title: Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men.
abstract: Prior studies have demonstrated that combined treatment of testosterone with a progestin induces a more rapid and greater suppression of spermatogenesis than testosterone treatment alone. We hypothesized that the suppressive effects of the combination of testosterone undecanoate (TU) injections plus oral levonorgestrel (LNG) on spermatogenesis may be mediated through a greater perturbation of testicular gene expression than TU alone. To test this hypothesis, we performed open testicular biopsy on 12 different adult healthy subjects: 1) four healthy men as controls; 2) four men 2 wk after TU treatment; and 3) four men 2 wk after TU + LNG administration. RNA isolated from biopsies was used for DNA microarray using the Affymetrix Human Genome U133 Plus 2.0 oligonucleotide microarrays. Gene expression with >or=2-fold changes (P < 0.05) compared with control was analyzed using the National Institutes of Health Database for Annotation, Visualization, and Integrated Discovery 2008 resource. The TU treatment altered the gene expression in 109 transcripts, whereas TU + LNG altered the gene expression in 207 transcripts compared with control. Both TU and TU + LNG administration suppressed gene expression of insulin-like 3; cytochrome P450, family 17, subfamily A1 in Leydig cells; and inhibin alpha in Sertoli cells; they increased proapoptotic transcripts BCL2-like 14, insulin-like growth factor-binding protein 3; and they decreased X-linked inhibitor of apoptosis protein. In comparison with TU treatment alone, TU + LNG treatment upregulated insulin-like 6 and relaxin 1, and downregulated RNA-binding protein transcripts. We conclude that TU + LNG administration induces more changes in testicular gene expression than TU alone. This exploratory study provided a novel and valuable database to study the mechanisms of action of hormonal regulation of spermatogenesis in men and identified testicular-specific molecules that may serve as potential targets for male contraceptive development.
authors.affiliation: Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California 90502, USA.
authors.forename: YanHe
authors.initials: Y
authors.lastname: Lue
authors.forename: Christina
authors.initials: C
authors.lastname: Wang
authors.forename: YuGui
authors.initials: Y
authors.lastname: Cui
authors.forename: XingHai
authors.initials: X
authors.lastname: Wang
authors.forename: JiaHao
authors.initials: J
authors.lastname: Sha
authors.forename: ZuoMin
authors.initials: Z
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
authors.forename: Amiya P Sinha
authors.initials: AP
authors.lastname: Hikim
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Swerdloff
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001706:Biopsy; D003280:Contraceptives, Oral, Synthetic / Q000494:pharmacology*; D006801:Humans; D007265:Inhibins / Q000378:metabolism; D007273:Injections, Intramuscular; D007328:Insulin / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D016912:Levonorgestrel / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects*; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013739:Testosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D003280:Contraceptives, Oral, Synthetic; C515497:IGFBP3 protein, human; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; C084797:Leydig insulin-like protein; D011506:Proteins; C422362:inhibin A; C094377:inhibin-alpha subunit; D013739:Testosterone; D007265:Inhibins; D016912:Levonorgestrel; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; C010792:testosterone undecanoate