Testosterone that is bound to SHBG is inactive – it cannot enter or activate cellular androgen receptors or bring about any direct effects of testosterone on the body. The SHBG is a molecule that encapsulates the free testosterone by wrapping around it and transporting it to its final destination where it separates and returns the testosterone to its free state. It is only then that the testosterone can interact with the particular target cell to exert its action. The higher the SHBG levels in the body, the lower the free testosterone levels.
Adverse effects of testosterone supplementation may include increased cardiovascular events (including strokes and heart attacks ) and deaths based on three peer-reviewed studies involving men taking testosterone replacement.  In addition, an increase of 30% in deaths and heart attacks in older men has been reported.  Due to an increased incidence of adverse cardiovascular events compared to a placebo group , a Testosterone in Older Men with Mobility Limitations (TOM) trial (a National Institute of Aging randomized trial) was halted early by the Data Safety and Monitoring Committee .  On January 31, 2014, reports of strokes , heart attacks , and deaths in men taking FDA-approved testosterone-replacement led the FDA to announce that it would be investigating the issue.  Later, in September 2014, the FDA announced, as a result of the "potential for adverse cardiovascular outcomes", a review of the appropriateness and safety of Testosterone Replacement Therapy (TRT).    The FDA now requires warnings in the drug labeling of all approved testosterone products regarding deep vein thrombosis and pulmonary embolism .