A pharmacokinetic study of injectable testosterone undecanoate in hypogonadal men

Testosterone undecanoate (TU) provides testosterone (T) replacement for hyp ogonadal men when administered orally but requires multiple doses per day a nd produces widely variable serum T levels. We investigated the pharmacokin etics of a newly available TU preparation administered by intramuscular inj ection to hypogonadal men. Eight patients with Klinefelter's syndrome recei ved either 500 mg or 1,000 mg of TU by intramuscular injection; 3 months la ter, the other dose was given to each man (except to one, who did not recei ve the 1,000-mg dose). Serum levels of reproductive hormones were measured at regular intervals before and after the injections. Mean serum T levels i ncreased significantly at the end of the first week, from less than 10 nmol /L to 47.8 +/- 10.1 and 54.2 +/- 4.8 nmol/L for the lower and higher doses, respectively. Thereafter, serum T levels decreased progressively and reach ed the lower-normal limit for adult men by day 50 to 60. Pharmacokinetic an alysis showed a terminal elimination half-life of 18.3 +/- 2.3 and 23.7 +/- 2.7 days and showed a mean residence time of 21.7 +/- 1.1 and 23.0 +/- 0.8 days for the lower and higher doses, respectively. The area under the seru m T concentration-time curve and the T-distribution value related to serum T concentration were significantly higher following the 1,000-mg dose than following the 500-mg dose. The 500-mg dose, when given as the second inject ion, yielded optimal pharmacokinetics (defined as mean peak T values not ex ceeding the normal range and persistence of normal levels for at least 7 we eks), suggesting that repeated injections of 500 mg at 6-8-week intervals m ay provide optimal 7 replacement. The mean serum levels of estradiol were n ormalized following the injections, and prolactin levels were normal throug hout the study. Significant decrease of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels was observed, with the decrease i n LH levels being more pronounced. There were no significant differences in serum LH and FSH levels between the two doses. Sex hormone-binding globuli n (SHBG) revels before any T therapy were near the upper limit of normal fo r adult men and were reduced by approximately 50% just prior to the second dose of TU. The decreased SHBG levels produced by the first TU injection co uld have led to lower peak total T levels and to a more rapid clearance of T following the second TU injection. We conclude that single-dose injection s of TU to hypogonadal men can maintain serum T concentration within the no rmal range for at least 7 weeks without immediately apparent side effects. It is likely that this form of T would require injections only at 6-8-week or longer intervals, not at the 2-week intervals necessary with currently u sed T esters (enanthate and cypionate). This injectable TU preparation may provide improved substitution therapy for male hypogonadism and, in additio n, may be developed as an androgen component of male contraceptives.