Testosterone InjectionsTestosterone compounds have been available for almost 70 years, but the pharmaceutical formulations have been less than ideal. Traditionally, injectable testosterone esters have been testosterone therapy injection frequency for treatment, but they generate supranormal testosterone levels shortly after the 2- to 3-weekly injection interval and then testosterone levels decline very testosterone therapy injection frequency, becoming subnormal in the days before the next injection. The rapid fluctuations in plasma testosterone are subjectively experienced as disagreeable. Testosterone undecanoate is a new injectable testosterone preparation with a considerably better pharmacokinetic profile. Moobs cycling 2 initial injections with a 6-week interval, the following intervals between two injections are almost always weeks, amounting eventually to a total of 4 injections per year. Plasma testosterone levels with this preparation are nearly always in the range of normal men, so are its metabolic products estradiol and dihydrotestosterone.
The Complete Guide to T Replacement | T Nation
Testosterone compounds have been available for almost 70 years, but the pharmaceutical formulations have been less than ideal. Traditionally, injectable testosterone esters have been used for treatment, but they generate supranormal testosterone levels shortly after the 2- to 3-weekly injection interval and then testosterone levels decline very rapidly, becoming subnormal in the days before the next injection. The rapid fluctuations in plasma testosterone are subjectively experienced as disagreeable.
Testosterone undecanoate is a new injectable testosterone preparation with a considerably better pharmacokinetic profile. After 2 initial injections with a 6-week interval, the following intervals between two injections are almost always weeks, amounting eventually to a total of 4 injections per year.
Plasma testosterone levels with this preparation are nearly always in the range of normal men, so are its metabolic products estradiol and dihydrotestosterone. It reverses the effects of hypogonadism on bone and muscle and metabolic parameters and on sexual functions.
Its safety profile is excellent due to the continuous normalcy of plasma testosterone levels. No polycythemia has been observed, and no adverse effects on lipid profiles. Prostate safety parameters are well within reference limits. There was no impairment of uroflow. Testosterone undecanoate is a valuable contribution to the treatment options of androgen deficiency.
Soon after its chemical identification more than 70 years ago, the male hormone testosterone T became pharmaceutically available. But it took considerable time before convenient and safe preparations were developed.
Three approaches have been used to make T therapeutically effective: In clinical practice, particularly in the perception of the patient, the route of administration is most relevant, and is used to categorize the preparations described here. Recent reviews of treatment modalities may be recommended Gooren and Bunck ; Nieschlag Free unesterified T is absorbed well from the gut but is effectively metabolized and inactivated in the liver before it reaches the target organs.
Alkylated derivatives of T including methyltestosterone and fluoxymesterone are administered orally or sublingually. They are metabolized by the liver, like natural T, but more slowly, and, like T, interact directly with androgen receptors. Clinical responses are variable and plasma levels cannot be determined accurately, because alkylated androgens are not recognized by most T assays.
Due to its aliphatic chain it travels with lipids in the lymph and reaches the general circulation via the subclavian vein, thus avoiding a first pass through the liver and subsequent metabolism of T Behre et al The dosing is as a rule 80 mg twice daily.
For its adequate absorption from the gastrointestinal tract it is essential that oral TU is taken with a meal that contains dietary fat. Maximum serum levels are reached 2—6 hours after ingestion, and result in fluctuating serum T levels for a review see Behre et al To increase shelf-life the preparation was recently reformulated and the oil in the capsule is now castor oil.
Recent studies show that there is dose proportionality between serum T levels and the dose range of 20—80 mg. Transbuccal administration of T provides a means of oral administration of T.
It is marketed as a biopellet to be pressed on the gum above the incisor tooth; then the buccal film that develops is be put between the lower gum and cheek.
The resorption of T through the oral mucosa avoids intestinal absorption and subsequent hepatic inactivation of T. An informative study is the report of Dobs et al Mean total T values were not different in the T buccal system group C[ave 0—24 ] The effects of buccal T on sexual functioning were comparable with those of parenteral T enanthate Wang et al b.
Serum E 2 remained in the normal range. There were no accumulations of steroid hormones over the 7 day test period Stuenkel et al ; Wang et al Effects on sexual behavior were comparable to those of parenteral administration of mg T enanthate every 20 days.
Testosterone can be delivered to the circulation through the intact skin, both genital and non-genital Gooren and Bunck ; Nieschlag Transdermal administration delivers T at a controlled rate into the systemic circulation avoiding hepatic first pass and reproducing the diurnal rhythm of T secretion, without the peak and through levels observed in long-acting T injections. Scrotal patches were first designed to deliver T through the scrotal skin, where the permeability is 5 times greater than for other skin sites Behre et al Clinical results were satisfactory.
The patch may be irritating and the use is not feasible if the scrotal surface is not adequate. The scrotal patches sometimes fell off the scrotum, leaving the patient undersubstituted. To overcome these limitations, non-scrotal skin patches have been developed. These patches have a reservoir containing T with a permeation-enhancing vehicle and gelling agents Meikle et al Clinical efficacy was as good as with conventional T ester injections.
Though pharmacokinetically and clinically satisfactory, there are adverse effects such as local skin reactions. Fifty percent of men participating in a clinical trial reported transient, mild to moderate erythema at sometime during therapy Meikle et al Testosterone gel is also used for replacement therapy. The pharmacokinetics of T gel have been extensively studied Meikle et al Serum T levels rose 2- to 3-fold 2 hours after application and rose further to 4- to 5-fold after 24 hours.
Thereafter serum T remained steady in the upper range of normal and returned to baseline within 4 days after termination of application of T gel Meikle et al Mean DHT levels followed the same pattern as T and were at or above the normal adult male range. Serum E 2 levels rose and followed the same patterns as T.
Steady state T levels are achieved 48—72 hours after the first application Wang et al The formulation of the T gel allows easy dose adjustments 50—75— mg T gel Wang et al a.
The clinical efficacy of transdermal T gel on various androgen-dependent target organ systems has been well documented. The safety profile showed that prostate-specific antigen levels rose in proportion to the increase of T levels but did not exceed normal values. Skin irritation was noted in 5. Transfer from one person to another was found to be insignificant Rolf et al No increase of serum T was found after intense rubbing of skin with persons whose endogenous T levels had been suppressed Rolf et al But recently, three cases of transfer from fathers to their children have been reported Brachet et al Subdermal pellet implantation was among the earliest effective treatment modalities for clinical use of T and became an established form of androgen replacement by for review Kelleher et al Several reports have outlined its desirable pharmacological properties but its use and merits and its complications such as infection and extrusion have been best documented by the group of Handelsman Kelleher et al Commonly used intramuscular-injectable T esters are T enanthate and cypionate Behre et al ; Gooren and Bunck ; Nieschlag Testosterone enanthate is one of the most widely used intramuscular T esters.
At a dose of — mg the optimal injection interval is 2—3-weeks but peak and through values are clearly above and below the normal range Behre et al Testosterone propionate has a terminal half-life of only 19 hours.
After a single injection of 50 mg the maximum concentration is reached after approximately 14 hours Behre et al On the basis of this profile, injection intervals are only 2—3 days with peak and through values above and below the normal range and therefore not suitable for monotherapy of T deficiency. Alternatively, mg weekly may be given. Other T esters are T cypionate and T cyclohexanocarboxylate. The pharmacokinetics of these T esters are very simlar to those of T enanthate Behre et al Administration of mg every 2-weeks provides an acceptable form of T replacement.
Several commercially available T preparations contain a number of short- and longer-acting T esters aiming to deliver more even serum T levels. Pharmacokinetic studies of these preparations show that this goal is not achieved. The peak values are higher than in single T ester preparations and resulting plasma T levels show even larger fluctuations Behre et al So, most intramuscular presentations of T are not ideal.
With the most commonly used T esters a maximum concentration follows approximately 72 hours after injection. T levels slowly diminish during the following 10—14 days showing an exponential decline of serum T levels, reaching baseline at approximately day 21 Behre et al As a result the T levels before the next injection are low Behre et al ; Gooren and Bunck The normal pattern of circadian rhythm of T is not provided, though it is questionable whether the circadian rhythm has much therapeutic relevance.
The injections are painful Gooren and Bunck The profile of T levels may be accompanied by disturbing fluctuations in sexual function, energy level, and mood Gooren and Bunck ; Nieschlag High post-injection levels of T predispose the patient to acne and polycythemia, and elevated estradiol predisposes to gynecomastia. In some patients, injections may be associated with bleeding or bruising Nieschlag However, these long-acting testosterone preparations have long been the mainstay of T treatment and they are the most cost-effective methods, with administration of to mg every 2—4-weeks.
The mg injection will maintain normal T for approximately 2-weeks while mg doses are required for eugonadal ranges for approximately 3-weeks Behre et al DHT binds to the same receptor as T but its receptor binding is stronger, resulting in a considerable higher biopotency than T itself.
DHT, as opposed to T, cannot be aromatized to estradiol and acts, therefore, as a pure androgen. In certain clinical conditions a pure androgen might have advantages over aromatizable testosterone, such as cases of a microphallus, hypogonadal men with a susceptibility to gynecomastia or constitutionally delayed puberty in boys.
Oestrogens are pivotal in closure of the epiphyses in puberty, and a nonaromatizable androgen might allow some extra gain in height by slowing the closure of the pubertal epiphyses. Oestrogen effects on the prostate might be deleterious Carruba and in this regard DHT might be the preferred androgen for the androgen-deficient aging male. Studies of DHT administration to hypogonadal men show that DHT maintains sex characteristics, increases muscle mass and improves sexual functions without significant increases in prostate size Ly et al ; Wang and Swerdloff In search of a better intramuscular long-acting testosterone preparation for male contraception, the world health organization WHO Special Programme of Research, Development and Research Training in Human Reproduction initiated search activities for identification of suitable fatty acid side chains for esterification of T Crabbe et al It appeared that T esterified with TU showed more favorable long-term kinetics Herz et al ; Behre et al Unfortunately, the injection volume of 8 mL for mg TU caused problems at the injection site.
The active pharmacological principle of TU is testosterone itself. After entering the peripheral circulation, TU molecular weight Therefore, in principle, the toxicology of TU is the same as for other cleavable T fatty acid esters such as T propionate 3 carbon atoms , T enanthate 7 carbon atoms , or T cypionate 8 carbon atoms.