Antiandrogens and estrogens
Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block the androgenic and anabolic effects of testosterone. Estrogens can reduce the effects of testosterone by increasing the hepatic production and in turn circulating levels of sex hormone-binding globulin (SHBG), a carrier protein that binds to and occupies androgens like testosterone and DHT, and thereby reducing free concentrations of these androgens. Pharmacology
Pharmacodynamics
Testosterone is a high affinity ligand for and agonist of the nuclear androgen receptor (AR). In addition, testosterone binds to and activates membrane androgen receptors (mARs) such as GPRC6A and ZIP9. Testosterone is also potentiated via transformation by 5α-reductase into the more potent androgen DHT in so-called androgenic tissues such as the prostate gland, seminal vesicles, skin, and hair follicles. In contrast to the case of testosterone, such potentiation occurs to a reduced extent or not at all with most synthetic AAS (as well as with DHT), and this is primarily responsible for the dissociation of anabolic and androgenic effects with these agents. In addition to DHT, testosterone is converted at a rate of approximately 0.3% into the estrogen estradiol via aromatase. This occurs in many tissues, especially adipose tissue, the liver, and the brain, but primarily in adipose tissue. Testosterone, after conversion into DHT, is also metabolized into 3α-androstanediol, a neurosteroid and potent positive allosteric modulator of the GABAA receptor, and 3β-androstanediol, a potent and preferential agonist of the ERβ.
A postmarketing analysis by the manufacturer of Aveed (testosterone undeconate injection) found that POME occurred at a rate of less than 1% per injection per year for Aveed. Long-term adverse effects
Cardiovascular disease
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.Up to the year 2010, studies had not shown any effect on the risk of death, prostate cancer or cardiovascular disease; more recent studies, however, do raise concerns. A 2013 study, published in the Journal of the American Medical Association, reported "the use of testosterone therapy was significantly associated with increased risk of adverse outcomes."