Updated: Jan 24
The difference between Testosterone Cypionate, Testosterone Propionate Testosterone Enanthate, Sustanon, & Testosterone Ester combinations explained.
The history of Testosterone formulations
The difference between IM Testosterone formulations and Testosterone Gels
Androgel vs Testim Testosterone Gel, which one is better?
Keywords: Testosterone Cypionate, Testosterone Propionate, Testosterone Enanthate, Androgel, Axiron, Testim, Fortesta, Testavan, Jatenzo, Natesto, Testosterone Cream, Nasal Testosterone, Oral Testosterone, Buccal Testosterone, Injectable Testosterone, Esterification, Androgen Ester, Testosterone Ester, Testosterone Undecanoate, 2% Testosterone Gel, Nebido, Aging, Androgens, Testosterone Replacement Therapy, Testosterone, Hormones.
History of Testosterone Formulations
Testosterone is the most important androgenic and anabolic hormone in men. Exogenous testosterone for the treatment of hypogonadism (Low-T) has been used since the 1940’s and testosterone is one of the most researched and studied medications. Furthermore, testosterone is one the oldest medications and has been demonstrated to be safe for clinical use. The aim of testosterone therapy as set forth in 1990 by the FDA, WHO and NIH: “the major goal of testosterone replacement therapy is to replace testosterone levels as close to physiological levels as possible” (World Health Organization 1992).
Since testosterone’s first clinical use, methods have been developed to improve testosterone’s application, bioavailability and dosing regimen through a variety of testosterone formulations. The first testosterone formulation was developed in 1940 as subcutaneous implantable pellets. The pellets maintained a consistent level of testosterone and were long acting. The side effects of the pellets included having to be implanted by a physician, associated procedure pain and possible pellet extrusion. Today, Testopel is the most widely used implantable testosterone pellet.
In the 1950’s intramuscular (IM) testosterone injections entered the market. IM testosterone injections provided patients the ease of at home use, often performed weekly and easy to administer. The undesired effects of IM testosterone injections are the large fluctuations in testosterone levels, injection site discomfort, and elevated risk for erythrocytosis. IM testosterone injections remain the most common formulation used today. In the 1980’s attempts to make testosterone an oral tablet was without success. Oral testosterone tablets while easy to administer caused significant liver toxicity and the tablets had be take almost three times daily. They were removed from the market, until recently with the approval of Jatenzo. Jatenzo is a new and novel oral testosterone tablet that bypasses liver metabolism and maintains consistent testosterone levels.
In 1993 transdermal patches became available and were applied to the scrotum. The scrotal skin provides the highest rate of testosterone absorption, hence the reason for this location of the patch application. The patches were easy to use and apply but caused skin irritation, itching and discomfort and the patch was visible. By the year 2000, topical testosterone gels provided men an easy once a daily application that maintained steady state testosterone levels. The gel is clear and absorbs quickly with rapid onset. Drawbacks of testosterone gels include the possible transference to children or women. In 2014, a new nasal testosterone formulation, Natesto, provided men another option of therapy, yet the medication must be applied several times to each nostril throughout the day and can cause nasal irritation.
There are a variety of testosterone formulations ranging from short and long acting IM injections, patches, gels, cream, pellets and oral tablets. How do these testosterone formulations compare, what is the difference and which one is most suitable for the hypogonadal male? Let’s discuss.
Three approaches that have been used to make testosterone therapeutically effective in clinical use.
1) Provide various routes of administration
2) Chemical modification
3) Esterification in position 17
The most widely used form of testosterone is the intramuscular injection preparation of a testosterone ester. A testosterone ester is a modified version of the natural testosterone a body produces. Natural testosterone is known as unmodified testosterone. Unfortunately, unmodified testosterone cannot be injected on its own. Pure testosterone that the body produces cannot be utilized to increase testosterone levels in patients, it cannot be injected. Unmodified testosterone only has a half-life of 10 minutes. A medication’s half-life is the amount of time for the concentration of a medication to be reduced by the body 50%. On average is takes approximately 4-5 half-lives before a medication is eliminated from the body completely. If unmodified testosterone were to be injected it would be completely eliminated by the body in approximately 40-60 min (4-5 half-lives). A patient would have to inject testosterone almost every hour in order to maintain testosterone levels and this is not economical or practical. As thus, testosterone has been modified by a process called esterification. This process adds an addition side chain to testosterone prolonging its’ activity in the body. The acid used in esterification of testosterone is the name of the formulation used. For instance, Testosterone Enanthate is Testosterone esterified by enanthic acid. Testosterone Propionate is Testosterone esterified by propionic acid. As, thus modifications of testosterone have been performed to improve the testosterone’s half-life and delivery convenience of once a week dosing.
Different acids add different length side chains to testosterone. The length and structure of the side chain added to testosterone determines testosterone's half-life. This explains how testosterone enanthate, testosterone propionate, testosterone cypionate and testosterone undecanoate all have different half-lives.
Once injected into the body, esterified testosterone is slowly absorbed into the tissues before being rapidly converted to unmodified testosterone (i.e. the active form). It should be noted, that the testicles synthesize and secrete unmodified testosterone into circulation, this is termed endogenous testosterone. Modified testosterone, that which is injected, is called exogenous testosterone. Exogenous testosterone is modified by esterification as described earlier. When a patient takes a drug test endogenous versus exogenous testosterone can be determined because only exogenous testosterone is modified.
Testosterone Ester and Plasma Half Life in Days
testosterone propionate 0.8
testosterone enanthate 4.5
testosterone undecanoate 33.9
Testosterone propionate has a very short half-life. After injection testosterone levels in the supraphysiological range are noticed at 14 hours. Testosterone levels are then seen below normal levels after 2 days. Most dosing regiments of this ester are 2-3 times per week. Because short-term kinetics, multi weekly administrations and large fluctuations of testosterone levels, testosterone propionate is not utilized for the testosterone replacement therapy in hypogonadal men.
Testosterone Enanthate has a favorable plasma half-life. After injection supraphysiological levels of testosterone are experienced at 10 hours. Testosterone levels are sustained above normal until day 12. Testosterone Enanthate if often dosed once weekly given the prolonged half-life. After several once a week dosing, a steady state (stable) testosterone level is achieved.
The pharmacokinetics of testosterone cypionate are comparable and similar to that of testosterone enanthate. Testosterone cypionate is the most commonly prescribed form of testosterone in the United States.
Testosterone Ester Combinations
Testosterone ester mixtures such as Testoviron and Sustanon are widely used for the treatment of men with hypogonadism (Low-T). The reason behind their use is provide a short acting testosterone ester for the beginning of the cycle combined with a long acting testosterone acting for the end of the cycle. These combination esters provide a more sustained and often times supraphysiological level of testosterone levels when utilized.
Testosterone Undecanoate is now utilized in the United States under the drug name Nebido (Aveed). Yet, testosterone undecanoate was initial formulated as oral therapy for hypogonadism in the 1970’s. It was not until 1991 that studies dissolving testosterone undecanoate in tea seed oil revealed the medication had a prolonged duration of action compared to other testosterone esters. Studies revealed that after injection of 1000mg of testosterone undecanoate mean serum testosterone levels could stay consistently above normal levels for 9 weeks. Testosterone undecanoate has since been reformulated and dissolved in castor oil and given its long duration of action, extended 10-week injection interval and achievement of steady state testosterone levels, this particular formula has become a popular treatment for men with hypogonadism.
Testosterone undecanoate does require a loading does protocol of one injection to start. An addition IM injection at 4 weeks and then one IM injection every 10 weeks to maintain steady state testosterone levels.
Testosterone Undecanoate (Aveed) currently must be given in a doctor’s office, clinic or hospital. After each injection a patient must wait in the doctors for 30 minutes to be observed for any post injection reaction. (Aveed) is only available through the Aveed Risk Evaluation and Mitigation Strategy (REMS) program.
Oral testosterone therapy was historically considered a non-suitable form of testosterone replacement given the large doses that must be ingested in order to increase testosterone levels. These large doses were toxic to the liver and had unwanted side effects. Several attempts to improve testosterone’s oral bioavailability and prevent liver metabolism have been made.
17Alpha Methyltestosterone was one of the first oral testosterone substitutes but significant increases in liver enzymes and cholestasis prevented it widespread adaptation for use. This particular formulation was also found to induce liver tumors and it is no longer in use. In 1981 the medication was removed from the market.
Fluoxymesterone & Mesterolone are other forms of oral testosterone no longer used today given liver toxicity and weak androgenic potential respectively.
Recently, the FDA approve a new propriety form of testosterone undecanoate called Jatenzo. This new testosterone oral formulation is very unique given it’s the first FDA approved oral testosterone formulation approved in the United States to treat male hypogonadism. Jatenzo, unlike other testosterone formulations, is a prodrug. This means the medication is not activated until it is broken down by the body. Jatenzo is a combination of a testosterone molecule attached to a fatty acid. Jatenzo is absorbed preferentially in the intestinal lymphatic system after oral ingestion. This unique absorption method bypasses exposure and delivery of the medication to the liver, reducing liver toxicity. Jatenzo must be taken with food and is taken no less than twice daily. In clinical trials, in particular the inTUne Trial, reported 87% of men treated with Jatenzo achieved steady state and maintained physiological testosterone levels.
Testosterone Gels & Creams & Patches
Transdermal Testosterone (Androgel, Axiron, Testim, Fortesta)
In 2000 Androgel ™ 1% became the first testosterone gel approved for use in the United States by the FDA. Androgel 1% is a colorless gel that contains 25 or 50mg of testosterone dissolved in 2.5 or 5g of gel. The gel dries in approximately 5 min after applied to the skin. Approximately 9-14% of the testosterone in the gel is available and active. After one hour of application testosterone levels have been shown to rise into the normal range. Androgel expanded its line to include a 1.62% testosterone gel strength in April of 2013. The difference between Androgel 1% and 1.62% is the strength of testosterone in each metered dose. Androgel 1% is no longer being manufactured.
Testim was the second testosterone gel to enter the market. Testim is provided in small single use packets as opposed to a pump applicator. A study in 2008 reviewed the efficacy of changing testosterone gel preparations (Androgel or Testim) in hypogonadal men who fail to achieve a biochemical response to the initial gel selection. The study found that total and free serum testosterone levels increased significantly following a switch from Androgel to Testim and not vice versa. Testim has different (more enhanced) pharmacokinetic properties when compared to Androgel. This phenomenon is most likely explained by peak serum concentrations of total testosterone, free testosterone and dihydrotestosterone (DHT) are greater following Testim use then when compared to Androgel even with equivalent dosing. Testim provides a more enhanced absorption profile secondary to pentadecalactone used in the gel compared to Androgel. The most common reason men switch from Androgel to Testim is first scent (46%) followed by poor efficacy (30%). Men switching from Testim to Androgel did so most commonly because of the scent (92%).
Fortesta and Axiron are both 2% topical testosterone gels, higher strength compared to Androgel and Fortesta. Axiron is applied under the arm pit, similar to a deodorant stick, while Fortesta is applied to the inner thighs.
A new 2% testosterone gel called Testavan is very unique. The gel is very transparent and alcohol based. The amount of gel applied is significantly less than other brand names while still delivering the allocated strength of testosterone. In a controlled study, Testavan provided higher bioavailable testosterone and delivering more testosterone in a smaller amount of gel when compared to Androgel.
The first testosterone patch, Androderm, was approved by the FDA for use in the United States in 1998. The patch is applied directly to the scrotum. Scrotal skin shows the highest absorption rate of a steroid compound compared to other bodily skin, as much as 40-fold higher absorption. In order to apply the patch, the hairs on the scrotum are shaved and clipped and patches are exchanged daily. Skin irritation and itching made testosterone patches less than desirable, but effective.
Intramuscular Testosterone Injections compared to Transdermal Testosterone:
More physiological testosterone level achieved
Flexibility in Dosing
Risk of secondary transference.
Less frequent administration
Able to achieve supra-physiologic levels of Testosterone
Less expensive compared to other formulations
Higher testosterone fluctuations
Injection site reaction/ redness
1) ED Grober et al. Efficacy of changing testosterone gel preparations (Androgel or Testim) among sub optimally responsive hypogonadal men International Journal of Impotence Research (2008) 20, 213–217
2) Katherine A. Lyseng-Williamson, Testosterone 2% gel (Testavan®, Testarzon®) in adult male hypogonadism: a profile of its use, Drugs & Therapy Perspectives, 10.1007/s40267-019-00627-7, (2019).
3) Nieschlag et al. Testosterone Action, Deficiency, Substitution. Fourth Edition, Cambridge Medicine. 2012. 309- 330.