Beta cell adaptation to pregnancy requires prolactin action on both beta and non-beta cells.

Pancreatic islets adapt to insulin resistance of pregnancy by up regulating ß-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr+/-), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects ß-cell development, to understand ß-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from ß-cells. Here, we found that ß-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed ß-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr+/-) versus ß-cell-specific Prlr reduction (ßPrlR+/-), we found 95 differentially expressed gene, most of them down regulated in the Prlr+/- mice in comparison to the ßPrlR+/- mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr+/- mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant ßPrlR+/- mice. These observations suggest that down regulation of prolactin action during pregnancy in non-ß-cells secondarily and negatively affect ß-cell gene expression, and increased ß-cell susceptibility to external insults.

Lrrc55 is a novel prosurvival factor in pancreatic islets.

Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating ß-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower ß-cell mass. Prolactin also prevents ß-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in ß-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate ß-cell proliferation/apoptosis (thus ß-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in ß-cells had minimal effect on ß-cell proliferation and glucose-stimulated insulin secretion but protected ß-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects ß-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in ß-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting ß-cell survival.

Excessive ovarian response is associated with increased expression of interleukin-2 in the periimplantation endometrium.

OBJECTIVE: To evaluate and compare in vivo expression of T helper type 1 (Th1) cytokines in the peri-implantation endometrium of infertile patients between natural and stimulated cycles. DESIGN: An observational study. SETTING: A tertiary assisted reproduction center. PATIENT(S): Infertile patients. INTERVENTION(S): Uterine flushings and endometrial biopsies were collected 7 days after LH surge in natural cycles or after hCG injection in stimulated cycles. MAIN OUTCOME MEASURE(S): T helper type 1 cytokines were determined by immunolocalization and by ELISA. RESULT(S): Natural cycles were classified as group A (n = 17), whereas stimulated cycles with peak serum E(2) of 20,000 pmol/L (excessive responders) were classified as group B (n = 32) and group C (n = 32), respectively. Higher serum E(2) concentration was associated with increased expressions of interleukin (IL)-2 in the endometrium and uterine flushing. Group C demonstrated a statistically significantly higher IL-2 expression in endometrial biopsies by glandular and stromal immunostaining and by ELISA, compared with group A and group B. There was no difference in IL-2 concentration between group A and group B. Interferon-gamma protein concentration was comparable for the three groups. CONCLUSION(S): Increased expression of IL-2 in the peri-implantation endometrium may account for the lower implantation rate in excessive responders.

Reduced expression of interleukin-11 and interleukin-6 in the periimplantation endometrium of excessive ovarian responders during in vitro fertilization treatment.

CONTEXT: Impaired implantation in assisted reproduction cycles with high serum estradiol (E2) concentrations may be related to abnormal endometrial functions. OBJECTIVE: The in vivo expression of T helper type 2 (Th2) cytokines in the periimplantation endometrium of infertile patients was compared between natural and stimulated cycles. INTERVENTIONS AND MAIN OUTCOME MEASURES: Uterine flushings and endometrial biopsies were collected 7 d after the LH surge in natural cycles or after human chorionic gonadotropin injection in stimulated cycles. Th2 cytokines were determined by immunolocalization and by ELISA. Natural cycles were in group A, whereas stimulated cycles with peak serum E2 of no more than 20,000 pmol/liter (moderate responders) and more than 20,000 pmol/liter (excessive responders) were classified as group B and group C, respectively. RESULTS: Higher E2 had a negative effect on IL-11 and IL-6 expression in the endometrium and IL-11 concentration in the uterine flushing. In endometrial biopsies, a significantly lower immunostaining of stromal IL-11 (P < 0.001) and glandular IL-6 (P < 0.05) was detected in group C compared with that of groups A and B. IL-11 concentration by ELISA was significantly lower in group C (P < 0.05). Endometrial leukemia inhibitory factor and IL-4 expression was similar in the three groups. In uterine flushings, a significantly higher percentage of women in group C had undetectable IL-11 and a lower IL-11 concentration (P < 0.01) compared with group A, whereas no difference in IL-6 concentration was noted in the three groups. CONCLUSION: Reduced expression of IL-11 and IL-6 in periimplantation endometrium may account for lower implantation in excessive responders.

A randomized comparison of three insemination methods in an artificial insemination program using husbands' semen.

OBJECTIVE: To compare pregnancy rates with single intrauterine insemination (SIUI), double intrauterine insemination (DIUI) and fallopian tube sperm perfusion (FSP). STUDY DESIGN: Ninety patients undergoing a standard ovarian stimulation regimen were randomized to receive SIUI, DIUI or FSP. The end point was either pregnancy or completion of 3 treatment cycles without pregnancy. RESULTS: There were no differences in demographic data or ovarian responses. The total number of motile spermatozoa inseminated in the FSP group was significantly lower than in the SIUI group. No significant differences were found in pregnancy rate per cycle or patient, multiple pregnancy rate and outcome of pregnancy between the 3 groups. CONCLUSION: Similar pregnancy rates were achieved after SIUI, DIUI and FSP during stimulated cycles.

The significance of the ionophore-challenged acrosome reaction in the prediction of successful outcome of controlled ovarian stimulation and intrauterine insemination.

BACKGROUND: This prospective study compared the acrosome reaction following ionophore challenge (ARIC) versus conventional sperm parameters and sperm velocities in predicting successful outcome following ovarian stimulation and intrauterine insemination. METHODS: All patients were offered a maximum of three treatment cycles. Conventional semen analysis was performed and sperm velocities were measured using computer-aided sperm analysis. Acrosome-reacted sperm were stained using chlortetracycline after ionophore challenge. Multiple logistic regression analysis and the receiver-operator characteristic curve analysis were applied to determine the best predictive variables and their cut-off values. RESULTS: ARIC score was the most significant variable in predicting pregnancy, followed by the percentage of induced acrosome-reacted sperm, serum estradiol levels on the day of hCG and sperm morphology by strict criteria. Higher spontaneous acrosome reaction had a negative relationship with pregnancy. ARIC score of 10% had a sensitivity of 85.3% and a specificity of 85.5%. The positive and negative predictive values were 64.2 and 96.6% respectively and the false positive and negative rates were 14.7 and 14.5% respectively. CONCLUSION: ARIC score was a better predictor of pregnancy than conventional sperm parameters and sperm velocities.