conclusions
Though testosterone has been traditionally thought to have effects predominantly in men, several studies have documented that its effects are varied and somewhat unpredictable. The benefits of testosterone with regard to mental health, mood, cognition, bone density, and pain control should not be overlooked. It is important to remain cognizant of the risks, primarily cardiovascular, associated with elevated testosterone levels. Based on the current review, we conclude that the clinical role of testosterone should be reassessed, and that physicians should be aware of its potential but uncommon uses.

Main Points
  • Testosterone is a pleiotropic hormone that plays an important role in the human body. Through its conversion to estrogen, testosterone affects bone health, including bone density. Recently, there has been a renewed interest in the systemic role of testosterone in pain, well-being, and cardiovascular function in both women and men.
  • Experts have debated the use of testosterone therapy in men who might benefit from replacement of declining hormone levels. The controversy surrounding this issue stems mostly from the dearth of long-term randomized studies that answer the question of whether or not testosterone therapy in normal, healthy, aging men is safe and improves quality of life. With the recent prolongation of life expectancy, especially in men, the question concerning testosterone replacement in older men has become more important.
  • There are greater uncertainties regarding testosterone therapy in women. It is more difficult to make broad recommendations regarding testosterone therapy in women because there is no well-defined clinical syndrome caused by androgen deficiency.
  • The benefits of testosterone with regard to mental health, mood, cognition, bone density, and pain control should not be overlooked; however, it is important to remain cognizant of the risks, primarily cardiovascular, associated with elevated testosterone levels.

Article information
Rev Urol. 2017; 19(1): 16–24.
doi: 10.3909/riu0716
PMCID: PMC5434832
PMID: 28522926
Vineet Tyagi, MD,1 Michael Scordo, MD,2 Richard S. Yoon, MD,1 Frank A. Liporace, MD,1 and Loren Wissner Greene, MD, MA1
Department of Orthopaedic Surgery and Rehabilitation, Yale University School of Medicine, New Haven, CT,
Department of Hematology/Oncology, Memorial Sloan Kettering Cancer Center, New York, NY,
Division of Orthopaedic Trauma, Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY,
Division of Endocrinology/Departments of Medicine and Obstetrics and Gynecology, New York University School of Medicine, New York, NY,

Copyright © 2017 MedReviews®, LLC
This article has been cited by other articles in PMC.
Articles from Reviews in Urology are provided here courtesy of MedReviews, LLC
 
1bigun11

1bigun11

VIP Member
Oct 23, 2010
1,852
1,275
#16
New study from University of Pennsylvania shows that women while ovulating are highly attracted sexually to men with high testosterone levels. On their period, however, these same women are most attracted to men strapped to a pole while being set on fire.

No further studies are contemplated at this time..,
 
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