Potential of testosterone buciclate for male contraception: endocrine differences between responders and nonresponders.
Suppression of serum LH and FSH, by testosterone (T) alone or in combination with other agents, has proved to be the most promising approach to male contraception. T enanthate, the only androgen preparation tested in male contraceptive efficacy trials so far, must be injected every week due to its short terminal elimination half-life of 4.5 days and leads to supraphysiological T serum levels. A new T ester synthesized under WHO and NIH auspices, testosterone buciclate (TB), showed a favorable pharmacokinetic profile, with a terminal half-life of 29.5 days when tested in hypogonadal men. Here we describe the results of the first clinical trial with TB for male contraception. After two control examinations, normal healthy male volunteers were given a single im injection of 600 mg TB (group I; n = 4) and 1200 mg TB (group II; n = 8) on day 0. Follow-up examinations were performed every 2 weeks up to week 32. In both groups mean serum T levels remained in the normal physiological range throughout the study course. Serum levels of dihydrotestosterone (DHT) showed a dose- and time-dependent increase, with serum levels slightly above the normal range in group II for several weeks and a maximal concentration of 3.8 +/- 0.5 nmol/L (mean +/- SE) in week 6. No suppression of spermatogenesis to oligozoospermia was observed in group I. However, in group II, spermatogenesis was suppressed to azoospermia in three of eight volunteers in week 10 that persisted up to weeks 14, 20, and 22, respectively. In these three men, LH and FSH were suppressed by TB injections to the respective assay detection limits, whereas in the other five subjects, mean serum levels were only decreased to values near the lower normal limit for LH and FSH, respectively. In addition, throughout the study course, a significant difference in serum sex hormone-binding globulin was detected between the responders (mean values, 21.2-26.4 nmol/L) and nonresponders (mean values, 36.2-46.3 nmol/L). Serum levels of LH as well as total and free T at baseline and after TB injection were lower in the responders than in the nonresponders. Both subgroups showed similar increases in serum LH and FSH after GnRH stimulation. In a newly introduced GnRH antagonist suppression test, serum LH and T were decreased to significantly lower levels in the responders. These results indicate a different hormonal equilibrium and probably different susceptibility to feedback regulation of the responders compared to the nonresponders.(ABSTRACT TRUNCATED AT 400 WORDS)
Behre
H M
HM
Institute of Reproductive Medicine of the University (WHO Collaborating Center for Research in Human Reproduction), Münster, Germany.
Baus
S
S
Kliesch
S
S
Keck
C
C
Simoni
M
M
Nieschlag
E
E
D000704:Analysis of Variance; D003272:Contraceptive Agents, Male / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000097:blood*; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood*; D008297:Male; D009845:Oligospermia; D017430:Prostate-Specific Antigen / Q000097:blood; D012661:Semen / Q000737:chemistry / Q000187:drug effects; D012738:Sex Hormone-Binding Globulin / Q000032:analysis; D012725:Sexual Behavior / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000000981:diagnostic imaging / Q000187:drug effects*; D013739:Testosterone / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology; D013997:Time Factors; D014463:Ultrasonography
D003272:Contraceptive Agents, Male; D012738:Sex Hormone-Binding Globulin; D013196:Dihydrotestosterone; C050320:testosterone 4-n-butylcyclohexylcarboxylic acid; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D017430:Prostate-Specific Antigen