title: Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.
abstract: Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR(-/-)) mice, the basic principle of the T-based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR(-/-) mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, and.
authors.forename: Olayiwola O
authors.initials: OO
authors.lastname: Oduwole
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, and Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland;
authors.forename: Natalia
authors.initials: N
authors.lastname: Vydra
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, and.
authors.forename: Nicholas E M
authors.initials: NE
authors.lastname: Wood
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, and Biochemistry Laboratory, Department of Zoology, School of Life Sciences, Ravenshaw University, Cuttack, India;
authors.forename: Luna
authors.initials: L
authors.lastname: Samanta
authors.affiliation: Biochemistry Department, University Hospital of South Manchester, Manchester, UK; and.
authors.forename: Laura
authors.initials: L
authors.lastname: Owen
authors.affiliation: Biochemistry Department, University Hospital of South Manchester, Manchester, UK; and.
authors.forename: Brian
authors.initials: B
authors.lastname: Keevil
authors.affiliation: Department of Clinical Biochemistry, Imperial College Healthcare National Health Service Trust, Charing Cross Hospital, London, UK.
authors.forename: Mandy
authors.initials: M
authors.lastname: Donaldson
authors.affiliation: Department of Histopathology, Imperial College Healthcare National Health Service Trust, Imperial College London, Hammersmith Campus, London, UK;
authors.forename: Kikkeri
authors.initials: K
authors.lastname: Naresh
authors.affiliation: Institute of Reproductive and Developmental Biology, Department of Surgery and Cancer, and ilpo.huhtaniemi@imperial.ac.uk.
authors.forename: Ilpo T
authors.initials: IT
authors.lastname: Huhtaniemi
mesh_terms: D000818:Animals; D053713:Azoospermia / Q000139:chemically induced; D003267:Contraception / Q000379:methods*; D006062:Gonadotropins / Q000037:antagonists & inhibitors / Q000097:blood; D007986:Luteinizing Hormone / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011974:Receptors, LH / Q000235:genetics; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects*; D013737:Testis / Q000187:drug effects; D013739:Testosterone / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D006062:Gonadotropins; D011974:Receptors, LH; D013739:Testosterone; D007986:Luteinizing Hormone
keywords: azoospermia; hypothalamic-pituitary-testicular axis; oligozoospermia