Molecular profiling of the human testis reveals stringent pathway-specific regulation of RNA expression following gonadotropin suppression and progestogen treatment.
Gonadotropin withdrawal induces changes in gene expression in all 3 major cell types of the testis. Knowledge of the genes affected, in both the presence and absence of additional progestogen, will give insight into the regulation of human testicular function and aid development of novel contraceptive methods. We have undertaken a whole-genome analysis of RNA expression in testicular biopsies from normal men and after 4 weeks of gonadotropin suppression induced by gonadotropin-releasing hormone antagonist plus testosterone administration sufficient to cause marked suppression of spermatogenesis. Microarray analysis shows that interindividual variability is markedly low, and the response to treatment is focused on a small subset of genes particularly related to pathways in steroidogenesis and cholesterol biosynthesis or metabolism, the Leydig cell gene INSL3, and genes involved in early meiosis or Sertoli-germ cell junctions. These changes in expression were confirmed by quantitative reverse transcriptase polymerase chain reaction. No major changes in gene expression were identified in men additionally treated with a progestogen, although FLJ35767, an expressed sequence tag that is expressed in the germ cell compartment, did show a small but significant additional effect of progestogen. Overall, the results of this investigation disclose a remarkably stringent regulation of testicular gene expression, revealing the genes most sensitive to gonadotropin withdrawal, and might reflect the most labile pathways in the regulation of testicular function.
Bayne
Rosemary A L
RA
MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. r.bayne@hrsu.mrc.ac.uk
Forster
Thorsten
T
Burgess
Stewart T G
ST
Craigon
Marie
M
Walton
Melanie J
MJ
Baird
David T
DT
Ghazal
Peter
P
Anderson
Richard A
RA
D000328:Adult; D016000:Cluster Analysis; D017135:Desogestrel / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000627:therapeutic use; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011372:Progestins / Q000627:therapeutic use*; D012313:RNA; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa; D013737:Testis / Q000187:drug effects / Q000502:physiology*; D013739:Testosterone / Q000031:analogs & derivatives / Q000627:therapeutic use
D006727:Hormone Antagonists; D011372:Progestins; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D012313:RNA; C004648:testosterone enanthate; D017135:Desogestrel; C062876:cetrorelix