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.—O’Hara, L., McInnes, K., Simitsidellis, I., Morgan, S., Atanassova, N., Slowikowska-Hilczer, J., Kula, K., Szarras-Czapnik, M., Milne, L., Mitchell, R. T., Smith, L. B. Autocrine androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men.
Highlights
(continued on page) androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men
The Leydig cell androgen receptor knockout (LCARKO) mouse model with its normal T levels and lack of functioning androgen receptor (AR) is reminiscent of complete androgen insensitivity syndrome (CAIS) in humans, unlike the testicular feminization mouse (Tfm) or androgen receptor knockout (ARKO) mouse, which has low T levels and absent steroidogenesis, and because we have recently identified that adult Leydig cells arise from the same stem cell population in both mice and humans [16], we assayed for apoptosis in testicular biopsies of patients with CAIS at different ages
Because 25% of Leydig cells retain AR, this model provides a unique opportunity to determine the roles of autocrine AR signaling within Leydig cells in vivo because it permits the comparison of adjacent Leydig cells, all exposed to the same endocrine and paracrine environment, with one difference: retention or absence of Leydig cell AR
Summary
(continued on page) androgen action is essential for Leydig cell maturation and function, and protects against late-onset Leydig cell apoptosis in both mice and men. The adult Leydig cells are maintained as a stable, terminally differentiated population with little evidence of cell turnover throughout the majority of adulthood [8]. Men experience both a reduction in Leydig cell number [9, 10] and reduced testosterone (T) production per Leydig cell [11] as they age, but the underlying cause for this is unclear. 0892-6638/15/0029-0894 © FASEB do not express AR [12]; adult Leydig cells acquire AR expression and become responsive to autocrine androgen signaling at their stem/progenitor cell stage (in fetal life) [13]. Recent data from our group support the notion that androgenic programming of adult Leydig stem cell/cell progenitors may have lifelong consequences [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
