title: A Potential Role for Endoplasmic Reticulum Stress in Progesterone Deficiency in Obese Women.
abstract: Obesity in reproductive-aged women is associated with a shorter luteal phase and lower progesterone levels. Lipid accumulation in follicles of obese women compromises endoplasmic reticulum (ER) function, activating ER stress in granulosa cells. We hypothesized that ER stress activation in granulosa-lutein cells (GLCs) would modulate progesterone production and contribute to obesity-associated progesterone deficiency. Pretreatment with an ER stress inducer, tunicamycin or thapsigargin, inhibited human chorionic gonadotropin (hCG)-stimulated progesterone production in cultured human GLCs. Pretreatment of human GLCs with tunicamycin inhibited hCG-stimulated expression of steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) messenger RNAs (mRNAs) without affecting expression of cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), as determined by real-time quantitative polymerase chain reaction. Pretreatment with tunicamycin also inhibited hCG-stimulated expression of StAR protein and 3β-HSD enzyme activity in cultured human GLCs, as determined by Western blot analysis and an enzyme immunoassay, respectively, but did not affect hCG-induced intracellular 3',5'-cyclic adenosine monophosphate accumulation. Furthermore, tunicamycin attenuated hCG-induced protein kinase A and extracellular signal-regulated kinase activation, as determined by Western blot analysis. In vivo administration of tunicamycin to pregnant mare serum gonadotropin-treated immature mice prior to hCG treatment inhibited the hCG-stimulated increase in serum progesterone levels and hCG-induced expression of StAR and 3β-HSD mRNA in the ovary without affecting serum estradiol levels or the number of corpora lutea. Our findings indicate that ER stress in the follicles of obese women contributes to progesterone deficiency by inhibiting hCG-induced progesterone production in granulosa cells.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hirota
authors.affiliation: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Dalian Medical University, Liaoning, 116044, People's Republic of China; and.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Jerilee M K
authors.initials: JM
authors.lastname: Azhary
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshino
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Gentaro
authors.initials: G
authors.lastname: Izumi
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hirata
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Koga
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis; D006107:Granulosa Cells / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011374:Progesterone / Q000172:deficiency* / Q000378:metabolism; D011974:Receptors, LH / Q000378:metabolism; D019284:Thapsigargin; D014415:Tunicamycin; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D006063:Chorionic Gonadotropin; D012739:Gonadal Steroid Hormones; D010750:Phosphoproteins; D011974:Receptors, LH; D000098682:Steroidogenic Acute Regulatory Protein; D014415:Tunicamycin; D011374:Progesterone; D019284:Thapsigargin; D015096:3-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D002786:Cholesterol Side-Chain Cleavage Enzyme