title: Autocrine androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men.
abstract: Leydig cell number and function decline as men age, and low testosterone is associated with all "Western" cardio-metabolic disorders. However, whether perturbed androgen action within the adult Leydig cell lineage predisposes individuals to this late-onset degeneration remains unknown. To address this, we generated a novel mouse model in which androgen receptor (AR) is ablated from ∼75% of adult Leydig stem cell/cell progenitors, from fetal life onward (Leydig cell AR knockout mice), permitting interrogation of the specific roles of autocrine Leydig cell AR signaling through comparison to adjacent AR-retaining Leydig cells, testes from littermate controls, and to human testes, including from patients with complete androgen insensitivity syndrome (CAIS). This revealed that autocrine AR signaling is dispensable for the attainment of final Leydig cell number but is essential for Leydig cell maturation and regulation of steroidogenic enzymes in adulthood. Furthermore, these studies reveal that autocrine AR signaling in Leydig cells protects against late-onset degeneration of the seminiferous epithelium in mice and inhibits Leydig cell apoptosis in both adult mice and patients with CAIS, possibly via opposing aberrant estrogen signaling. We conclude that autocrine androgen action within Leydig cells is essential for the lifelong support of spermatogenesis and the development and lifelong health of Leydig cells.
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Laura
authors.initials: L
authors.lastname: O'Hara
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Kerry
authors.initials: K
authors.lastname: McInnes
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Simitsidellis
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Morgan
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Nina
authors.initials: N
authors.lastname: Atanassova
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Slowikowska-Hilczer
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kula
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Szarras-Czapnik
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Laura
authors.initials: L
authors.lastname: Milne
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Rod T
authors.initials: RT
authors.lastname: Mitchell
authors.affiliation: *MRC Centre for Reproductive Health and BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, United Kingdom; Institute of Experimental Morphology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria; Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland; and Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, Poland lee.smith@ed.ac.uk.
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D013734:Androgen-Insensitivity Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019898:Autocrine Communication; D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D007124:Immunoenzyme Techniques; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020011:Protective Agents / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
chemical_list: D000728:Androgens; D020011:Protective Agents; D012333:RNA, Messenger; D011944:Receptors, Androgen
keywords: estrogen; spermatogenesis; steroidogenesis; testis; testosterone