title: Crowding and Follicular Fate: Spatial Determinants of Follicular Reserve and Activation of Follicular Growth in the Mammalian Ovary.
abstract: Initiation of growth of resting ovarian follicles is a key phenomenon for providing an adequate number of mature oocytes in each ovulation, while preventing premature exhaustion of primordial follicle reserve during the reproductive lifespan. Resting follicle dynamics strongly suggest that primordial follicles are under constant inhibitory influences, by mechanisms and factors whose nature remains ill defined. In this work, we aimed to assess the influence of spatial determinants, with special attention to clustering patterns and crowding, on the fate of early follicles in the adult mouse and human ovary. To this end, detailed histological and morphometric analyses, targeting resting and early growing follicles, were conducted in ovaries from mice, either wild type (WT) or genetically modified to lack kisspeptin receptor expression (Kiss1r KO), and healthy adult women. Kiss1r KO mice were studied as model of persistent hypogonadotropism and anovulation. Different qualitative and quantitative indices of the patterns of spatial distribution of resting and early growing follicles in the mouse and human ovary, including the Morisita's index of clustering, were obtained. Our results show that resting primordial follicles display a clear-cut clustered pattern of spatial distribution in adult mouse and human ovaries, and that resting follicle aggrupation is inversely correlated with the proportion of follicles initiating growth and entering into the growing pool. As a whole, our data suggest that resting follicle crowding, defined by changes in density and clustered pattern of distribution, is a major determinant of follicular activation and the fate of ovarian reserve. Uneven follicle crowding would constitute the structural counterpart of the major humoral regulators of early follicular growth, with potential implications in ovarian ageing and pathophysiology.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004, Córdoba, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004, Córdoba, Spain.|Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, 14004, Córdoba, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gaytan
authors.affiliation: Department of Pathology, University of Córdoba, 14004, Córdoba, Spain.
authors.forename: Concepcion
authors.initials: C
authors.lastname: Morales
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004, Córdoba, Spain.|Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, 14004, Córdoba, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Leon
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004, Córdoba, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Garcia-Galiano
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004, Córdoba, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004, Córdoba, Spain.|Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, 14004, Córdoba, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004, Córdoba, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004, Córdoba, Spain.|Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Universitario Reina Sofía, 14004, Córdoba, Spain.|FiDiPro Program, Department of Physiology, University of Turku, Kiinamyllynkatu 10, FIN-20520, Turku, Finland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000858:Anovulation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000254:growth & development*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1
chemical_list: C492248:Kiss1r protein, mouse; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1