Endocrinologist Groups Reject FDA's Testosterone Therapy Position

Two endocrinologist societies have issued a joint position statement recommending that the decision to prescribe testosterone replacement therapy (TRT) to hypogonadal men should be guided by signs and symptoms and testosterone levels rather than the underlying cause, as recommended by the FDA in response to concerns about cardiovascular risks associated with TRT. In the position statement, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) say the evidence for increased cardiovascular risks associated with testosterone use is weak. Two retrospective studies raised concern that testosterone therapy increases cardiovascular risk, but these studies have major flaws “precluding meaningful conclusions to be drawn,” according to the statement.

The statement, which was published recently in Endocrine Practice (2015;21:1066-1073), was prepared by Neil Goodman, MD, of the University of Miami Miller School of Medicine, and other members of the AACE Reproductive Endocrinology Scientific Committee.

“Epidemiologic studies strongly support the association of low testosterone concentrations and hypogonadism with cardiovascular events and all-cause mortality, especially in elderly men,” the position statement reads. “However, low testosterone could be a marker of illness and not a causal factor.”

The statement also pointed out that TRT “favorably changes many cardiovascular risk factors. It decreases fat mass, increases muscle mass, decreases insulin resistance and can reverse metabolic syndrome in some men.”

In March, the FDA issued a statement that read, “Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests.” According to the FDA, testosterone “should not be used to relieve symptoms in men who have low testosterone for no reasons other than aging.”

The AACE/ACE statement recommends that TRT be considered “for symptomatic men who have unequivocally low total and/or free testosterone levels that are assayed on at least 2 samples drawn before 10 am.” All men being considered for TRT must undergo a thorough diagnostic work-up.

“Since the risk/benefit ratio of TRT is not well established in aging-associated hypogonadism, we advise the practicing clinician to be extra cautious in the symptomatic elderly with demonstrably low testosterone levels prior to embarking on replacement therapy and to avoid treatment of the frail elderly altogether.”

Why Estrogen Balance is Critical to Aging Men

By William Faloon

We tested estrogen based on published data indicating that when estrogen levels are unbalanced, the risk of degenerative disease in aging men skyrockets.1-7 Of concern to us 14 years ago were reports showing that excess estrogen contributes to the development of atherosclerosis.  Human clinical studies conducted more than a decade later confirmed our suspicions. Men with even slightly elevated estrogen levels doubled their risk of stroke and had far higher incidences ofcoronary artery disease.10-12 Our early observations also revealed that men presenting with benign prostate enlargement or prostate cancer had higherblood estrogen levels (and often low free testosterone blood levels). Insufficient estrogen, on the other hand, predisposes men to osteoporosis and bone fracture. The fact that 99% of men today have no idea what their blood estrogen levels are helps explain the epidemic of age-related disease that is bankrupting this nation’s medical system. New Study Published in the Journal of the American Medical Association Conventional doctors tend to ignore hard science until it appears in their own medical journals. A study published in the Journal of the American Medical Association (JAMA) measured blood estradiol (a dominant estrogen) in 501 men with chronic heart failure. Compared to men in thebalanced estrogen quintile, men in the lowest estradiol quintile were 317% more likely to die during a 3-year follow-up, while men in the highest estradiol quintile were 133% more likely to die.24 The men in the balanced quintile—with the fewest deaths—had serum estradiol levels between 21.80 and 30.11 pg/mL. This is virtually the ideal range that Life Extension® has long recommended male members strive for. The men in the highest quintile who suffered 133% increased death rates had serum estradiol levels of 37.40 pg/mL or above. The lowest estradiol group that suffered a 317% increased death rate had serum estradiol levels under 12.90 pg/mL. The dramatic increase in mortality in men with unbalanced estrogen (i.e., estradiol levels either too high or too low) is nothing short of astounding. It uncovers a gaping hole in conventional cardiology practice that is easily correctable. This study revealing the lethal dangers of estrogen imbalance was published in conventional medicine’s Bastille of knowledge—the Journal of the American Medical Association. Low Estradiol and Testosterone Predict Mortality in Aging Men Sales of testosterone replacement drugs have surged more than 20-fold in response to studies linking low testosterone to a host of common maladies. In a recent study of 3,014 men aged 69-80 years, serum levels of testosterone and estradiol were measured during a mean follow-up of 4.5 years. Men with low testosterone had 65% greater all-cause mortality, while men with low estradiol suffered 54% more deaths.25 Those men low in estradiol and testosterone were almost twice as likely to die (a 96% increase in mortality) compared to men in the optimal ranges.25 This large study of aged men corroborates prior published reports linking imbalances of testosterone and/or estradiol with greater incidences of degenerative disease and death.26-36 How Do Men Naturally Make Estrogen? Women synthesize most of their estrogen in their ovaries and other reproductive tissues. Since men lack this female anatomy, they need to produce estrogen through a process involving an enzyme called aromatase that transforms testosterone into estradiol. Aging men sometimes have too much aromatase activity, which causes their testosterone to convert to excess estradiol. This results in depletionof vital testosterone while spiking estradiol to unsafe ranges. Some men lack aromatase and suffer an estrogen deficit. Other men produce so little endogenous testosterone that there is not enough to convert into estrogen, which causes low levels of both free testosteroneand estradiol. Fortunately, no matter what the underlying cause, aging men can easily achieve optimal free testosterone and estradiol serum levels. Free testosterone is the unbound form that is biologically available to cell receptor sites throughout the body. Measuring free testosterone blood levels is the most accurate way of assessing testosterone status in aging men. How Aging Men Can Control Their Estrogen Levels An epidemic problem in aging male members is insufficient free testosterone, i.e., less than 15-20 pg/mL of serum. When accompanied by excess estradiol (over 30 pg/mL of serum), this can signal excess aromatase enzyme activity. Excess aromatase robs men of their testosterone while exposing them to higher than desirableestradiol.37 Aromatase can be suppressed with absorbable forms of chrysin (a plant flavonoid) and/orlignans such as those extracted from the Norway spruce tree (HMRlignan™).38-42 If these nutrients fail to reduce estradiol adequately, then we suggest that men ask their doctor to prescribe an aromatase-inhibiting drug like Arimidex® in the very low dose of 0.5 mg twice a week. When aromatase is properly suppressed, estradiol levels are reduced to safe ranges, while free testosterone often increases, since less testosterone is being aromatized into estradiol.

Testosterone Therapy: No Link with Blood Clot Disorders

Source: EurekaAlert! 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.

This research was supported by the National Institutes of Health.