Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A.

Endometrial cancer (EC) is a hormone-dependent cancer that currently represents the most frequent malignancy of the female reproductive tract. The involvement of steroid hormones in its etiology and progression has been reported. The possibility that even gonadotropins (GT) could play a role in the genesis and establishment of EC is supported by the fact that specific receptors for the GT luteinizing hormone/human chorionic GT (LH/hCG) have been detected in a high percentage of ECs, and their expression is apparently related to the cancer grading. However, the precise mechanisms by which GTs might exert their effect on EC is still obscure. The aim of this study was to determine the effects of LH/hCG on the invasion potential of EC cell lines and primary human EC cells. Human recombinant (hr) LH (and hCG) induced a significant increase in cell invasiveness through Matrigel-coated porous membranes in an EC human cell line Hec1A, which expresses the LH/hCG receptor. This effect turned out to depend on hrLH binding to its specific receptors and to the subsequent activation of protein kinase A (PKA). Moreover the hrLH-induced increase in Hec1A invasiveness relied upon a PKA-dependent functional activation of beta(1) integrin receptors, as well as the subsequent induction of matrix metalloproteinase-2 secretion in its active form. The same mechanisms were also found to be operative in primary EC cells. In fact, a significant percentage of primary ECs expressed the LH/hCG receptor, and hrLH addition to primary EC cells, which expressed the specific receptors produced an increase in cell invasiveness only in those tumor cells possessing the specific receptors. This effect was also dependent on PKA activity. We conclude that LH/hCG can regulate EC cells invasiveness, and this result provides a rationale for the use of inhibitors of LH secretion such as GnRH analogues in the treatment of EC.

Sonographic evaluation of fetal growth and body composition in women with different degrees of normal glucose metabolism.

OBJECTIVE: To investigate the maternal demographic and metabolic factors contributing to the growth of fetal lean and fat body mass in women whose degree of glucose intolerance is less than that defining gestational diabetes in comparison with women with normal glucose metabolism. RESEARCH DESIGN AND METHODS: Longitudinal sonographic examinations of 66 singleton fetuses without anomalies of nonobese mothers with abnormal oral glucose challenge test (GCT) results and without gestational diabetes (group 1) were compared with those of 123 singleton fetuses without anomalies of nonobese mothers with normal GCT values (group 2). Lean body mass measurements included head circumference, femur length, mid-upper arm, and mid-thigh central areas. Fat body mass measurements included the anterior abdominal wall thickness, the subscapular thickness, and the mid-upper arm and mid-thigh subcutaneous areas. All the women performed a 24-h glucose profile on the day preceding the ultrasound scan. Multivariate logistic regression analysis established best-fit equations for fetal sonographic measurements of fat and lean body mass. Independent variables included groups 1 and 2, maternal age, parity, prepregnancy BMI, gestational age, weight gain during pregnancy, fetal sex, and the following averaged 24-h profile maternal capillary blood glucose values: preprandial, 1-h postprandial, and 2-h postprandial. RESULTS: No difference was found between the two groups with respect to fetal lean body mass parameters; the factors that contributed significantly and most frequently were gestational age and fetal sex (male). With respect to fetal fat body mass, all the measurements were significantly higher in group 1 than in group 2. In all instances, the significantly contributing factors were gestational age and maternal 1-h postprandial glucose values, whereas another frequent contributor was prepregnancy BMI. CONCLUSIONS: Our study suggests the possibility of using sonographically determined fetal fat and lean mass measurements as indicators of body composition. The assessment of these parameters, achievable in a noninvasive and reproducible fashion in pregnancies complicated by glucose intolerance, might enable the real-time detection of fetal overgrowth and disproportion, thus opening the possibility of exploring interventions to limit fetal fat accretion, birth weight, and potential resulting morbidity.