UTMB study finds that testosterone therapy is not linked with blood clot disorders in veins

UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON A new study from The University of Texas Medical Branch at Galveston of more than 30,000 commercially insured men is the first large comparative analysis to show that there is no link between testosterone therapy and blood clots in veins. The study found that middle-aged and older men who receive testosterone therapy are not at increased risk of this illness. The findings are detailed in Mayo Clinic Proceedings.

Venous thromboembolism is a disease where blood clots form in the veins and cause blockages. The most common forms of VTE are deep vein thrombosis, which occurs often in the legs and pulmonary embolism, which is a clot in the lungs. VTE is the third most common cardiovascular illness, after heart attack and stoke.

"In 2014, the Federal Drug Administration required manufacturers to add a warning about potential risks of VTE to the label of all approved testosterone products," said Jacques Baillargeon, professor of epidemiology in the department of preventive medicine and community health and lead author of the study. "The warning, however, is based primarily on post-marketing drug surveillance and case reports. To date, there have been no published comparative, large-scale studies examining the association of testosterone therapy and the risk of VTE."

As a result of this conflicting evidence and the broad media attention it has received, there are many men with medically confirmed low testosterone who are afraid to receive testosterone therapy and there may be physicians who are reluctant to prescribe testosterone therapy based on this conflicting information.

The case-control study included 30,572 men 40 years and older who were enrolled in one of the nation's largest commercial insurance programs between Jan. 1, 2007 and Dec. 31, 2012. Cases were defined as men who had a primary diagnosis of VTE and received an anticoagulant drug or an intravascular vena cava filter in the 60 days following their diagnoses. Cases were matched with three control subjects on age, geographic region, diagnosis of low testosterone and diagnosis of any underlying pro-clotting condition.

The researchers found that having a prescription for testosterone therapy was not associated with an increased risk of VTE. In addition, none of the specific routes of administration examined -- topical creams, transdermal patches or intramuscular injections -- were associated with an increased risk. There were no differences between men who received the therapy 15, 30 or 60 days before being diagnosed with VTE.

"It is important to acknowledge, for a man who has medically-diagnosed low testosterone, that there are clear risks to not receiving testosterone therapy, including osteoporosis, sexual dysfunction, increased amounts of fat tissue, decreased lean muscle mass, possible metabolic syndrome and cardiovascular disease," said Baillargeon. "It's also important to note that further research needs to be conducted to rigorously assess the long-term risks of testosterone therapy.

These findings may help to inform the benefit-risk assessment for men with testosterone deficiency considering treatment.

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Other authors include UTMB's Randall J. Urban, Gwen Baillargeon, Gulshan Sharma and Yong-Fang Kuo; Abraham Morgentaler from Men's Health Boston at Harvard Medical School and Charles J. Glueck from Jewish Hospital at Mercy Medical Physicians in Cincinnati, OH.

Saw Palmetto: Benefits Prostate Health, Modulates Hormones, and May Help Prevent Hair Loss

As men grow older, many experience declining prostate health that significantly affects their lifestyle and well-being. One of the most common conditions threatening the prostate gland is benign prostatic hypertrophy. This swelling of the prostate gland can lead to myriad symptoms such as increased urinary frequency, weak urinary stream, and difficulty initiating urination. For more than a century, saw palmetto (Sabal serrulata) has been recognized for its ability to relieve swelling of the prostate gland. In fact, saw palmetto is one of the most popular plant-derived remedies for benign prostatic hypertrophy. Doctors in Germany, Austria, and Italy use saw palmetto, along with other plant extracts like pygeum and nettle root, as a first-line treatment for enlargement of the prostate gland.1

By helping to prevent the conversion of testosterone to its potent metabolite dihydrotestosterone (DHT),2-6 saw palmetto may have important implications for preventing hormone-related cancers in men, such as prostate cancer. Saw palmetto's ability to modulate hormonal balance also makes it a promising candidate for preventing and treating hair loss, with initial studies demonstrating positive effects.7

Benefits for Prostate Health

Benign prostatic hypertrophy (BPH) is a common condition that becomes increasingly prevalent in aging men. BPH affects 8% of all men at the age of 40, 60% of men in their seventies, and 90% of men in their eighties.8 One fourth of these men will develop moderate-to-severe lower urinary tract symptoms that will greatly affect their quality of life.8

The prostate gland's sole function is to secrete fluid containing substances needed for reproduction. This process requires an extremely high concentration of androgen hormones in the prostatic tissues. BPH seems to be related to the prostate's long-term exposure to the strong androgen dihydrotestosterone (DHT), as well as to estrogens.9 The enzyme necessary to convert testosterone into DHT is called 5-alpha-reductase.

Research has shown that saw palmetto is an effective inhibitor of 5-alpha-reductase activity in prostate gland tissue.2-6 In patients with BPH, saw palmetto relieved urinary symptoms as effectively as the pharmaceutical 5-alpha-reductase inhibitor, finasteride (Proscar®).9 In addition to inhibiting 5-alpha-reductase activity, saw palmetto exerts anti-inflammatory effects that also may have complementary effects on prostate health.9

Extensive research supports saw palmetto's benefits for prostate health. An analysis of 2,939 men with symptomatic BPH found that those taking saw palmetto extract reported greater improvement of urinary tract symptoms and urinary flow measures compared to control subjects. Furthermore, the experimental group saw a decrease in episodes of nocturia (nighttime urination) and an improvement in peak urinary flow.1

In one trial, researchers assessed the efficacy of 160 mg of saw palmetto given twice daily for two years. The study enrolled men with clinically diagnosed BPH and complaints of prostate symptoms. The patients were evaluated at 6, 12, 18, and 24 months. At each subsequent evaluation, the patients' quality of life and maximum urinary flow had improved, and both prostate size and symptoms had decreased. The study participants reported that sexual function remained stable for the first year of treatment and significantly improved during the second year. Another study examined men aged 45 or older with moderate-to-severe symptoms of BPH. After receiving placebo for one month, the men were randomly assigned to receive either saw palmetto or placebo for an additional six months. The men were evaluated using the International Prostate Symptom Score and measurement of urinary flow rate. The saw palmetto group experienced a significant decrease in its prostate symptom scores. Moreover, its quality-of-life scores increased to a greater degree than in those taking a placebo. The researchers concluded that saw palmetto significantly improved urinary symptoms compared to placebo.11

Potent Hormone-Modulating Effects

Growing numbers of aging adults are turning to a novel therapy called hormone restoration to fight the signs of aging and regain their youthful vitality. Proper hormone restorative therapy involves balancing and maintaining youthful levels of the body's key hormones. For optimal health, pregnenolone, dehydroepiandrosterone (DHEA), progesterone, cortisol, estrogen, testosterone, and DHT all need to be in proper balance.

More and more men are using testosterone therapy to regain their youthful vigor. Testosterone not only can transform itself into DHT via the 5-alpha-reductase enzyme, but also can convert to estradiol via the aromatase enzyme. These are undesirable effects, since elevated DHT may lead to enlargement of the prostate and possibly to loss of scalp hair.7,12 Furthermore, elevated estradiol in men has been linked to gynecomastia (breast enlargement in men), decreased sexual function, and weight gain.13,14

Fortunately, such side effects of testosterone therapy can be avoided by taking some simple steps. Studies show that an extract of saw palmetto can block the conversion of testosterone to DHT.3 Research has also shown that zinc may block testosterone's conversion (aromatization) to estradiol. In a study published in the Journal of Nutrition, researchers examined the effects of zinc deficiency on androgen metabolism and aromatization. The formation of estradiol from testosterone was significantly greater in rats fed a zinc-deficient diet than in freely fed rats. The researchers concluded that zinc deficiency reduces circulating testosterone concentrations, alters hepatic steroid metabolism, and may increase circulating estradiol concentrations.15 Ensuring adequate zinc status may thus help prevent the undesirable conversion of testosterone to estradiol.

Preventing and Managing Hair Loss

Intriguing research suggests that supplementation with saw palmetto may prove useful in preventing and managing hair loss. It has been estimated that there are between 100,000 and 150,000 hairs on the human scalp. On average, between 50 and 150 hairs may be lost each day. Baldness occurs when this hair loss occurs at an abnormally high rate or when hair replacement occurs at an abnormally slow rate. About 95% of all cases of hair loss are the result of androgenic alopecia, or male pattern hair loss.

Biochemically, one contributing factor to this disorder is the conversion of testosterone to DHT via the 5-alpha-reductase enzyme.7,16,17 Accordingly, agents that block the 5-alpha-reductase enzyme are attracting attention as treatments for androgenic alopecia.

Finasteride, marketed under the brand names Propecia® and Proscar®, is an FDA-approved treatment for men with androgenic alopecia. Clinical studies in balding men have demonstrated that finasteride reduces scalp DHT levels and improves hair growth, confirming DHT's role in the pathophysiology of androgenic alopecia.17 Studies have shown that both finasteride and saw palmetto are effective inhibitors of the 5-alpha reductase enzyme.2-6,9,17 However, researchers have also discovered that finasteride is associated with a greater risk of erectile dysfunction, ejaculatory disorders, and decreased libido.18 Thus, many men are seeking effective solutions for hair loss that are free of these side effects.

One study sought to examine saw palmetto's effects in treating androgenic alopecia. The study followed 19 healthy men, aged 23-64, with mild-to-moderate androgenic alopecia. The men were given either 200 mg of saw palmetto and 50 mg of beta-sitosterol twice a day or a matching placebo for an average of 4.6 months. Overall hair assessment was determined using a standardized scale. The patients were asked to evaluate any changes with respect to their current satisfaction with their hair. Assessments were performed at baseline and at the study's completion. Sixty percent of the study subjects were rated as improved at the final visit.7 Larger, gender-specific clinical trials are needed to further elucidate these promising initial findings.

Summary

For over 200 years, saw palmetto has been used to prevent and improve the symptoms associated with benign prostatic hypertrophy in men.1 Growing evidence indicates that supplementing with saw palmetto may also positively modulate the complex system of hormone metabolism in men and women alike. Saw palmetto's effects on hormone metabolism may have important implications for hormone restoration programs as well as for supporting healthy hair growth and preventing hair loss.

Saw palmetto has no known drug interactions, and reported side effects are minor and rare.5,12,19,20 However, some health care practitioners have noted that high doses of saw palmetto may lead to a loss of libido in both men and women.21 Life Extension suggests a daily dose of 160 mg of saw palmetto for women and 160-320 mg for men. Reprinted with kind permission of Life Extension

Low Testosterone May Raise Depression Risk

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Men with lower levels of testosterone may be at increased risk of depression , a new study finds. Researchers found that more than half of the men in the study who had lower levels of testosterone had a diagnosis of depression, or showed symptoms of the condition, while a quarter of participants were taking medication for the disease. The vast majority of male participants in the new George Washington University study also were found to be overweight or obese, and so for comparison, the researchers pointed to a recent survey of U.S. adults finding that 6 percent of those overweight or obese were depressed.

"Depression and/or depressive symptoms were present in 56 percent of the subjects," in the study, the authors concluded.

Produced primarily by the testicles, testosterone helps maintain a man's sperm production, sex drive , muscle strength and mass, bone density, and facial and body hair. Men who do not produce a "normal" amount of testosterone may be diagnosed with a condition called hypogonadism, but exactly what level should be considered normal is difficult to define, the authors wrote.

One reason for this is that blood levels of testosterone may be less important to a man's health than the effects of the hormone in muscle, bone, the brain and the reproductive organs, explained the authors. But even with blood tests, there is no level of testosterone that is universally accepted within the medical community as being too low.

Testosterone levels generally peak during adolescence and early adulthood. As men age, their testosterone levels gradually decline, typically by about 1 percent a year after age 30 or 40, according to the Mayo Clinic’s website.

In the new study, the researchers probed the medical charts of 200 men with an average age of 48. All had been referred to an endocrinologist after a blood test indicated their testosterone levels were borderline low (between 200 and 350 ng/dL).

The researchers looked at the men's demographic data, medical histories, medication use, and symptoms of hypogonadism. They also looked at whether the men had been diagnosed with depression or if they took an anti-depressants, and all study participants who weren't diagnosed with depression or taking medications for the condition answered standardized test questions aimed at measuring their mood.

Analysis showed that the study participants had higher rates of obesity and lower rates of physical activity than their peers in the general population. Participants also suffered from erectile dysfunction , decreased libido, fewer morning erections, low energy and sleep disturbances. Rates of depression were 62 percent for study participants in their 20s and 30s, 65 percent for those in their 40s, 51 percent for those in their 50s and 45 percent for those age 60 and over.

"In an era where more and more men are being tested for '"Low T' — or lower levels of testosterone — there is very little data about the men who have borderline low testosterone levels," study researcher Dr. Michael Irwig, an associate professor of medicine and director of the Center for Andrology at the George Washington School of Medicine and Health Sciences in Washington, D.C., said in a statement. "We felt it important to explore the mental health of this population."

More research is still needed in this area, but doctors and other healthcare professionals "should recognize the high rates of depression and depressive symptoms in men referred for borderline testosterone levels," the authors wrote in their study.

Testosterone replacement therapy can improve the signs and symptoms of low testosterone in these men, the researchers said. In the decade ending in 2011, one commercial health insurance group in the United States saw the number of testosterone prescriptions triple, according to a 2013 study published in JAMA Internal Medicine. The researchers noted a corresponding trend of increased direct-to-consumer marketing leading men to believe "Low T" may be the underlying cause for their decreased sexual function and low energy.

The study was published July 1 in the Journal of Sexual Medicine.