Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid levels in normal men.
BACKGROUND
Combination of a GnRH antagonist (acyline), types I and II, 5alpha-reductase inhibitor (dutasteride) or levonorgestrel (LNG) with testosterone (T) treatment may augment the suppression of spermatogenesis and intratesticular (iT) steroids.


OBJECTIVE
The objective of this study was to assess the effects of combined hormonal contraceptive regimens on germ cell populations and iT steroids.


METHODS
Twenty-nine normal health men enrolled in this prospective, randomized, 14-wk study at the University of Washington.


METHODS
Twenty-two men (n = 5-6/group) received 8 wk of T enanthate (TE; 100 mg, i.m., weekly) combined with 1) 125 microg LNG daily, orally; 2) 125 microg LNG plus 0.5 mg dutasteride daily, orally; 3) 300 microg/kg acyline twice weekly, s.c.; or 4) 125 microg LNG daily, orally, plus 300 microg/kg acyline twice weekly, s.c. Subjects then underwent a vasectomy and testicular biopsy. Control men (n = 7) proceeded directly to surgery.


METHODS
The main outcome measures were germ cells and iT steroids [T, dihydrotestosterone, 3alpha- and beta-androstanediol (Adiol), and estradiol (E2)].


RESULTS
High iT levels of all androgens (6- to 123-fold serum levels) and E2 (407-fold serum levels) were found in control men. iTT (1.9-2.6% control; P < 0.001) and iT3betaAdiol (16-34% control; P < 0.05) levels decreased with all treatments. iT dihydrotestosterone (13-29% control; P < 0.05) and iT3alphaAdiol (44-47% control; P < 0.05) levels decreased with all but the TE plus LNG treatment. iTE2 levels decreased only in the TE plus acyline group (28% control; P = 0.01). Germ cells from type B spermatogonia onward were suppressed, with no differences between groups found. Variable sites of impairment of germ cell progression were evident between men (spermagonial maturation, meiosis 1 entry, and spermiation). Other than a negative correlation between iT3alphaAdiol and haploid germ cell number (P < 0.006), no correlations between germ cell number and gonadotropins, sperm concentration, or iT steroids were found.


CONCLUSIONS
A similar high testicular:serum gradient exists for E2 and T in normal men, and 8 wk of gonadotropin suppression markedly reduces iTT, with 5alpha-reduced androgens and E2 levels decreasing to a much lesser degree. The heterogeneity of the germ cell response, regardless of treatment, gonadotropins or iT steroids, points to the individual sensitivity of sites in germ cell development, which is worthy of additional exploration.
Matthiesson
Kati L
KL
Prince Henry's Institute of Medical Research, Monash University, Monash Medical Center, Clayton, Victoria 3168, Australia. kati.matthiesson@phimr.monash.edu.au
Stanton
Peter G
PG
O'Donnell
Liza
L
Meachem
Sarah J
SJ
Amory
John K
JK
Berger
Richard
R
Bremner
William J
WJ
McLachlan
Robert I
RI
D058891:5-alpha Reductase Inhibitors; D000328:Adult; D000731:Androstanes / Q000097:blood; D001378:Azasteroids / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000097:blood; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000097:blood; D005854:Germ Cells / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D016912:Levonorgestrel / Q000494:pharmacology*; D008297:Male; D045167:Progesterone Congeners / Q000494:pharmacology*; D011446:Prospective Studies; D012708:Sertoli Cells / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects*; D013256:Steroids / Q000378:metabolism*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism*; D013739:Testosterone / Q000097:blood / Q000494:pharmacology*; D014659:Vasectomy
D058891:5-alpha Reductase Inhibitors; D000731:Androstanes; D001378:Azasteroids; D004791:Enzyme Inhibitors; D045167:Progesterone Congeners; D013256:Steroids; D013196:Dihydrotestosterone; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D016912:Levonorgestrel; D000068538:Dutasteride