Testosterone Replacement Does Not Degrade — And Sometimes Improves — Arterial Endothelial Function in Men with Hypogonadism

Daniel Shoskes, MD, MSc, FRCS(C)

Testosterone replacement therapy (TRT), which has come under scrutiny recently for a suspected link to cardiovascular disease, improves arterial endothelial function in some men when prescribed for symptomatic hypogonadism, Cleveland Clinic researchers have found.

Data from a study of 20 men treated for at least 3 months with topical TRT or TRT pellets for symptomatic hypogonadism revealed either no change or an improvement in reactive hyperemia index (RHI) and augmentation index (AI), measures of endothelial function and arterial stiffness, compared with pre-therapy, reported Daniel Shoskes, MD, at the American Urological Association’s 2016 annual meeting.

“In response to the early concern that TRT may increase the risk of cardiac events, we undertook a surrogate study that showed that TRT was either neutral or beneficial with respect to cardiac risk in men with hypogonadism,” said Dr. Shoskes of Cleveland Clinic’s Glickman Urological & Kidney Institute. ”This conclusion has been bolstered by recent clinical data showing that TRT can be expected to reduce the risk of subsequent cardiac events.”

A mixed picture for TRT

Men with low levels of testosterone are often at elevated risk of myocardial infarction (MI) and stroke. TRT’s positive or negative influence on cardiac events is a matter of debate. Some retrospective studies suggest that TRT may increase the risk of cardiac events as early as 3 months after initiating therapy, although mechanisms to explain the increased risk are lacking. In contrast, a recent retrospective study demonstrated a decrease in the risk of such events after normalization of testosterone levels using TRT.

In 2015, based on an expert panel’s review of existing research, the Food and Drug Administration required manufacturers of approved prescription testosterone products to change their labeling to clarify the approved uses of these medications, and to add information about a possible increased risk of heart attacks and strokes in patients taking testosterone. The FDA reiterated that physicians should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests.

Assessing TRT’s impact on endothelial function

Against this background, Dr. Shoskes and colleagues undertook their study to assess the impact of TRT on arterial endothelial function in men with symptomatic hypogonadism, defined as a total testosterone level < 350 ng/mL. Twenty-three men were enrolled and treated with either TRT gels or pellets. Endothelial function was chosen as an endpoint because it correlates strongly with cardiovascular risk. “If TRT raises the early risk of cardiovascular events, then arterial endothelial function should deteriorate after therapy normalizes testosterone levels,” said Dr. Shoskes.

At baseline and at least 3 months after starting TRT, the researchers assessed patients’ endothelial function noninvasively using a device attached to the finger that records endothelium-mediated arterial pulsatile volume changes.

Of the 23 patients enrolled, four had a history of diabetes, 10 had hypertension and five had coronary artery disease. Their mean testosterone level at baseline was 196.9 ng/dL (range: 35 to 339 ng/dL). Many of the men had abnormal arterial endothelial function before initiating TRT. The initial mean RHI was 1.67, and was abnormal in 70 percent, and the mean AI was 2.57 percent, and was abnormal in 39 percent.

Twenty patients were compliant with TRT and had their endothelial function retested at 3 to 6 months. No patient subsequently developed a clinical cardiac event during follow-up.

Following therapy, the patients’ mean total testosterone increased from 203 ng/dL to 511 ng/dL (p < 0.0001). Mean RHI improved from 1.70 to 2.14 (p = 0.01). Four patients had numerically lower RHI but within the 10 percent error margin of the test. Mean AI improved from 2.9 percent to -1.75 percent (p = 0.01). No patient’s AI worsened following TRT.

“When you look patient by patient, endothelial function was either unchanged or improved, and arterial stiffness improved in everyone,” said Dr. Shoskes

The findings are “an early indication, which has since been supported by a published clinical trial, that TRT is either neutral or beneficial on heart disease and cardiac events,” he said. “Since the first two high-profile studies suggesting harm with TRT, every bit of evidence that has come out since suggests the opposite.”