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Insufficient luteinizing hormone-induced intracellular signaling disrupts ovulation in preovulatory follicles lacking estrogen receptor-{beta}.

ABSTRACT: 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.

SUBMITTER: Rodriguez KF

PROVIDER: S-EPMC2875826 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Insufficient luteinizing hormone-induced intracellular signaling disrupts ovulation in preovulatory follicles lacking estrogen receptor-{beta}.

Rodriguez Karina F KF Couse John F JF Jayes Friederike L FL Hamilton Katherine J KJ Burns Katherine A KA Taniguchi Fuminori F Korach Kenneth S KS

Endocrinology 20100408 6

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 ...[more]

PMID: 20378682

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Project description:Objective:To study the best possible luteinizing hormone (LH) threshold to predict ovulation within the 24, 48, and 72?h. Design:Observational study. Setting:Multicenter collaborative study. Patients:A total of 107 women. Interventions:Women collected daily first morning urine for hormonal assessment and underwent serial ovarian ultrasound. This is a secondary analysis of 283 cycles. Main outcome measures:The sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were estimated for varying ranges of LH thresholds. Receiver operating characteristic curves and cost-benefit ratios were used to estimate the best thresholds to predict ovulation. Results:The best scenario to predict ovulation at random was within 24?h after the first single positive test. The false-positive rate was found to increase as (1) the cycle progressed or (2) two or three consecutive tests were used, or (3) ovulation was predicted within 48 or 72?h. Testing earlier in the cycle increases the predictive value of the test. The ideal thresholds to predict ovulation ranged between 25 and 30?mIU/ml with a PPV (50-60%), NPV (98%), LR+ (20-30), and LR- (0.5). At least, one day with LH ?25?mIU/ml followed by three negatives (LH <25) occurred before ovulation in 31% of all cycles. When used throughout the cycle and evaluated together, peak-fertility type mucus with a positive LH test ?25?mIU/ml provides a higher specificity than either mucus or LH testing alone (97-99 vs. 77-95 vs. 91%, respectively). Conclusion:We identified that beginning LH testing earlier in the cycle (day 7) with a threshold of 25-30?mIU/ml may present the best predictive value for ovulation within 24?h. However, prediction by LH testing alone may be affected negatively by several confounding factors so LH testing alone should not be used to define the end of the fertile window. Complementary markers should be further investigated to predict ovulation and identify the fertile window. The use of the peak cervical mucus along with an LH test may provide a higher specificity and predictive value than either of them alone. We recommend that manufacturers disclose their tests' threshold to the public.

Dataset Information

Insufficient luteinizing hormone-induced intracellular signaling disrupts ovulation in preovulatory follicles lacking estrogen receptor-{beta}.

Publications

Insufficient luteinizing hormone-induced intracellular signaling disrupts ovulation in preovulatory follicles lacking estrogen receptor-{beta}.

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