Hormonal suppression of spermatogenesis is currently being investigated as a method of reversible male contraception. However, administration of exogenous testosterone (T) induces azoospermia in only 40-70% of Caucasian men, whereas the remainder suppresses to severe oligozoospermia (< 5 x 10(5)/mL). The reason(s) for the heterogeneity in the spermatogenic response is not clear. We have prospectively investigated the possibilities that higher plasma concentrations of T and/or differences in the extent and rate of gonadotropin suppression could maintain a low level of spermatogenesis in subjects taking part in a clinical efficacy trial of hormonal male contraception. Thirty-three healthy adult men, aged 21-41 yr, were given 200 mg T enanthate (TE), im, weekly for up to 18 months. Azoospermia was achieved in 18 men (55%) after 20 weeks of treatment, at which time the remaining 15 (45%) stabilized at a mean sperm density of 2.0 +/- 0.8 (+/- SD) x 10(6)/mL. These 15 subjects remained oligozoospermic for the rest of the efficacy study. To compare the pharmacokinetics and pharmacodynamics of TE between the azoospermic and oligozoospermic responders, plasma samples were obtained immediately before and 1, 2, 4, and 7 days after the 1st and 16th TE injections. Further samples were taken after 2, 4, 8, and 12 weeks of treatment. Plasma concentrations of total, free, and non-sex hormone-binding globulin (non-SHBG)-bound T, estradiol, LH, and FSH were measured. Compared to baseline, preinjection levels of total T increased 2.5-fold, reaching a steady state around 12 weeks of treatment. Peak concentrations of total T increased by 5-fold, but free and non-SHBG-bound T levels were increased by 10-fold after 16 weeks. The plasma levels of estradiol showed similar changes as T. However, neither T (bound or free) nor estradiol was significantly different between azoospermic and oligozoospermic responders. Plasma SHBG was reduced to a similar degree in both groups of men after 16 weeks of TE treatment. Plasma concentrations of both LH and FSH decreased rapidly after the first TE injection; a significant decline in LH was detectable after 24 h. Mean levels of both gonadotropins decreased to less than 0.5 U/L by the end of 4 weeks and to below the limit of sensitivity of the assays (0.05 IU/L) by 12 weeks. There were no significant differences in plasma concentrations of LH or FSH or in the rates of suppression between azoospermic and oligozoospermic responders. We conclude that the polymorphism of spermatogenic suppression in response to exogenous T is unlikely to be due to differences in the pharmacokinetics or pharmacodynamics of TE or in the sensitivity of the hypothalamo-pituitary-testicular axis to sex steroid inhibition. Measurements of total plasma T considerably underestimate the increase in bioavailable T during the weekly TE regimen.