title: Corpus luteum as a novel target of weight changes that contribute to impaired female reproductive physiology and function.
abstract: Obesity and malnutrition are associated with decreased fecundity in women. Impaired reproductive capacity in obese women is often attributed to anovulation. However, obese women with ovulatory cycles also have reduced fertility, but the etiology of their impaired reproduction is only partially understood. Accumulating evidence suggests that obesity directly impairs oocyte and embryo quality as well as endometrial receptivity. In obese women, urinary progesterone metabolite excretion is decreased, but in excess of what can be explained by suppressed gonadotropin secretion, suggesting that apart from its central effect obesity may directly affect progesterone (P4) production. These observations have led to the novel hypothesis that obesity directly affects corpus luteum (CL) function. Similarly, we hypothesize that weight loss may contribute to luteal dysfunction. Here, we propose a non-human primate model, the vervet monkey, to examine the effect of weight gain and loss on menstrual cycle parameters and CL gene expression. In this model, weight gain and loss did not significantly alter menstrual cyclicity; however, both induced alterations in the CL transcriptome. In the weight gain monkey, we observed that impaired mid-luteal P4 secretion was associated with downregulation of steroidogenic pathways in CL. Collectively, these preliminary findings support our hypothesis that weight gain and loss may contribute to CL dysfunction. The vervet model described and preliminary observations provide a basis for a larger study to address this important question. Understanding the mechanisms by which weight gain and loss contribute to reproductive dysfunction can assist in the development of targeted treatments to enhance women's reproductive capability when it is desired.
  
  
  BACKGROUND
  CL: corpus luteum; P4: progesterone; E2: estradiol; PDG: pregnanediol 3-glucoronide; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin releasing hormone; BMI: body mass index; qrtPCR: quantitative real-time PCR; PGR: progesterone receptor; ART: assisted reproductive technology; IVF: in vitro fertilization; HPO: hypothalamic-pituitary-ovarian axis; MMPs: matrix metalloproteinases Gene symbols: LH receptor (LHGCR); cholesterol side-chain cleavage enzyme (CYP11A1); 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2); steroidogenic acute regulatory protein (STAR); LDL receptor (LDLR); scavenger receptor B1 (SCARB1); ATP-binding cassette sub-family A member 1 (ABCA1); ATP-binding cassette sub-family G member 1 (ABCG1); apolipoprotein A (APOA1); 24 dehydrocholesterol reductase (DHCR24); 3-hydroxy-3-methylglytaryl-CoA reductase (HMGCR); vascular endothelial growth factor A (VEGFA); vascular endothelial growth factor C (VEGFC); vascular endothelial growth factor receptor 1 (VEGFR1); and TIMP metallopeptidase inhibitor 1 (TIMP1); amphiregulin (AREG); epiregulin (EREG); CCAAT/enhancer binding protein alpha (CEBPBA); cAMP responsive element binding protein 3-like 1 (CREB3L1); ADAM metallopeptidase with thrombospodin type 1 motif 1 (ADAMTS1); matrix metallopeptidase 9 (MMP9); cytochrome b-245 beta polypeptide (CYBB or NOX2); NADH oxidase (NCF2 or NOXA2); Fc fragment of IgG receptor IIb (FCGR2B); Fc fragment of IgG receptor IIb (FCGR2C); ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1); RAB27A member RAS oncofamily (RAB27A); hydroxyprostaglandin dehydrogenase (HPGD); prostaglandin-endoperoxidase synthase 1 (PTGS1); integrin B2 (ITGB2); leukotriene A4 hydrolase (LTA4H); radixin (RDX); ezrin (EZR); nuclear receptor subfamily 5 group A member 2 (NR5A2).
authors.affiliation: a Department of Obstetrics and Gynecology and Women's Health, Montefiore Medical Center , Albert Einstein College of Medicine , Bronx , New York , USA.
authors.forename: Satu
authors.initials: S
authors.lastname: Kuokkanen
authors.affiliation: b Department of Obstetrics and Gynecology , University of Colorado Denver , Aurora , Colorado , USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Polotsky
authors.affiliation: b Department of Obstetrics and Gynecology , University of Colorado Denver , Aurora , Colorado , USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Chosich
authors.affiliation: b Department of Obstetrics and Gynecology , University of Colorado Denver , Aurora , Colorado , USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Bradford
authors.affiliation: c Center of Neurobehavioral Genetics , University of California at Los Angeles , California , USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Jasinska
authors.affiliation: d Department of Medicine , University of Colorado Denver , Aurora , Colorado , USA.
authors.forename: Tzu
authors.initials: T
authors.lastname: Phang
authors.affiliation: b Department of Obstetrics and Gynecology , University of Colorado Denver , Aurora , Colorado , USA.
authors.forename: Nanette
authors.initials: N
authors.lastname: Santoro
authors.affiliation: e Department of Pathology (Comparative Medicine) , Wake Forest School of Medicine , Winston-Salem , North Carolina , USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Appt
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D003338:Corpus Luteum / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D006728:Hormones / Q000097:blood; D007247:Infertility, Female / Q000209:etiology; D008597:Menstrual Cycle; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D011374:Progesterone / Q000378:metabolism; D015430:Weight Gain; D015431:Weight Loss / Q000235:genetics
chemical_list: D006728:Hormones; D011374:Progesterone
keywords: Corpus luteum; gene expression; microarray; obesity; vervet monkey