Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot.
Hormonally induced azoospermia induced by weekly im injections of testosterone enanthate provides effective and reversible male contraception, but more practical regimens are needed. Given our previous findings that six 200-mg pellets implanted subdermally produced more stable, physiological T levels and reduced the delivered T dose by more than 50% while maintaining equally effective suppression of sperm output with fewer metabolic side-effects than weekly 200-mg testosterone enanthate injections, we sought in this study to determine 1) whether further dose-sparing could be achieved by lower testosterone doses while maintaining efficacy and 2) the efficacy of adding a depot progestin to a suboptimally suppressive depot testosterone dose as a model depot progestin/androgen combination male contraceptive. Healthy volunteers were randomized into groups (n = 10) who received either of two lower T doses (two or four 200-mg T pellets) or four 200-mg T pellets plus a single im injection of 300 mg depot medroxyprogesterone acetate (DMPA). Two T pellets (400 mg, 3 mg/day) had a negligible effect on sperm output. Four T pellets (800 mg, 6 mg/day) suppressed sperm output between the second to fourth postimplant months; output returned to normal by the seventh postimplant month, although only 4 of 10 men became azoospermic or severely oligozoospermic (< 3 mol/L/mL). The addition of a depot progestin markedly increased the extent, but not the rate, of sperm output suppression, with 9 of 10 becoming azoospermic and 10 of 10 becoming severely oligozoospermic. There were no serious adverse effects during the study. Plasma total and free testosterone levels remained within the eugonadal range at all times with each treatment. Plasma epitestosterone was suppressed by all 3 regimens, consistent with a dose-dependent inhibition of endogenous Leydig cell steroidogenesis. Plasma LH and FSH measured by a two-site immunoassay were suppressed in a dose-dependent fashion by T and further suppressed by the addition of DMPA. Sex hormone-binding globulin levels were decreased by DMPA, but not by either T dose. Prostate-specific antigen and lipids (total, low or high density lipoprotein cholesterol, and triglycerides) were not significantly changed in any group. Thus, a depot testosterone preparation with zero order release must be delivered at between 6-9 mg/day to provide optimal (but not uniform) efficacy at inducing azoospermia. The addition of a single depot dose of a progestin to a suboptimal testosterone dose (6 mg/day) markedly enhances the extent, but not the rate, of spermatogenic suppression, with negligible biochemical androgenic side-effects. These findings provide a basis for the use of a progestin/androgen combination depot for hormonal male contraception.
Handelsman
D J
DJ
Andrology Unit, Royal Prince Alfred Hospital, New South Wales, Australia. djh@med.su.oz.au
Conway
A J
AJ
Howe
C J
CJ
Turner
L
L
Mackey
M A
MA
D000328:Adult; D003267:Contraception / Q000379:methods; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004357:Drug Synergism; D004845:Epitestosterone / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D008875:Middle Aged; D009845:Oligospermia / Q000139:chemically induced; D045167:Progesterone Congeners / Q000008:administration & dosage*; D013091:Spermatogenesis / Q000187:drug effects*; D013092:Spermatogenesis-Blocking Agents / Q000008:administration & dosage; D013739:Testosterone / Q000008:administration & dosage* / Q000097:blood
D003692:Delayed-Action Preparations; D004343:Drug Implants; D045167:Progesterone Congeners; D013092:Spermatogenesis-Blocking Agents; D013739:Testosterone; D004845:Epitestosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D017258:Medroxyprogesterone Acetate