title: The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders.
abstract: BACKGROUND
  A large number of studies have contributed to understanding the general mechanisms driving ovarian folliculogenesis in humans and show a complex endocrine dialog between the central nervous system, the pituitary and the ovary, integrated by various intraovarian paracrine messages. The role of intraovarian paracrine regulation has acquired more relevance in the recent years owing to the discovery of previously unknown factors, such as the oocyte-derived bone morphogenetic protein (BMP)15.
  
  
  METHODS
  A thorough literature search was carried out in order to summarize what has been reported so far on the role of BMP15, and the BMP15 paralog, growth and differentiation factor 9 (GDF9), in ovarian function and female fertility. Research articles published in English until March 2014 were included.
  
  
  RESULTS
  The biological actions of BMP15 include: (i) the promotion of follicle growth and maturation starting from the primary gonadotrophin-independent phases of folliculogenesis; (ii) the regulation of follicular granulosa cell (GC) sensitivity to FSH action and the determination of ovulation quota; (iii) the prevention of GC apoptosis and (iv) the promotion of oocyte developmental competence. The existence of biologically active heterodimers with GDF9, and/or the synergistic co-operation of BMP15 and GDF9 homodimers are indeed relevant in this context. Experimental disruption of the bmp15 gene in mice resulted in a mild fertility defect limited to females, whereas natural missense mutations in ewes cause variable phenotypes (ranging from hyperprolificacy to complete sterility) depending on a fine gene dosage mechanism also involving GDF9. Strong evidence supports the concept that such a mechanism plays an important role in the regulation of ovulation rate across mammalian and non-mammalian species. Following the discovery of sheep fecundity genes, several research groups have focused on alterations in human BMP15 associated with primary ovarian insufficiency (POI) or polycystic ovary syndrome. Several variants of BMP15 are significantly associated with POI supporting their pathogenic role, but the underlying biological mechanism is still under investigation and of great interest in medicine. BMP15 maps to the Xp locus involved in the determination of the ovarian defect in Turner syndrome and significantly contributes to the determination of ovarian reserve. Pioneering studies in women undergoing controlled ovarian stimulation indicate that BMP15 may represent a marker of ovarian response or oocyte quality.
  
  
  CONCLUSIONS
  BMP15, an oocyte-derived growth and differentiation factor, is a critical regulator of folliculogenesis and GC activities. Variations in BMP15 gene dosage have a relevant influence on ovarian function and can account for several defects of female fertility. The modulation of BMP15 action may have interesting pharmacological perspectives and the analysis of BMP15 may become a useful marker in IVF procedures. Recent outcomes indicate that the close interactions of BMP15/GDF9 have a critical biological impact that should be taken into account in future studies.
authors: Department of Clinical Sciences & Community Health, University of Milan, 20100 Milan, Italy Laboratory of Endocrine & Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149 Milan, Italy luca.persani@unimi.it.
authors: Luca
authors: L
authors: Persani
authors: Department of Clinical Sciences & Community Health, University of Milan, 20100 Milan, Italy.
authors: Raffaella
authors: R
authors: Rossetti
authors: Institute of Genetic and Biomedical Research - UOS of Milan, National Research Council (CNR) and Istituto Clinico Humanitas, Via Manzoni 59, Rozzano, 20089 Milan, Italy.
authors: Elisa
authors: E
authors: Di Pasquale
authors: Department of Clinical Sciences & Community Health, University of Milan, 20100 Milan, Italy Laboratory of Endocrine & Metabolic Research and Division of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149 Milan, Italy.
authors: Chiara
authors: C
authors: Cacciatore
authors: INRA, Université de Toulouse INPT, UMR1388, Génétique, Physiologie et Systèmes D'Elevage, F-31326 Castanet-Tolosan, France.
authors: Stéphane
authors: S
authors: Fabre
mesh_terms: D000818:Animals; D055430:Bone Morphogenetic Protein 15 / Q000502:physiology*; D005260:Female; D005298:Fertility / Q000502:physiology*; D006107:Granulosa Cells / Q000502:physiology*; D055429:Growth Differentiation Factor 9 / Q000502:physiology*; D006801:Humans; D007247:Infertility, Female / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D023421:Models, Animal; D009865:Oocytes / Q000502:physiology; D006080:Ovarian Follicle / Q000502:physiology; D010053:Ovary / Q000502:physiology*; D010060:Ovulation / Q000502:physiology; D011085:Polycystic Ovary Syndrome / Q000503:physiopathology; D016649:Primary Ovarian Insufficiency / Q000503:physiopathology
chemical_list: D055430:Bone Morphogenetic Protein 15; D055429:Growth Differentiation Factor 9; D036341:Intercellular Signaling Peptides and Proteins
keywords: bone morphogenetic protein 15; female infertility; growth and differentiation factor 9; polycystic ovary syndrome; primary ovarian insufficiency