title: Elevated end-of-treatment serum INSL3 is associated with failure to completely suppress spermatogenesis in men receiving male hormonal contraception.
abstract: The administration of testosterone plus a progestogen functions as a male contraceptive by inhibiting the release of pituitary gonadotropins. After 3 to 4 months of treatment, most men are azoospermic or severely oligospermic (< or =1 million sperm/mL). However, 10% to 20% of men have persistent sperm production despite profound gonadotropin suppression. Since insulin-like factor 3 (INSL3) has been shown to prevent germ cell apoptosis in mice, we hypothesized that INSL3 might be higher in men with persistent spermatogenesis during treatment with male hormonal contraceptives. In a retrospective analysis, we measured serum INSL3 in 107 men from 3 recent male hormonal contraceptive studies and determined the relationship between suppression of spermatogenesis and serum INSL3. At the end of treatment 63 men (59%) were azoospermic and 44 men (41%) had detectable sperm in their ejaculates. Baseline INSL3 did not predict azoospermia; however, end of treatment serum INSL3 was significantly higher in nonazoospermic men compared with those with azoospermia (median [interquartile range]: 95 [73-127] pg/mL vs 80 [67-101] pg/mL; P = .03). Furthermore, serum INSL3 was positively correlated with sperm concentration (r = .25; P = .009) at the end of treatment and was significantly associated with nonazoospermia by multivariate logistic regression (P = .03). After 6 months of treatment with a hormonal male contraceptive regimen, higher serum INSL3 concentrations were associated with persistent sperm production. INSL3 may play a role in preventing complete suppression of spermatogenesis in some men on hormonal contraceptive regimens. This finding suggests that INSL3 may be a potential target for male contraceptive development.
authors.affiliation: Department of Medicine, University of Washington, 1959 NE Pacific, Seattle, WA 98195, USA. jamory@u.washington.edu
authors.forename: John K
authors.initials: JK
authors.lastname: Amory
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Page
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Anawalt
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Coviello
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Matsumoto
authors.forename: William J
authors.initials: WJ
authors.lastname: Bremner
mesh_terms: D015415:Biomarkers / Q000097:blood; D003272:Contraceptive Agents, Male; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D011506:Proteins; D011863:Radioimmunoassay; D012016:Reference Values; D012189:Retrospective Studies; D013076:Sperm Count; D013091:Spermatogenesis / Q000187:drug effects / Q000502:physiology*; D017211:Treatment Failure
chemical_list: D015415:Biomarkers; D003272:Contraceptive Agents, Male; D007328:Insulin; C084797:Leydig insulin-like protein; D011506:Proteins