The i.m. administration of testosterone esters, such as testosterone enanthate and testosterone cypionate, is the preferred and most widely used treatment modality for providing testosterone replacement in FtM subjects [3, 12]. Injectable testosterone esters do not undergo first-pass metabolism and thus do not cause hepatotoxicity. Moreover, esterization allows for a sustained release of testosterone from the site of injection to the blood. Consistent with it, i.m. injectable testosterone esters have been recommended due to their lipophilicity, resulting in the storage and gradual release from the oil-based vehicle in which they are administered and limiting the need for frequent injections [13]. Testosterone enanthate and testosterone cypionate are almost interchangeable, apart from the fact that they may be mixed with different oils, so some individuals may tolerate one better than the other. Other i.m. injectable formulations of testosterone esters include a mixture of short- and long-acting testosterone esters and testosterone undecanoate. The testosterone mixture, also known as Sustanon, is an oil-based blend of testosterone propionate, testosterone phenylpropionate, testosterone isocaproate, and testosterone decanoate [14]. On the other hand, testosterone undecanoate is a newly marketed formulation of i.m. injectable testosterone in oil, which allows for only four yearly injections [15]. Nevertheless, each dose of testosterone undecanoate consists of 4 ml which may require multiple simultaneous injections, without considering that it is much more expensive and currently unavailable in the United States. Limitations of i.m. injectable testosterone esters include high peak levels of androgens in the first few days after an injection (except for testosterone undecanoate), which can be ameliorated by reducing the dosing interval while maintaining the same total dose [12]. Moreover, due to the variability in absorption between users, some subjects may experience fluctuations in energy [16]. In the third place, injection site reactions are frequent side effects [16]. In addition to this, due to the viscous nature of the vehicle in which testosterone is delivered and the muscularity of the injection site, a long, large-gauge needle is required to administer the drug, which can be a barrier to someone [12].

Transdermal testosterone is available in either patches or gels, and both reproduce normal testosterone levels better than injectable preparations. Both are absorbed quickly when applied and produce a temporary drug depot in the skin, whereby testosterone diffuses into the circulation, peaking at 4 h and decreasing slowly over the rest of the day. Clinical studies have demonstrated that gels allow for longer-lasting serum testosterone levels as compared to transdermal patches [17]. Notwithstanding these clear advantages, transdermal testosterone preparations are often poorly effective to induce rapid and complete amenorrhea and may translate to a lessened change in physical appearance and virilization [12]. In addition to this, patches cause skin irritation in 2 patients out of 3 [16], while gels put patients at risk of testosterone transmission with skin contact. This is particularly worrisome if the transfer occurs in children, where it may cause penile or clitoral enlargement, premature development, and aggressive behavior [16, 18]. Lastly, all transdermal formulations of testosterone can be quite costly for patients who cannot apply prescription insurance benefits for this elective therapy.

Oral testosterone is occasionally used in Europe while it is not available in the United States due to its risk of hepatotoxicity [16, 19]. The safest oral formulation is testosterone undecanoate, but it is still less effective than intramuscular or transdermal testosterone and much more expensive than testosterone enanthate and testosterone cypionate. Moreover, testosterone undecanoate bioavailability seem to be affected by food and dietary fat content.

Testosterone may also be taken by buccal tablets, which release it as excipients are slowly hydrated in the mouth [16]. These buccal systems release testosterone in a pulsatile manner, which is similar to endogenous testosterone secretion. Peak testosterone levels are reached rapidly, and the steady state is achieved by the second dose. The advantages of this route of administration include avoidance of first-pass hepatic metabolism and patient compliance, since it is well tolerated. On the other hand, though, transient mouth and gum reactions, as well as a bitter taste or other forms of dysgeusia, are the chief complaints. At the moment, its use in FtM transsexuals is limited.

Implants of crystalline testosterone can be inserted into the subcutaneous tissue to maintain adequate serum testosterone levels for up to 6 months [16]. The chief adverse events with testosterone pellets include pellet extrusion, minor bleeding, and infection, which are not frequent and may also result in pellet extrusion.

Progestins may be used with testosterone if menses do not cease [20]. At the beginning of FtM cross-sex hormone therapy, medroxyprogesterone can be given by i.m. injection at a dose of 150 mg every 3 months in addition to testosterone, and it is usually discontinued once the patient has had 3–6 months of testosterone therapy [12]. Progestins may be also indicated in order to avoid endometrial hyperplasia in those rare patients who take testosterone for more than 3 years and are not willing to undergo hysterectomy [6].