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The treatment of hypogonadism or low Testosterone has been described in medical textbooks for decades, and the symptoms are observed daily in medical practices. Still, the use of supplemental testosterone has always been controversial. Its ability to improve men’s sexual symptoms, boost energy, and enhance well-being were quickly recognized after it was first synthesized in 1935. By 1941, however, it was reported that testosterone “activated” prostate cancer, inciting a fear among physicians that has persisted for more than 70 years.
Surprisingly, the decades-old belief that testosterone therapy would precipitate rapid prostate cancer growth was based on uninterpretable results in a single patient.
Testosterone replacement therapy actually lowers risk for prostate cancer, and prostate cancer is believed to be cause by bad metabolites of estrogen including 4 and 16OH estrone.
The latest concern about testosterone is over potential cardiovascular (CV) risks.In March, the US Food and Drug Administration (FDA) issued a warning about testosterone’s possible CV risks, and advised that testosterone therapy not be initiated for “age-related” symptoms.
Recent concerns about the CV risks of testosterone grew out of a study by Vigen and colleagues published in 2013 in JAMA. The investigators analyzed records from 8709 men in the Veterans Affairs health system who underwent coronary angiography and had low testosterone levels. The primary findings were that the absolute rate of stroke, myocardial infarction (MI), and death was 25.7% among men who had received a testosterone prescription compared with 19.9% in the untreated group at 3 years after angiography.
These findings received enormous media attention and were repeated in a widely quoted accompanying editorial. However they were incorrect, and the error was immediately noted by readers. The correct absolute rate of events (number of adverse events divided by the number of individuals) was lower by one half in the testosterone-treated group compared with the untreated group (10.1% vs 21.2%).
In response, JAMA published a new version of the study in which the same reported values were said to represent “Kaplan-Meier estimated cumulative percentages with events. Curiously, this little-known statistical methodology (stabilized inverse propensity weighting) counted events in the testosterone group as about three events, whereas events in the untreated group were counted as fewer than one event. This questionable methodology effectively reversed the true results of the study.
In March 2014, JAMA published a second correction of several data errors involving more than 1000 individuals. Moreover, it was revealed that the “all-male” study population actually comprised nearly 10% women. To date, 29 medical societies have called for the retraction of this article, arguing that the data are not credible.
A second study published 2 months later, by Finkle and colleagues reported increased rates of nonfatal MI within a short period after receipt of a testosterone prescription compared with the previous 12 months. This analysis of an insurance data set suffered from such serious methodological concerns that the FDA’s own conclusions were that “…it is difficult to attribute the increased risk for non-fatal MI seen in the Finkle study to testosterone alone….”
Several dozen studies showed the following:
Although no large, long-term controlled studies have definitively determined risk, the weight of evidence right now strongly favors the CV benefits of having a normal serum testosterone concentration, whether achieved naturally or with testosterone therapy.
The testosterone cardiovascular risk story has given apparent legitimacy to several erroneous notions about testosterone.
The data suggest otherwise. In 2010, during the steepest increase in testosterone prescriptions, no testosterone product was within the top 20 most-advertised drugs. For those of us who teach at continuing medical education events, it was clear that the rise in prescriptions coincided with an increased awareness of testosterone deficiency and a reduced fear about prostate cancer among providers.
From 1996 to 2007, an FDA website (now defunct) asserted that only 5% of men with hypogonadism receive treatment, while estimating that the size of the hypogonadal population in the United States was about 2-4 million. Current data indicate that about 2 million men are being treated with testosterone. Thus, it is hard to argue that testosterone is overprescribed.
Some clinicians have suggested that testosterone treatment should be initiated only when there is a documented cause for hypogonadism, such as a pituitary tumor, but not when low testosterone is a consequence of aging.
Deficiencies of hormones, such as testosterone, produce certain symptoms. The effect is the same whether an underlying cause is identified or not.
Imagine limiting antihypertensive therapy to the minority of men with known causes. This makes no sense.
Should we deny treatment for diabetes, arthritis, and cataracts because they are more prevalent with age?
With respect to age-related testosterone deficiency, let us recognize that many common medical conditions are age-related, including diabetes, arthritis, cataracts, coronary artery disease, and cancer. Should we deny treatment for these too because they become more prevalent with age? Illogical.
Testosterone is not estrogen, and men are not women. To conflate the two is unscientific.
In any case, readers may be surprised to learn that 2013 follow-up data from the WHI revealed significantly fewer cases of invasive breast cancer among women who took estrogen alone compared with women who took placebo. Once headlines assert risks, it can take years for the true evidence to be acknowledged.
I have yet to see any data to support this, and I question whether any overuse of testosterone products is different from that seen with other pharmaceuticals. Critics often point to studies showing that 25% of testosterone prescriptions were not preceded by a serum testosterone test.
There is level 1 evidence that testosterone therapy improves libido, erections, and mood ; it also increases muscle mass and bone density ; and it reduces fat mass. These benefits are seen every day in clinical practice.
Indeed, one only needs to treat five symptomatic men with low testosterone values to become convinced: two will thank the physician profusely for restoring their sexuality and vitality, another two will report solid benefits, and one will not respond.
Testosterone therapy is an established, effective treatment for symptomatic men with low levels of serum testosterone. Symptoms may be sexual (reduced libido, erectile dysfunction, difficulty achieving orgasm) or nonsexual (fatigue, loss of vitality or energy, poor motivation, depressed mood, weakness). Treatment improves symptoms in most men. Although the medical goal of testosterone therapy is to alleviate symptoms, it is increasingly recognized that general health may also be improved.
At this point, there is no credible evidence that testosterone therapy increases the risk for CV disease or prostate cancer. Known risks include erythrocytosis, gynecomastia, acne, and peripheral edema. Exogenous testosterone also reduces fertility and may reduce testicular size.
Testosterone therapy is good medicine for the appropriate patient. There is value in identifying men who are testosterone-deficient, and offering them a trial of treatment.