PMID- 20378682 OWN - NLM STAT- MEDLINE DCOM- 20100630 LR - 20211028 IS - 1945-7170 (Electronic) IS - 0013-7227 (Print) IS - 0013-7227 (Linking) VI - 151 IP - 6 DP - 2010 Jun TI - Insufficient luteinizing hormone-induced intracellular signaling disrupts ovulation in preovulatory follicles lacking estrogen receptor-beta. PG - 2826-34 LID - 10.1210/en.2009-1446 [doi] AB - Gonadotropin-stimulated estrogen receptor-beta (ERbeta)-null preovulatory follicles exhibit submaximal estradiol production, insufficient acquisition of LH receptor, and attenuated expression of essential ovulatory genes. These observations lead to low ovulatory rates compared with wild-type (WT) follicles. We hypothesize that insufficient LH receptor results in reduced cAMP production after an ovulatory stimulus. Individual preantral follicles were cultured with FSH for 4 d and then induced to ovulate with a single dose of human chorionic gonadotropin (hCG). cAMP levels 1 h after hCG were 50% lower in ERbeta-null than WT follicles. To determine whether the lack of LH receptor, and resulting lack of cAMP, could be bypassed by direct activation of adenylyl cyclase, WT and ERbeta-null follicles were induced to ovulate with forskolin. Ten micromolar forskolin doubled the ovulatory rate of ERbeta-null follicles compared with treatment with hCG ( approximately 50 vs. 25%, respectively). In WT follicles, 10 microm forskolin reduced the ovulation rate compared with hCG (14 vs. 83%, respectively), indicating that high doses of forskolin inhibited WT ovulation. A 10 microm concentration of forskolin induced cAMP levels in ERbeta-null follicles that were comparable to levels produced in WT follicles after hCG and either partially or completely rescued the attenuated expression of LH-responsive genes. These data indicate that direct activation of adenylyl cyclase, resulting in increased production of cAMP, partially rescues the ovulatory response of ERbeta-null follicles, suggesting that insufficient LH receptor and low cAMP levels contribute to their poor ovulatory rates. We also determined that ERbeta-null ovaries exhibit an alteration in the activation of ERK1/2. Our evaluation of the ERbeta-null ovarian phenotype indicates that ERbeta plays a role in facilitating folliculogenesis. We show that expression of ERbeta in preovulatory follicles is required for adequate cAMP production and propose that an optimal level of cAMP is required for hCG-stimulated ovulation. FAU - Rodriguez, Karina F AU - Rodriguez KF AD - Director, Environmental Disease Medicine Program, Chief, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, North Carolina 27709, USA. korach@niehs.nih.gov FAU - Couse, John F AU - Couse JF FAU - Jayes, Friederike L AU - Jayes FL FAU - Hamilton, Katherine J AU - Hamilton KJ FAU - Burns, Katherine A AU - Burns KA FAU - Taniguchi, Fuminori AU - Taniguchi F FAU - Korach, Kenneth S AU - Korach KS LA - eng GR - Z01 ES070065/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20100408 PL - United States TA - Endocrinology JT - Endocrinology JID - 0375040 RN - 0 (Chorionic Gonadotropin) RN - 0 (Estrogen Receptor beta) RN - 1F7A44V6OU (Colforsin) RN - 9002-67-9 (Luteinizing Hormone) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) SB - IM MH - Animals MH - Blotting, Western MH - Chorionic Gonadotropin/pharmacology MH - Colforsin/pharmacology MH - Cyclic AMP/metabolism MH - Estrogen Receptor beta/genetics/*physiology MH - Female MH - Gene Expression/drug effects MH - Humans MH - Luteinizing Hormone/*pharmacology MH - Male MH - Mice MH - Mice, Mutant Strains MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Organ Culture Techniques MH - Ovarian Follicle/drug effects/*metabolism MH - Ovulation/*drug effects MH - Phosphorylation/drug effects MH - Signal Transduction/*drug effects PMC - PMC2875826 EDAT- 2010/04/10 06:00 MHDA- 2010/07/01 06:00 PMCR- 2011/06/01 CRDT- 2010/04/10 06:00 PHST- 2010/04/10 06:00 [entrez] PHST- 2010/04/10 06:00 [pubmed] PHST- 2010/07/01 06:00 [medline] PHST- 2011/06/01 00:00 [pmc-release] AID - en.2009-1446 [pii] AID - 5380 [pii] AID - 10.1210/en.2009-1446 [doi] PST - ppublish SO - Endocrinology. 2010 Jun;151(6):2826-34. doi: 10.1210/en.2009-1446. Epub 2010 Apr 8.