The earliest forms of androgens were unmodified metabolites extracted from urine, and finally testosterone itself, injected to provide a short burst of increased androgen exposure that was rapidly cleared. Chemists realized they would need to modify the chemical structure of the androgens to survive metabolic clearance, so they initially alkylated the anabolic-androgenic steroids (AAS) at the C17 position of the molecule. This allowed AAS to be taken orally, and provide a sustained effect for roughly a day. However, it became evident that this form of modification (17alphaalkylation) causes toxic effects to the liver in many. Finally, long-acting injectable versions of AAS were developed that esterified varying length fatty acids, again to the C17 carbon. 1
17beta-esterification is the form of modification that accounts for most injected AAS, including the various testosterone esters: propionate, enanthate, cypionate and undecanoate. Suspended in an oil carrier, these 17beta-esters of testosterone are capable of providing a reasonably steady concentration of testosterone for periods dependent upon the length of the fatty acid ester, up to 12 weeks in the case of testosterone undecanoate. Testosterone esters are injected, typically into muscle (e.g., gluteus, deltoid, vastus lateralis) and are slowly released from the oil globule into the bloodstream. Once the testosterone ester is “floating” in the blood, it is attacked by esterase enzymes that cleave (cut) the ester bond – releasing the fatty acid from the testosterone portion of the molecule. The now-freed testosterone has a short time to work, as it is metabolized just as quickly as if it had never been esterified. The benefit of esterified testosterone is that it continuously releases testosterone at a concentration that can be titrated by adjusting the dose and frequency of the injections.
Safety of Testosterone Esters
Testosterone esters have a decades-long history of use with an admirable safety record when dispensed under the supervision of a qualified physician. 2,3 Even when misused in supraphysiologic manner, testosterone esters are generally well tolerated, though there are clear health risks that escalate considerably with abusively dosed cycles. Further, certain individuals are predisposed to clotting, psychological distress, estrogen excess, liver damage and other side effects. 4,5 This may result in significant harm, even death.
Cynics might believe that there was little clinical demand during the latter part of last century for testosterone replacement therapy (TRT) due to the campaigning of the anti-doping agencies, and absence of any financial incentive for pharmaceutical manufacturers, as patents for the esters were expired. A notable exception was the approval of the testosterone undecanoate Aveed, that has been marketed since 2003 in many other countries under the brand name Nebido. 6 In their place, patentable topical testosterone formulations were formulated. The claimed benefits included a more physiologic release, convenience and safety compared to the injected esters. 7 Though there was long a lack of awareness and acceptance of “testosterone deficiency” as a clinical condition, much of the demand for TRT is the result of direct-to-consumer marketing by pharmaceutical companies selling topically delivered testosterone. In fact, the Endocrine Society openly discourages screening men for testosterone deficiency, impeding physician intervention and patient care.
Little real benefit has been noted in studies comparing injected testosterone esters to topical formulations. 7 Further, the increase in certain adverse events (increased hematocrit, gynecomastia) associated with injected testosterone are offset by distinct adverse effects caused by topical testosterone (local site irritation, transference). 8,9 Even the (highly disputed) studies that claim (after considerable statistical manipulation) that TRT is associated with an increase in cardiovascular risks found no increase based upon the delivery method used. 10,11 In fact, the most damning study used topical testosterone to treat older men with limited mobility, not an injected ester.
Cardiovascular Risk Factors
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