Two new studies suggest millions of men may be risking a heart attack, stroke or premature death by using testosterone replacement therapy. Based on these studies, the FDA issued a safety announcement on January 31, 2014, saying that they are conducting an investigation and cautioning health-care professionals to carefully weigh the pros and cons of testosterone medications before writing prescriptions.
The news is surprising, and the media frenzy has added fuel to the flames of what one men’s health expert has called “hormonophobia.”
So should you or someone you care about be using testosterone replacement therapy? The short answer is maybe, if it really is low T, and after a careful assessment of total health. MedShadow took a close look at the new studies and spoke to two men’s health experts to separate the facts from the frenzy.
The testosterone replacement market
The overall market for testosterone replacement drugs was worth about $2 billion in 2012 and is projected to grow to $5 billion in 2015. The FDA-approved products include a topical gel, transdermal patch, buccal system (an adhesive, tablet-shaped patch applied to the upper gum or inner cheek) and injection delivery formats.
Available only by prescription, testosterone drugs are approved for use in men who have low testosterone (low T) and an associated medical condition, such as a failure of the testicles to produce testosterone due to chemotherapy, genetic problems, or conditions affecting the hypothalamus and pituitary gland, the brain structures responsible for controlling testosterone production by the testicles.
How many men have low T?
Testosterone levels decline with age, starting when a man is in his 30s, but the incidence of low T varies depending the source. The FDA estimates that 4 to 5 million American men have low T, also called testosterone deficiency, but that only about 5 percent are treated. One U.S. study in 2006 found a rate of 39 per cent among 2,162 men age 45 and older, classifying men as having low T if their total T level was below 300 ng/dL (nanograms per deciliter). Scaling that incidence rate up to the general population would mean that 13.8 million men might have low T. The researchers also found that for every 10-year increase in age, the risk of testosterone deficiency increased by 17 percent.
Symptoms of low testosterone
Low libido or erectile dysfunction are hallmark indications, but only some men with testosterone deficiency will have symptoms. The Endocrine Society’s Clinical Practice Guideline for Testosterone Therapy in Adult Men provides an overview of signs and symptoms:
More specific signs and symptoms of low T:
- Incomplete or delayed development of sexual characteristics
- Reduced libido and activity
- Decreased spontaneous erections, decreased ability to maintain erections
- Breast discomfort from gynecomastia (swollen breast tissue)
- Loss of axillary and pubic hair, reduced shaving
- Very small or shrinking testes
- Low sperm count
- Loss of height, low-trauma fracture, low bone mineral density
- Hot flushes, sweats
Less specific signs and symptoms of low T:
- Decreased motivation, energy and self-confidence
- Depressed mood
- Poor concentration and memory
- Sleep disturbances
- Mild anemia
- Reduced muscle mass and strength
- Increased body fat and body mass index (BMI)
- Decreased physical performance
The benefits of testosterone replacement therapy
The health benefits of testosterone replacement therapy go beyond improving sexual function. Correcting testosterone deficiency can increase lean muscle mass, decrease body fat, and improve bone density, blood sugar, energy levels and mood.
Dr. Abraham Morgentaler, a urologist at Harvard Medical School who has been treating men with low T for more than 20 years, and director of Men’s Health Boston, says in his book Testosterone for Life that many men who are originally referred to him for some form of sexual dysfunction, report that they experience improvements in mood and energy levels, their partners find them less irritable and their workouts at the gym are improved.
Filling out an online checklist at a drug manufacturer’s website is not sufficient to diagnose testosterone deficiency, though it may encourage men to speak to their doctors about symptoms. Blood work is needed to determine actual hormone levels, and this test must be separately requested in addition to the usual blood work for an annual health screening.
The trouble, though, is that there is no medical consensus on the level of testosterone that indicates a need for treatment and different labs use different ranges to define ‘normal.’ The Endocrine Society states that the threshold level to decide if therapy will address symptoms is not known, but that men are more likely to be symptomatic below a total T level of ~300 ng/dL. Dr. Morgentaler (@DrMorgentaler)says men are likely to be experiencing symptoms when total T is less than 350 ng/dL. Dr. Florence Comite, an endocrinologist practicing precision medicine for age management at ComiteMD (@ComiteMD) in New York, considers a total T below 350 ng/dL to be worthy of further investigation and says that men are usually symptomatic when total T is less than 280 ng/dL.
Importantly, both experts agree that looking at total testosterone is not enough. “Lots of physicians are fooled by just looking at total T. They should also look at free T, because most testosterone is bound up with a protein called SHGB and is not biologically available to bind to receptor sites,” says Dr. Comite. She advises that free T should fall within 150-250 pg/mL (picograms per milliliter), but the ranges and the calculation methods vary, so ask your doctor to explain your results. Another important consideration: “Men may be symptomatic at different levels of decline, depending on what was normal for them in their earlier years,” says Comite.
It May or May Not Be Low T
Testosterone levels can provide insight about a man’s health, but it’s important for doctors to look at a patient’s full health picture. Many signs and symptoms of low T can be associated with other health conditions, including erectile dysfunction, obesity, metabolic syndrome (a cluster of cardiovascular risk factors), type 2 diabetes and depression. The odds of having low T is significantly higher for men with high blood pressure, elevated blood fats, diabetes, obesity, prostate disease and asthma or chronic obstructive pulmonary disease than it is among men without those conditions. A complete health evaluation is the only way to confirm each individual’s precise challenges and underlying conditions.
Side Effects of Testosterone Therapy
- Increased red blood cell count: The National Institute of Health’s Medline notes that the average range for males is 4.7 to 6.1 million cells per microliter (cells/mcL) while Dr. Comite cites 5.1 million cells per microliter as high in her patient examples.
- Prostate enlargement
- Serious health risks for children and women
Consider the example of veteran Livingston A. Miller Sr., a personal trainer who was experiencing a lack of energy, frequent fainting episodes that resulted in trips to the ER, symptoms of frequent urination and thirst, and had abdominal fat that was hard to shake in spite of a diligent fitness program. He consulted Dr. Comite when he was 52, after a VA medical center was unable to find any health issues. Dr. Comite discovered he was diabetic, had suffered a silent heart attack and also had low T.
She designed a personalized treatment plan to address his total health, including shifting his workouts to focus more on cardiovascular fitness, a better diet to get his blood sugar in control and testosterone therapy. As a result, Miller dropped 30 pounds, trimmed excess abdominal fat, reversed the diabetes, and improved his heart function. Now 61, he is still taking testosterone therapy as part of his overall health maintenance plan and continues to work as an energetic fitness trainer, free of diabetes and heart problems.
Side Effects of Testosterone Therapy
- Testosterone therapy may help improve the health of men with testosterone deficiency, but there are some side effects that need to be carefully considered and monitored.
- Increased red blood cell count. Since testosterone therapy can trigger an increase in the number of red blood cells, it’s important to measure hematocrit and hemoglobin levels in follow up blood tests at least within three months of starting medication and at regular intervals. Left unchecked, a high red blood cell count can lead to blood clots and a risk of stroke.
- Gynecomastia. Breast tingling or enlarged breasts may occur if some testosterone converts to estrogen. This can be addressed by lowering the dose, switching from a skin delivery system to an injection format, or by taking another drug called an aromatase inhibitor, which can block the conversion.
- Prostate enlargement. Testosterone therapy can spur prostate enlargement, leading to benign prostate hyperplasia. PSA tests should be done at regular intervals to monitor reactions to therapy. Studies have been unable to confirm a link between prostate cancer and testosterone therapy.
- Serious health risks for children and women. AndroGel and Testim gel have carried FDA-mandated black-box warnings since 2009 in response to reports of worrying adverse effects in children who were exposed to the products. Children who have contact with the products can show early signs and symptoms of puberty, including an enlarged penis or clitoris; early development of pubic hair; increased erections or sex drive; and aggressive behavior. For women, testosterone contact may produce changes in body hair and a large increase in acne, and can seriously harm an unborn or breast-feeding baby. The medication guide contains specific instructions for application and what to do if accidental contact occurs. Switching to another drug format can reduce these risks.
The Facts Behind the Frenzy About Cardiovascular Risks
The FDA announcement was based on two recent studies, which were both observational, retrospective studies that compared historical data for prescriptions filled with historical data about adverse cardiovascular events. Neither study measured testosterone levels to confirm that the men actually took the drug, or if their testosterone levels changed, during the time period tracked. Neither study was a prospective, randomized, controlled trial, so no causal link can be concluded from the findings.
Dr. Morgentaler, the original men’s health expert who coined the term ‘low T’ long before it was co-opted by drug companies, says, “The overall increased reported risk in both studies is very small. People have looked at cardiovascular risks with testosterone in over 200 studies over 20 years. This is not a brand-new field. Nor did these studies provide some fantastical new and powerful way of looking at this topic. For that reason I’m surprised and somewhat dismayed at some of the comments that have been made about this. I think that the reason that these two relatively weak, highly statistical retrospective studies have generated so much media attention is because they tap into the hormonophobia that we last saw around women and hormones.”
- PLOS ONE: Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. Finkle WD, et al., January 29, 2014, DOI: 10.1371/journal.pone.0085805.
- JAMA: Association of Testosterone Therapy with Mortality, Myocardial Infarction, and Stroke in Men with Low Testosterone Levels. Vigen, R. et al. November 6 2013, correction January 15, 2014; 310(17):1829-1836. doi:10.1001/jama.2013.280386.
Both studies have serious drawbacks in how they were designed and how conclusions were drawn. Neither study provides the quality of evidence that we should expect to inform medical decisions. A further issue is that the JAMA paper was corrected since original publication, so many mainstream media outlets ran with stories based on incorrect original language that presented figures as absolute rates of occurrence. Refer to our blog post, The Low T Story: Hunting for the Truth, to read in depth about the drawbacks of each study and how it can be difficult to draw fair conclusions from retrospective, observational studies, especially when they rely on high-level statistical calculations.
On the bright side, there may be more reliable information soon. The National Institute of Aging and collaborating partners are currently conducting The Testosterone Trial in Older Men, a randomized, placebo-controlled prospective trial among 800 older men with low T levels. Researchers at 12 sites across the U.S. are studying whether testosterone treatment (AndroGel) results in favorable changes in physical function, sexual function, vitality, cognition and anemia as well as cardiovascular risk factors and bone mineral density. The study began in November 2009 and completion is expected by July 2015. As a randomized controlled trial among men using testosterone therapy who will have blood work and other health variables tracked as the study progresses, this approach promises to deliver the quality of evidence needed to make informed medical decisions.
In the meantime, The Endocrine Society is advising doctors to discuss potential risks of adverse cardiovascular events with patients and to continue monitoring patients carefully. Patients who have been using testosterone therapy should not stop their medication without consulting their health-care provider. Side effects from prescription testosterone products should continue to be reported to the FDA MedWatch program.
- Testosterone for Life: Recharge Your Vitality, Sex Drive, Muscle Mass & Overall Health by Abraham Morgentaler, MD, associate clinical professor of urology, Beth Israel Deaconess Medical Center, Harvard Medical School and director of Men’s Health Boston.
- Keep It Up: The Power of Precision Medicine to Conquer Low T and Revitalize Your Life By Florence Comite, MD, endocrinologist practicing precision medicine at ComiteMD in New York City.
- Testosterone Therapy for Men – Medline Plus
- Testosterone Topical Gel – Medline Plus
- Testosterone Buccal System – Medline Plus