Role Of Human Chorionic Gonadotropin Research Articles

Trisomy 21- affected placentas highlight prerequisite factors for human trophoblast fusion and differentiation

Trophoblastic cell fusion is one essential step of the human trophoblast differentiation pathway and is a multifactorial and dynamic process finely regulated and still poorly known. Disturbances of syncytiotrophoblast formation are observed in numerous pathological clinical conditions such as preeclampsia, intrauterine growth retardation and trisomy 21. In this review, we summarize current knowledge of the different membrane proteins directly involved in trophoblastic cell fusion, which we identified by using the physiological model of primary culture of villous trophoblastic cells. Connexin 43 and gap junctional intercellular communication point to the role of molecular exchanges through connexin channels preceding membrane fusion. Zona occludens-1, which can interact with connexin 43, is also directly involved in trophoblast fusion. The recently identified fusogenic membrane retroviral envelop glycoproteins syncytin 1 (encoded by the HERV-W gene) and syncytin 2 (encoded by the FRD gene) and their receptors are major factors involved in human placental development . We describe the increasing number of factors promoting or inhibiting trophoblast fusion and differentiation and emphasize the role of human chorionic gonadotropin (hCG) and its receptor. Indeed, in trisomy 21 the dynamic process leading to membrane fusion is impaired due to an abnormal hCG signaling. This abnormal trophoblast fusion and differentiation in trisomy 21-affected placenta is reversible in vitro. Trisomy 21 trophoblastic cell culture may therefore be useful to identify the possible large number of prerequisite factors involved in trophoblast fusion, the limiting step of trophoblast differentiation.

Role of Human Chorionic Gonadotropin in Maintaining 11β-hydroxysteroid Dehydrogenase Type 2 Expression in Human Placental Syncytiotrophoblasts

Proper glucocorticoid exposure in utero is vital for normal fetal organ maturation, but excess glucocorticoids are detrimental to fetal growth and can even predispose the individuals to the high risk of having certain diseases in adulthood. The fetus is protected from 10 times higher maternal glucocorticoid levels by the placental enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which converts biologically active cortisol to inactive cortisone. Thus it is of primary importance to understand how this enzyme is regulated. Activation of cAMP/PKA pathway is known to upregulate 11β-HSD2 expression in placental syncytiotrophoblasts, however the endogenous hormones utilizing this pathway remain largely unknown. By using cultured human placental syncytiotrophoblasts, we demonstrated that inhibition of protein kinase A with H89 attenuated 11β-HSD2 expression in the syncytiotrophoblasts, suggesting endogenous factors from the syncytiotrophoblasts using this pathway to maintain 11β-HSD2 expression in the syncytiotrophoblasts. Neutralization of human chorionic gonadotropin (hCG) secreted by the syncytiotrophoblasts with hCG antibody decreased 11β-HSD2 promoter activity, mRNA and protein expression as well as intracellular cAMP level, while treatment of the syncytiotrophoblasts with exogenous hCG increased 11β-HSD2 expression, which was attenuated by H89. Furthermore, we found that cortisol increased both hCG expression and secretion. The up-regulation of 11β-HSD2 expression by cortisol was significantly attenuated by co-treatment with hCG antibody or H89 in the syncytiotrophoblasts. In conclusion, hCG is an important paracrine or autocrine hormone maintaining 11β-HSD2 expression and the up-regulation of 11β-HSD2 expression by cortisol may be mediated in part by hCG in the syncytiotrophoblasts.

The Role of Human Chorionic Gonadotropin as a Thyroid Stimulator in Normal Pregnancy

The first clinical reports of a placental thyroid stimulator arose from studies indicating that placental tumors that secrete very large amount of human chorionic gonadotropin (hCG), hydatidiform moles and choriocarcinomas, were associated with hyperthyroidism [summarized by Yoshimura and Hershman (1)]. In 1967, Burger reported that impure, commercial hCG had thyroid-stimulating activity in a mouse bioassay (2). Several years later my laboratory (3) and that of Nisula (4) reported that highly purified hCG had activity in this bioassay. We found that the molar TSH was hCG (4). Because hCG varies in its carbohydrate composition, there has been considerable controversy in regard to the potency of these variants. hCG lacking its C-terminal tail, therefore closely resembling LH, is a more potent TSH than native hCG (5). Desialylated basic variants of hCG are more potent in binding to the TSH receptor than fully sialylated acidic hCG (6). However, the acidic hCG has a longer half-life in the circulation than the more basic partially desialylated hCG, and this may contribute to greater thyrotropic potency in humans (7). These studies mainly arose from patients with placental tumors or from a few patients with gestational thyrotoxicosis associated with high hCG levels. The possibility that hCG plays a role in regulation of the thyroid gland during normal pregnancy was first considered when there were more sensitive immunoassays for TSH. Braunstein and Hershman (8) reported that there was an inverse relationship between TSH and hCG at about 10–12 wk of pregnancy, the time of peak hCG levels. Harada et al. (9) further advanced this concept by showing the inverse relationship more clearly and amassing data showing an increase of free T4 and free T3 associated with the peak hCG. We postulated that hCG caused an increase of free thyroid hormone levels, thus suppressing TSH, albeit within the physiological range of serum TSH. Glinoer et al. (10), in a landmark study using a more sensitive TSH measurement, further refined the mirror image temporal relationship between hCG and TSH in normal pregnancies. Other reports also contributed to the concept that hCG is a thyroid stimulator in the early part of pregnancy when hCG levels are very high (11). In this issue of the Journal, Haddow et al. (12) have done a complex analysis of the relationship between hCG, TSH, and free T4 during the first trimester (wk 11–13) and second trimester (wk 15–18) in 9562 women with singleton pregnancies. They found that higher hCG levels were associated with a lower body mass index. This fits with the observation of Goodwin et al. (13) that hCG is higher in women with nausea of pregnancy and hyperemesis gravidarum than in women who do not have any nausea, assuming that weight gain is restricted by nausea. More importantly, the data of Haddow et al. further strengthen the role of hCG as a thyroid stimulator in normal pregnancy. At wk 11–13, higher hCG correlates with higher free T4 levels, although the relationship is a shallow slope, confirming the data of Glinoer et al. (10) that in normal pregnancy hCG only modestly increases free T4. The relationship between hCG and TSH is more difficult to appreciate in the complex analysis by Haddow et al. (12). It shows clearly that low TSH is associated with high levels of hCG, but when TSH is in the higher deciles, there is no correlation with hCG. My interpretation is simplistic. Placental secretion of hCG is not regulated by thyroid hormones. However, when hCG levels are high, they increase thyroid hormone secretion, and the negative feedback at the level of the pituitary suppresses TSH release. When TSH levels are in the higher part of the normal range, or perhaps slightly elevated for pregnancy, the contribution of hCG to increase free T4 and T3, resulting in lower TSH levels, is not sufficient to lower serum TSH significantly. Perhaps evolution designed the hCG system as a backup for stimulating the thyroid gland to produce essential amounts of thyroid hormone, but this backup system did not fully evolve to perfection.

Biochemistry in the Diagnosis and Management of Abnormal Early Pregnancy

To examine the current state of knowledge regarding the biochemical parameters of early pregnancy failure. Earlier studies have concentrated on the role of human chorionic gonadotropin and progesterone in early pregnancy failure and recent studies have also explored newer markers such as the inhibins and insulin growth factor binding proteins. Multiparameter models have now been created for the prediction of successful expectant management of early pregnancy failure. Examining the role of newer biochemical markers in the early pregnancy failure has led to an improved understanding of the underlying mechanisms and has clinical benefit in the selection of appropriate management for patients.

P-960: The role of human chorionic gonadotropin in the stimulation of cumulus granulosa cell production of inhibin A, progesterone and estradiol in culture: A predictor of functional viability

Hormone manipulation in cell culture may improve cell secretion in vitro. In this study the culture system of human cumulus granulosa cells (CGC) was established to express functional viability of secretion of dimeric inhibins, progesterone, and estradiol. The CGC were treated with sustained high dosage of Human Chorionic Gonadotropin (HCG) in a time dependent manner.

The central role of human chorionic gonadotropin in the formation of human placental syncytium.

A number of trophoblast products, including human chorionic gonadotropin (hCG), can increase the formation of human placental syncytium through the differentiation of mononuclear cytotrophoblasts. The present study investigated the central role of hCG in this process by using antisense receptor phosphorothioate oligodeoxynucleotides (ODNs). Culturing cytotrophoblasts with the hCG/LH receptor antisense, but not sense, ODN resulted in a significant decrease in receptor protein levels and inhibited spontaneous as well as exogenous hCG induced increase in differentiation. The hCG/LH receptor antisense ODN also inhibited epidermal growth factor (EGF), TGF-alpha, leukemia inhibitory factor (LIF), but not 8-bromo-cAMP, induced increases in differentiation, suggesting that hCG is required for EGF, TGF-alpha and LIF, but not for the cAMP actions. Although antisense EGF receptor and LIF receptor ODNs inhibited EGF and LIF induced increase in differentiation, respectively, they were ineffective against hCG, suggesting that they use separate pathways, but they both converge on a common pathway requiring the hCG actions. Mechanism of action studies revealed that EGF treatment activates its receptors and MAPK, both of which are required for EGF to increase the differentiation, cAMP levels and activate protein kinase A. In summary, our results demonstrate that hCG is an autocrine and paracrine regulator that is required for EGF, TGF-alpha, and LIF, but not for cAMP to increase human placental syncytium formation. Direct activation of protein kinase A seems to bypass the hCG pathway, perhaps by targeting genes associated with the differentiation.

The effects of human chorionic gonadotropin treatment on the contralateral side in unilateral testicular torsion.

Unilateral testicular torsion can cause histologic damage, consisting of aspermatogenesis and tubular atrophy, in the contralateral testis human chorionic gonadotropin (HCG) treatment is widely used in undescended testis, and has been shown to improve histomorphometric alterations beside the testicular descent. However, the role of HCG in testicular torsion has not been investigated before. Therefore, this experimental study was conducted to evaluate the effects of HCG treatment on contralateral testicular histology and function in unilateral testicular torsion. Forty adult male Wistar rats were randomized into 4 groups: SHAM, SHAM+HCG, TORSION, and TORSION+HCG. Torsion was created by twisting the righ testis 720 degrees and maintained by fixing it to the scrotum. HCG treatment started 24 hours after the torsion at a dose of 100 IU/kg, twice weekly for three weeks. Left orchiectomy was performed one month after the torsion and removed testes were immersed in Bouin's fixative for histopathological evaluation. Mean seminiferous tubule diameter (MSTD) was measured and Johnsen's score was calculated. Blood samples were taken for assaying serum testosteron level. Unilateral testicular torsion resulted in a significant decrease in spermatogenesis and MSTD on the contralateral side. Serum testosteron level was also reduced. HCG treatment improved these parameters in the contralateral 'untwisted' testis beside the serum testosteron. Our data demonstrates that unilateral testicular torsion adversely effects its counterpart. HCG treatment improves contralateral histomorphometric alterations and serum testosteron in unilateral torsion.

The Role of Human Chorionic Gonadotropin and cAMP/Protein Kinase A Signaling in the Differentiation of Human Endometrial Stromal Cells

The Role of Human Chorionic Gonadotropin and cAMP/Protein Kinase A Signaling in the Differentiation of Human Endometrial Stromal Cells

Author's Response: The Role of Human Chorionic Gonadotropin and cAMP/Protein Kinase A Signaling in the Differentiation of Human Endometrial Stromal Cells

Author's Response: The Role of Human Chorionic Gonadotropin and cAMP/Protein Kinase A Signaling in the Differentiation of Human Endometrial Stromal Cells

The role of human chorionic gonadotropin on decidualization of endometrial stromal cells in vitro.

Although decidualization of endometrial stromal cells (ESC) is crucial for blastocyst implantation and maintenance of pregnancy, its complex mechanism still remains largely unknown. It has long been believed that hCG can directly induce in vitro decidualization of ESC via cAMP signaling. Recently, however, it has been reported that the LH/CG receptor is not present in human endometrium, and the direct effect of hCG on decidualization has become controversial. To reevaluate the exact effect of hCG on decidualization, human ESC were isolated and cultured with hCG and/or ovarian steroids. ESC treated with 17beta-estradiol plus progesterone (E(2)/P) transformed morphologically and produced significant PRL, whereas ESC treated with hCG alone showed no significant increase in PRL in culture medium and exhibited no morphological changes. Moreover, hCG did not promote E(2)/P-induced PRL production or intracellular cAMP accumulation, and protein kinase A inhibitor failed to block E(2)/P-induced PRL production. These results suggest that hCG does not directly affect in vitro decidualization of human ESC and that the process of E(2)/P-induced in vitro decidualization might consist of several pathways, including the intracellular cAMP signaling cascade.

The Role of Human Chorionic Gonadotropin on Decidualization of Endometrial Stromal Cells in Vitro

The Role of Human Chorionic Gonadotropin on Decidualization of Endometrial Stromal Cells in Vitro

On the role of human chorionic gonadotropin (hCG) in the embryo-endometrial microenvironment: implications for differentiation and implantation.

Recent evidence suggests that human chorionic gonadotropin (hCG), in addition to its well-known endocrine effects on the corpus luteum, may act as a growth and differentiation factor during pregnancy. According to experimental results, its mode of action may be divided into three sequential phases. During the first phase, which begins at the blastocyst stage and lasts until the occurrence in the serum, hCG acts preferentially in a juxtacrine manner. We have used an intrauterine microdialysis system developed in our laboratory to administer low concentrations of hCG to the endometrium of women in the luteal phase of the menstrual cycle. HCG administration provoked profound effects on paracrine parameters of differentiation (IGFBP-1, prolactin) and implantation (LIF, M-CSF). VEGF, a cytokine important for neoangiogenesis, was significantly stimulated by hCG (P < .01), suggesting a role for hCG in the control of endometrial vascularization and placentation. The investigation of endometrial parameters of tissue remodeling revealed a significant increase of MMP-9 (P < .05) but not of TIMP-1 following hCG infusion. The second, endocrine, phase of hCG action is marked by the appearance of hCG in the maternal serum. Rising systemic hCG levels cause a very rapid elevation of serum progesterone reflecting the rescue of the corpus luteum. Other endocrine functions of hCG include its intrinsic thyrotropic activity as well as modulation of fetal testicular, ovarian, and adrenal function. The third phase may be characterized by the expression of full-length hCG/LH receptors on the trophoblasts themselves. Before the ninth week of gestation, human villous trophoblasts express a truncated hCG/LH receptor isoform (50 kDa) and are probably not responsive to hCG. Later, the expression pattern is switched to the full-length receptor (80 kDa), allowing hCG also to modulate the differentiation of the trophoblasts themselves. A special feature is the self-regulation of hCG biosynthesis that may in part explain the unique secretion profile of the hormone with peak levels during the first trimester followed by a rapid decline after the tenth week of gestation. In summary, hCG seems to have a variety of local and systemic functions in and outside the embryo-endometrial microenvironment.

Role of the placenta in fetal HIV infection

Role of the placenta in fetal HIV infection

Reappraisal of the Role of Human Chorionic Gonadotropin in the Diagnosis and Treatment of the Nonpalpable Testis: A 10-year Experience

Purpose We retrospectively evaluated the ability of human chorionic gonadotropin (HCG) to make the nonpalpable cryptorchid testis become palpable and promote testicular descent. Materials and Methods Through surgical bookings we identified 94 patients younger than 11 years who received HCG between 1984 and 1994 for the diagnosis or treatment of a nonpalpable undescended testis. The dose of HCG was 1,500 IU/m. 2 intramuscularly 2 times weekly for 4 weeks. Testis location was determined by physical examination before and after hormone administration, and confirmed at surgical exploration. Results Of the 99 nonpalpable testes identified in 94 patients 39 (39 percent) became palpable following HCG administration and only 2 (2 percent) completely descended. A total of 60 testes remained nonpalpable with the most common reason being an absent or severely atrophic testis (40, 67 percent). Of the testes remaining nonpalpable after hormonal stimulation 73 percent were surgically located at or distal to the internal ring. Conclusions HCG is preoperatively efficacious in causing the nonpalpable undescended testis to become palpable. For patients failing to respond to hormonal stimulation we recommend preliminary inguinal exploration, since most testes or testicular remanants are located within the inguinal canal or immediately below the internal ring.

Reappraisal of the role of human chorionic gonadotropin in the diagnosis and treatment of the nonpalpable testis: a 10-year experience.

We retrospectively evaluated the ability of human chorionic gonadotropin (HCG) to make the nonpalpable cryptorchid testis become palpable and promote testicular descent. Through surgical bookings we identified 94 patients younger than 11 years who received HCG between 1984 and 1994 for the diagnosis or treatment of a nonpalpable undescended testis. The dose of HCG was 1,500 IU/m.2 intramuscularly 2 times weekly for 4 weeks. Testis location was determined by physical examination before and after hormone administration, and confirmed at surgical exploration. Of the 99 nonpalpable testes identified in 94 patients 39 (39%) became palpable following HCG administration and only 2 (2%) completely descended. A total of 60 testes remained nonpalpable with the most common reason being an absent or severely atrophic testis (40, 67%). Of the testes remaining nonpalpable after hormonal stimulation 73% were surgically located at or distal to the internal ring. HCG is preoperatively efficacious in causing the nonpalpable undescended testis to become palpable. For patients failing to respond to hormonal stimulation we recommend preliminary inguinal exploration, since most testes or testicular remnants are located within the inguinal canal or immediately below the internal ring.

The role of human chorionic gonadotropin β subunit elevation in small-cell lung cancer patients: Szturmowicz M, Wiatr E, Sakowicz A, Slodkowska J, Roszkowski K, Filipecki S et al. Department of Internal Medicine, Institute Tuberculous/Lung Diseases, Plocka 26, 01-138 Warsaw. J Cancer Res Clin Oncol 1995;121:309–312

The role of human chorionic gonadotropin β subunit elevation in small-cell lung cancer patients: Szturmowicz M, Wiatr E, Sakowicz A, Slodkowska J, Roszkowski K, Filipecki S et al. Department of Internal Medicine, Institute Tuberculous/Lung Diseases, Plocka 26, 01-138 Warsaw. J Cancer Res Clin Oncol 1995;121:309–312

Role of human chorionic gonadotropin in patients with pure seminoma.

Human chorionic gonadotropin (beta-hCG) and alpha-fetoprotein (AFP) are widely established specific and sensitive tumor markers for nonseminomatous testicular cancer. In 106 patients with pure seminoma, a highly sensitive method detected beta-hCG both before and repeatedly during therapy. The low detection limit of the test (0.3 IU/l) coincided with the 95 percentile of a group of 60 healthy blood donors. Its 100 percentile of < 1.0 IU/l was applied as the upper limit of the normal range. In 30.2% of our patients with pure seminoma, elevated beta-hCG levels were noted prior to orchiectomy. The levels returned to normal in 76% of these patients thereafter, and in 34% after additional irradiation or chemotherapy. During an observation period of 2-84 months, all beta-hCG-positive patients were in complete remission. Prior to semicastration, 1 patient showed extremely high beta-hCG levels, while in another patient, beta-hCG and AFP were elevated simultaneously. In both cases, tumor marker levels did not seem to agree with the histology of 'pure seminoma' and rather suggested the presence of nonseminomatous tumor cells. Increased AFP levels contradict the presence of a pure seminoma and indicate a nonseminomatous testicular tumor. The same holds true for strongly elevated beta-hCG levels, whereas levels of up to 200 IU/l correlate with the diagnosis of pure seminoma.

Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts

Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts

Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts.

Our laboratory previously demonstrated that cytotrophoblasts and syncytiotrophoblasts in human placental tissue contain hCG/LH receptors. From this finding, we postulated that one role of hCG might be to promote the differentiation of cytotrophoblasts into syncytiotrophoblasts. To test this postulate, cytotrophoblasts were isolated from human term pregnancy placentas and cultured with and without increasing concentrations of highly purified hCG. The results showed that hCG had a biphasic effect on 1) the aggregation of cells without intervening plasma membranes; 2) the expression of cadherin, a cell adhesion receptor that facilitates cellular aggregation; 3) the expression of hCG/LH receptor gene; and 4) the expression of three different hormonal markers of differentiation. The hCG effects were time and dose dependent and hormone specific. The addition of excess polyclonal hCG antibody, but not normal rabbit serum or nonspecific antirabbit immunoglobulin G, decreased basal responses as well as those to exogenous hCG. The polyclonal hCG/LH receptor antibody increased differentiation and dramatically stimulated hCG secretion in the presence or absence of exogenous hCG. (Bu)2cAMP mimicked the actions of hCG. H-89, a protein kinase-A inhibitor, decreased basal as well as exogenous hCG responses. Calphostin, a protein kinase-C inhibitor and lavendustin, a tyrosine kinase inhibitor, on the other hand, had no effect. In summary, it is novel that hCG made in human placenta can regulate the differentiation of cytotrophoblasts, which make little hCG, into syncytiotrophoblasts, which make considerable amounts of hCG.

The role of human chorionic gonadotropin (HCG) elevation in small cell lung cancer patients

The role of human chorionic gonadotropin (HCG) elevation in small cell lung cancer patients