title: Interactions between androgens, FSH, anti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary.
abstract: Androgens, FSH, anti-Müllerian hormone (AMH) and estradiol (E2) are essential in human ovarian folliculogenesis. However, the interactions between these four players is not fully understood.
  
  
  
  The purpose of this review is to highlight the chronological sequence of the appearance and function of androgens, FSH, AMH and E2 and to discuss controversies in the relationship between FSH and AMH. A better understanding of this interaction could supplement our current knowledge about the pathophysiology of the polycystic ovary syndrome (PCOS).
  
  
  
  A literature review was performed using the following search terms: androgens, FSH, FSH receptor, anti-Mullerian hormone, AMHRII, estradiol, follicle, ovary, PCOS, aromatase, granulosa cell, oocyte. The time period searched was 1980-2015 and the databases interrogated were PubMed and Web of Science.
  
  
  
  During the pre-antral ('gonadotropin-independent') follicle growth, FSH is already active and promotes follicle growth in synergy with theca cell-derived androgens. Conversely, AMH is inhibitory by counteracting FSH. We challenge the hypothesis that AMH is regulated by androgens and propose rather an indirect effect through an androgen-dependent amplification of FSH action on granulosa cells (GCs) from small growing follicles. This hypothesis implies that FSH stimulates AMH expression. During the antral ('gonadotropin-dependent') follicle growth, E2 production results from FSH-dependent activation of aromatase. Conversely, AMH is inhibitory but the decline of its expression, amplified by E2, allows full expression of aromatase, characteristic of the large antral follicles. We propose a theoretical scheme made up of two triangles that follow each other chronologically. In PCOS, pre-antral follicle growth is excessive (triangle 1) because of intrinsic androgen excess that renders GCs hypersensitive to FSH, with consequently excessive AMH expression. Antral follicle growth and differentiation are disturbed (triangle 2) because of the abnormally persisting inhibition of FSH effects by AMH that blocks aromatase. Beside anovulation, this scenario may also serve to explain the higher receptiveness to gonadotropin therapy and the increased risk of ovarian hyperstimulation syndrome (OHSS) in patients with PCOS.
  
  
  
  Within GCs, the balance between FSH and AMH effects is pivotal in the shift from androgen- to oestrogen-driven follicles. Our two triangles hypothesis, based on updated data from the literature, offers a pedagogic template for the understanding of folliculogenesis in the normal and polycystic ovary. It opens new avenues for the treatment of anovulation due to PCOS.
authors: CHU Lille, Service de Gynécologie Endocrinienne et Médecine de la Reproduction, Hôpital Jeanne de Flandre, F-59037, Lille, France didier.dewailly@chru-lille.fr.|Faculté de Médecine, Université Lille Nord de France, 59000 Lille, France.
authors: Didier
authors: D
authors: Dewailly
authors: CHU Lille, Service de Gynécologie Endocrinienne et Médecine de la Reproduction, Hôpital Jeanne de Flandre, F-59037, Lille, France.
authors: Geoffroy
authors: G
authors: Robin
authors: CHU Lille, Service de Gynécologie Endocrinienne et Médecine de la Reproduction, Hôpital Jeanne de Flandre, F-59037, Lille, France.
authors: Maëliss
authors: M
authors: Peigne
authors: CHU Lille, Service de Gynécologie Endocrinienne et Médecine de la Reproduction, Hôpital Jeanne de Flandre, F-59037, Lille, France.
authors: Christine
authors: C
authors: Decanter
authors: Faculté de Médecine, Université Lille Nord de France, 59000 Lille, France.|CHU Lille, Laboratoire de Biochimie & Hormonologie, Centre de Biologie Pathologie, F-59037 Lille, France.
authors: Pascal
authors: P
authors: Pigny
authors: CHU Lille, Service de Gynécologie Endocrinienne et Médecine de la Reproduction, Hôpital Jeanne de Flandre, F-59037, Lille, France.|Faculté de Médecine, Université Lille Nord de France, 59000 Lille, France.
authors: Sophie
authors: S
authors: Catteau-Jonard
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000858:Anovulation / Q000378:metabolism; D054304:Anti-Mullerian Hormone / Q000378:metabolism*; D001141:Aromatase / Q000378:metabolism; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006107:Granulosa Cells / Q000502:physiology; D006801:Humans; D006080:Ovarian Follicle / Q000254:growth & development / Q000502:physiology*; D016471:Ovarian Hyperstimulation Syndrome / Q000209:etiology; D011085:Polycystic Ovary Syndrome / Q000378:metabolism / Q000503:physiopathology*; D011962:Receptors, FSH / Q000097:blood*; D012307:Risk Factors
chemical_list: D000728:Androgens; D011962:Receptors, FSH; D004958:Estradiol; D054304:Anti-Mullerian Hormone; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: FSH; PCOS; androgens; anti-Müllerian hormone; estradiol; folliculogenesis; granulosa cell