To the contrary, the group receiving the 200-mg IM injection achieved supraphysiologic levels during the first week after the injection. This was confirmed by pharmacokinetic studies that assessed the Cmax and tmax of testosterone in the serum, and the average serum total testosterone concentration during the steady state. This results in some of the esterified testosterone entering the lymphatics, thus prolonging the secondary absorption phase. Testosterone ester is also partly hydrolyzed within the interstitium, with free testosterone entering the circulation directly. With administration using either route, the ester exits the depot via diffusion into the interstitium, from where it enters the lymphatics and subsequently reaches the circulation where it undergoes hydrolysis by intracellular esterases. Absorption kinetics are affected by the viscosity of the oily vehicle, concentration of the ester (the higher the concentration in the depot, the higher the driving diffusion force for release), the volume of the product, and the site of the injection (35, 38). Sudden spikes may produce transient euphoria or irritability, while declining levels can bring fatigue, loss of motivation, and diminished libido. Proper timing and open communication between patient and clinician are often what differentiate a successful therapy from a frustrating one. Measuring testosterone at this point provides a reliable indicator of overall hormonal exposure and helps prevent both underdosing and overcorrection. The urologist’s decision often depends on the patient’s comfort with self-injection, travel distance to clinic, financial factors, and personal rhythm of life. This seemingly minor pharmacotechnical factor can shift absorption rate by several days enough to influence symptom stability in sensitive patients. Understanding these kinetic profiles is essential, because the pattern of peaks and troughs directly affects how patients feel between doses. Enanthate, often dissolved in sesame or cottonseed oil, releases slightly faster than cypionate, which is usually compounded in cottonseed or castor oil. Ratio of 5-dihydrotestosterone and estradiol to testosterone (T) by dose and route of administration during treatment with T enanthate Serum total A, testosterone; B, 5-dihydrotestosterone; and C, estradiol concentrations after subcutaneous (SC) or intramuscular (IM) administration of 1000 mg of testosterone undecanoate. In this context, SC administration of testosterone undecanoate could potentially be a safer route, because the SC compartment is less vascularized, thus reducing the chance of introducing the drug directly into the systemic circulation. A, Serum total testosterone concentrations in 63 transgender men on weekly subcutaneous testosterone enanthate or cypionate. IM testosterone therapy was maintained for 3 weeks after enrollment before switching to self-administration of the same dose via the SC route for 8 weeks. Mean serum testosterone concentrations did not change significantly after switching administration routes (Fig. 4B) (24), confirming similar bioavailability after SC administration. A, Mean trough concentrations of testosterone in hypogonadal men on weekly 75 mg subcutaneous (SC) testosterone enanthate (29). Since the blood flow at the site of drug administration influences the pharmacokinetics of the administered drug, SC injections display more stable vascular absorption patterns compared to IM injection. After IM or SC administration of a testosterone ester, absorption occurs first by diffusion from the depot into the interstitium (Fig. 2B). Unmodified testosterone has a half-life of 10 minutes; to overcome this limitation, testosterone is esterified and then dissolved in oil to allow for sustained release into the circulation after injection. Currently, testosterone therapy is indicated for men with unequivocal, organic, or pathologic androgen deficiency to alleviate symptoms and maintain secondary sexual characteristics by raising testosterone into the normal male range (1). The term ester is often used in the language of testosterone replacement therapy. You've come to our clinic after hearing about the benefits of testosterone replacement therapy (TRT), and you'd like to learn more before trying the treatment. Similar to IM injections, periodic monitoring of the patients for risks and benefits should continue as recommended by clinical practice guidelines (1). Patients should be informed that currently, data and experience with SC testosterone therapy both are limited. Once a patient qualifies for testosterone therapy (1, 2), risks and benefits of therapy as well as pros and cons of each formulation should be discussed (see Table 1). 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. Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block the androgenic and anabolic effects of testosterone. However, estradiol exerts negative feedback on the hypothalamic–pituitary–gonadal axis and, for this reason, prevention of its formation can reduce this feedback and disinhibit gonadal production of testosterone, which in turn can increase levels of endogenous testosterone. On the other hand, 5α-reductase inhibitors may prevent or reduce adverse androgenic side effects of testosterone like scalp hair loss, oily skin, acne, and seborrhea. However, these drugs do this via prevention of the conversion of testosterone into its more potent metabolite dihydrotestosterone (DHT), and this results in dramatically reduced circulating levels of DHT (which circulates at much lower relative concentrations). Skin irritation and itching made testosterone patches less than desirable, but effective. The first testosterone patch, Androderm, was approved by the FDA for use in the United States in 1998. The amount of gel applied is significantly less than other brand names while still delivering the allocated strength of testosterone.
