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Low Testosterone Linked to CVD; Individualized Treatment Needed
New Orleans, LA—Men with low levels of testosterone and erectile dysfunction (ED) are at higher risk for cardiovascular disease (CVD) and metabolic syndrome (MetS)—making risk stratification an important tool when treating these patients. Androgen deficiency and cardiometabolic risk were recently discussed at CRS. The session was led by Joel J. Heidelbaugh, MD, FAAFP, FACG, clinical professor, Department of Family Medicine and Urology, University of Michigan Medical School, who discussed the relationship between androgen deficiency and MetS, screening recommendations, current treatment guidelines, and ways to improve the patient and practitioner interaction.
The use of testosterone in men has made recent headlines and after several studies have found that prescribing testosterone to men with low levels of the hormone could increase these men’s risk of cardiovascular (CV) events, the FDA has urged that restrictions are placed on its use.
Dr Heidelbaugh mentioned the result has been a controversy in family medicine about whether or not to screen for testosterone deficiency (TD) in men. The advantages of screening are that testosterone declines in men as they age, TD is a real syndrome with real symptoms, there have been major flaws in the studies linking testosterone use to increased CV risks, and testosterone replacement therapy has demonstrated a proven benefit in cardiometabolic syndrome.
The disadvantages of screening, however, are that aging adults are a profitable market and are often susceptible to messages promising the recapture of one’s youth. In addition, pharmaceutical companies use nonspecific symptoms to foster disease states and there has been no consistent relationship found between testosterone levels and symptoms associated with low testosterone.
Studies have found that hypogonadism seems to increase with age. It has also been found, Dr Heidelbaugh said, to adversely affect metabolic and CV risk factors. Insulin resistance and endothelial function are also adversely impacted. “Hypogonadism” is defined as a low serum testosterone level along with specific signs and symptoms. There are several levels of classification, including primary, secondary, or mixed, and each have separate causes. For instance, primary hypogonadism has testicular causes, while secondary forms can have hypothalamic or pituitary causes.
Patients with hypogonadism may see age-related changes in physiologic function such as increased body mass index, low bone mineral density, reduced cognition and memory, depressed mood, decreased sexual desire, or reduced energy.
But, according to Dr Heidelbaugh, identifying and diagnosing patients who have TD is not always easy. The symptoms of the deficiency can be nonspecific or vague such as aging or depression. There has also been industry disagreement about what constitutes a normal or low testosterone level, with no clearly defined lower limit of testosterone.
There have been some efforts to provide direction when it comes to the treatment of these individuals. The Endocrine Society released guidelines in 2010 to help physicians navigate the treatment of testicular hypogonadism, which included recommendations about what to exclude before adding medical therapy and suggested drugs.
Testosterone replacement formulations are currently available in injectable, topical, buccal, or implant formulations, however, these drugs are also associated with adverse effects. For instance, the injectable testosterone cypionate/enanthate can cause mood fluctuations, pain at the injection site, or erythrocytosis, while the topical gel and solution can cause skin-to-skin transference. Implants can cause infections or expulsion.
Aside from drug-specific adverse events, testosterone replacement therapy can also cause other risks. These risks can range from oily skin and breast enlargement to liver func- tion abnormalities or COPD.
Men who are receiving testosterone replacement therapy should be well-monitored. In addition to watching for any drug specific adverse events at visits, Dr. Heidelbaugh also suggested checking hematocrit and hemoglobin levels at 3 months and then checking the levels again each year. Digital rectal scans should be done at the 3 to 6 month mark along with checking the prostate specific antigen, he said. These tests should be repeated as outlined in screening guidelines. Finally, bone mineral density should be taken at baseline and every subsequent 2 years.
The presentation also discussed the relationship between TD and MetS.
Research has shown there is a bidirectional association between them, with 1 study finding that of 803 patients who had sexual dysfunction, 29.4% of them had MetS. Previous cross-sectional studies have also found a direct correlation between serum testosterone and an increased risk of developing diabetes mellitus. Some observational studies have found patients with low testosterone are at an increased risk for CVD mortality.
However, other research has shown that testosterone replacement can put patients at risk for developing other serious conditions. For instance, 1 study using a placebo and testosterone gel was discontinued because the testosterone group had an increased number of CV events. Another study found an increased risk of non-fatal myocardial infarction (MI) after testosterone therapy.
These studies, according to Dr Heidelbaugh, are not without their flaws. He said the research that points to an association between testosterone therapy and mortality, MI and stroke cannot be generalizable to the whole male population because all men investigated went to cardiac catheterization. In addition, he stated there was no standardized method of assigning statistical weights and believes the study was biased toward men with coronary artery disease.
With conflicting messages, it can be difficult for physicians to decide how to treat men with TD. The Princeton III Consensus guidelines provide some in- formation about the management of CVD risk in men with ED. The ASCVD (Atherosclerotic Cardiovascular Disease) Risk Assessment can also serve as a tool to help assess a patient’s CVD risk.
Overall, Dr Heidelbaugh stressed it is important to develop individualized strategies for how to treat men with low testosterone and ED based on the individual’s CVD risk factors. He recommended that physicians discuss realistic goals of treatment with their patients and assess CVD risk overtime.
The debate about testosterone replacement therapy continues to wage and Dr Heidelbaugh believes there are still necessary actions to help physicians determine the best treatment options. These next steps include a large randomized trial to compare testosterone therapy to placebo to further study its safety implications, along with a registry to help answer questions about overprescribing testosterone and its relation to CVD events.—Jill Sederstrom
