It has been well documented that a significant proportion of chronic anovulatory patients have elevated levels of dehydroepiandrosterone sulfate (DHEAS) and luteinizing hormone (LH) and normal levels of adrenocortiocotropic hormone (ACTH). We tested the hypothesis that the zones of human adrenal cortex that secrete DHEAS may contain LH/human chorionic gonadotropin (hCG) receptors. In situ hybridization showed the presence of hybridization signals representing LH/hCG receptor mRNA transcripts in the zona reticularis. Immunocytochemistry demonstrated that the zona reticularis also contained LH/hCG receptor protein. The receptor transcripts and receptor protein are also present in the deeper layer of the zona fasciculata which can also secrete DHEAS. Double immunostaining revealed that LH/hCG receptors are present in the same cells that contain cytochrome P450 side chain cleavage enzyme, suggesting that the receptor containing cells are steroidogenic. These findings may potentially explain higher DHEAS levels in chronic anovulatory women who have normal ACTH and elevated LH levels.
The present study investigated 1) whether extra- and intramyometrial arteries contain hCG/human LH receptor messenger ribonucleic acid (mRNA) and receptor protein, 2) whether hCG can bind to its vascular receptors and regulate the formation of vasoactive eicosanoids, and 3) whether hCG administration for ovulation induction can affect the vascular resistance in uterine arteries. The uterine arteries contain multiple hCG/LH receptor mRNA transcripts in endothelial and smooth muscle cells. The uterine arteries also contain an 80-kilodalton immunoreactive receptor protein in endothelial and smooth muscle cells. The extra- and intramyometrial arteries and an 80-kilodalton receptor protein bind [125I]hCG, which is inhibited by excess unlabeled hCG. The receptor mRNA, receptor protein, and ligand binding are higher in smaller intramyometrial arteries than in larger extramyometrial arteries. Incubation of uterine arteries with highly purified hCG resulted in a dose-dependent increase in immunoreactive cyclooxygenase-1, cyclooxygenase-2, prostacyclin synthase, and 6-keto-prostaglandin-F1 alpha and a decrease in prostaglandin-E2, thromboxane-A2 synthase, and thromboxane-B2. There was a significant decrease in the resistance index in uterine arteries, but not in common carotid arteries, by 16 h after the administration of 10,000 IU hCG for ovulation induction in women. This decrease is positively correlated with serum hCG levels, but not with progesterone or estradiol levels. In summary, these data, demonstrating the expression of functional hCG/LH receptors in human uterine arteries, are novel and may have important implications for physiological uterine blood flow regulation, reproductive failure, and obstetrical hemorrhage.
Normal human skin contains a major 4.5 kb and several minor mRNA transcripts and a 66 kDa protein of luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptors which are capable of binding exogenous 125I-hCG. The distribution of receptor transcripts and receptor protein are the highest in epidermis followed by hair follicles, sebaceous and sweat glands. LH/hCG receptors are co-localized with androgen receptors in all the skin appendages. These data are the first demonstration of skin containing LH/hCG receptors and would suggest that LH and hCG may regulate skin functions.
The present study characterized hCG/LH receptors from messenger ribonucleic acid (mRNA) to protein and whether exogenous hCG can bind and regulate the expression of the cyclooxygenase-1 (COX-1) gene in human fetal membranes from term pregnancy. Northern blotting showed that fetal membranes contain 6.0, 4.4, 2.4, and 1.4 kilobases of hCG/LH receptor mRNA transcripts. In situ hybridization revealed that amnion, chorion, and decidua contain receptor transcripts. Western immunoblotting and immunocytochemistry showed that amnion, chorion, and decidua also contain an 80-kDa receptor protein. Ligand blotting demonstrated that the 80-kDa receptor protein in fetal membranes can bind [125I]hCG, and this binding was inhibited by excess unlabeled hCG. Treatment of fetal membranes with highly purified hCG resulted in a dose- and time-dependent increase in immunoreactive COX-1 protein. The response of hCG was seen in all layers of fetal membranes. The treatment with hCG also resulted in an increase in steady state COX-1 mRNA levels. The action of hCG was prevented by cotreatment with H-89, an inhibitor of protein kinase A, but not by calphostin or lavendustin, which inhibit protein kinase C and tyrosine kinase, respectively. In summary, human fetal membranes contain hCG receptor transcripts and receptor protein that can bind hCG and up-regulate the expression of COX-1 gene.
Preeclampsia is a disease of late pregnancy characterized by hypertension, edema, and proteinuria, in which vasoconstriction, platelet aggregation, and reduced uteroplacental blood flow contribute to preterm delivery, perinatal morbidity, and mortality. Increased thromboxane-A2 (TXA2) and/or decreased prostacyclin (PGI2) have been implicated as causative factors of this disease. The present studies investigated the expression of TXA2 synthase gene along with those of TXA2 receptors, PGI2 synthase, cyclooxygenase-1 (COX-1), and COX-2 in placental and decidual tissue from preeclamptic and normal pregnancies. In situ hybridization and immunocytochemistry showed that primarily trophoblast layer and decidual cells express TXA2 synthase, COX-1, and COX-2 enzymes. Immunocytochemistry for PGI2 synthase and in situ hybridization for TXA2 receptors showed similar results. Trophoblast layer and decidua from preeclamptic pregnancies contained a greater abundance of mRNA and protein of TXA2 synthase than the matched normal pregnancies. In summary, our findings suggest that an increased local expression of TXA2 synthase could be responsible for local and/or peripheral vascular changes in preeclampsia.
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