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PubMed1986

Transcriptional enhancer within the human placental lactogen and growth hormone multigene cluster.

Human placental lactogen (hPL) and human growth hormone (hGH) are members of a multigene family that share amino acid sequence homology and similarity in gene structure and nucleotide sequence, but differ in both function and expression. To determine the sequence requirements for tissue specific expression recombinant plasmids containing the members of the hPL-hGH multigene family and flanking regions were analyzed by both transient and stable transfection assays. We have identified a transcriptional enhancer in a 1.0 kb region located 2.0 kb downstream of the hPL3 structural gene. This enhancer sequence is not strictly cell-type specific since it functions in cell lines of both placental (JEG-3) and pituitary (18-54,SF) origin. However, its efficiency is several fold higher in placental cells than in pituitary cells.

Base Sequence↗

PubMed1976

Immunoreactive ACTH, immunoreactive human chorionic somatomammotrophin (HCS) and 11-OH steroids plasma levels in normal and pathological pregnancies.

Plasma immunoreactive ACTH (I.R.ACTH), immunoreactive human chorionic somatomammotrophin (I.R.HCS) and 11-OH steroids levels were measured during normal and pathological pregnancies. Plasma I.R.ACTH levels were found to be above normal during pregnancy, with a slight decrease near term. This observation correlates well with the recent description of human chorionic corticotrophin (HCC), i.e. a factor of placental origin possessing a high biological adrenocorticotrophic activity and presenting partial immunological cross-reaction with human ACTH. The 11-OH steroids levels, as measured by a fluorimetric method, increased regularly during pregnancy but, unlike ACTH, reached their highest value near term, I.R.HCS increased progressively until term when a slight decrease was observed. In pathological pregnancies, I.R.ACTH levels behaved like other placental hormones. On the contrary, 11-OH steroids levels remained generally unmodified. Treatment with high doses of prednisolone caused no inhibition of the plasma I.R.ACTH and of plasma 11-OH steroids levels. These data suggest placental autonomy of the secretion of HCC and low adrenal responsiveness to endogenous ACTH variations throughout pregnancy.

Abortion, Spontaneous↗

PubMed2006

Dual action of H2O2 on placental hCG secretion: implications for oxidative stress in preeclampsia.

OBJECTIVE: Our previously published findings showed that circulating levels of H(2)O(2) were increased and correlated with high levels of hCG in women with preeclampsia, suggesting that oxidative stress modulates placental hormone synthesis. The aim of this study was to investigate in vitro the effects of H(2)O(2) on placental secretion of hCG. DESIGN AND METHODS: In vitro trophoblasts were stimulated with increasing concentrations of H(2)O(2) and the de novo hCG secretion was assayed. RESULTS: Stimulation with low concentrations of H(2)O(2) (1-50 microM) enhances cytotrophoblastic hCG secretion, whereas concentrations of H(2)O(2) >50 microM reduce hCG secretion in a dose-dependent manner. CONCLUSIONS: Our findings emphasize that: (1) H(2)O(2) may have dual action on placental activity and acts not only as a cytotoxic mediator, but also as a signaling molecule able to induce hCG secretion; (2) hCG may be a protective antioxidant released by the placenta to counter low oxidative stress challenge.

Chorionic Gonadotropin↗

PubMed1985

[Immunoregulatory aspects of placental function].

An immunological response from mother to foetus is known to exist during pregnancy. Multiple mechanism ensure that this response is not one of rejection but of "tolerance" of the foetus, and the placenta, as the site of maternal-foetal exchanges, plays a prominent role in this respect: (1) the placenta cell bears foetal antigens, half of which are of paternal origin; it constitutes therefore the antigenic stimulus of maternal immune response; (2) this response can be modulated quantitatively through placental hormones and glycoproteins - an action which has been demonstrated in vitro but which may well take place at utero-placental level; (3) finally, the placenta can act qualitatively on the maternal response itself by reducing cytotoxic reactions responsible for graft rejection and by stimulating immunosuppressor cell populations. The therapeutic applications of some of these properties of the placenta are being investigated in the fields of rheumatology and renal transplantation. They will be considered in obstetrics only when more precise data are available concerning the immunopathological mechanisms involved in spontaneous abortion, preeclampsia and foetal growth retardation.

Animals↗

PubMed1993

Effects of sex and pregnancy hormones on growth hormone and prolactin receptor gene expression in insulin-producing cells.

During pregnancy, marked hyperplasia of the pancreatic islet cells has been observed. This effect may be mediated by the pregnancy-associated peptide hormones, placental lactogen, PRL, and GH, which were previously shown to be mitogenic to beta-cells in vitro. To study whether the responsiveness of islet cells to these hormones is regulated on the receptor level, GH and PRL receptor gene expression was studied in pancreata from male rats and virgin, pregnant, and lactating female rats and in cultured islets and insulinoma cells (RIN-5AH) in response to various hormones. The mRNA levels were quantitated by ribonuclease protection assay, using probes specific for mRNA encoding, extracellular and intracellular domains of the GH receptor, and short and long forms of the PRL receptor, respectively. Specific transcripts for the GH receptor were present in pancreas, islets, and RIN-5AH cells. Furthermore, as previously observed in RIN-5AH cells, a predominant expression of the long form of PRL receptor vs. the short form was also found in pancreas and islet cells. Male and nonpregnant female pancreas did not differ significantly in their levels of GH and PRL receptor mRNAs. On day 14 of pregnancy, increases in both GH and PRL receptor mRNA levels were observed (1.7- and 2.4-fold, respectively), and a further increase occurred in late pregnancy (day 19), when GH and PRL receptor mRNA levels were 2.7- and 3.9-fold higher than those in the nonpregnant state. mRNA levels returned toward the basal level during lactation. In the cultured islets, PRL receptor mRNA levels were markedly increased by GH and PRL (3.5- and 6.5-fold, respectively) after exposure for 24 h, whereas estradiol and testosterone had modest stimulating effects (1.8- and 1.5-fold increases, respectively). Dexamethasone induced a 2.5-fold increase in GH receptor mRNA levels, and a weak stimulatory effect was also observed for progesterone. In RIN-5AH cells, the effect of dexamethasone on GH receptor mRNA was detectable after 2 h and maximal after 16 h. In contrast, the effects of GH and PRL on PRL receptor mRNA required 24-48 h of exposure. The effective doses were within the physiological ranges. In conclusion, these results show a differential hormonal regulation of GH and PRL receptor gene expression in the pancreatic islets, which may play a role in the adaptive beta-cell growth during pregnancy.

Animals↗

PubMed1992

An antipodean perception of the mode of action of glycoprotein hormones.

Continuance of vertebrate species and maintenance of metabolism have an absolute requirement for the glycoprotein hormones of the anterior pituitary gland. It is now firmly accepted that the N-glycans of these and the related placental hormone, chorionic gonadotropin, have essential if undefined roles in their mechanism of action. However, recent investigations by Weisshaar and his colleagues on the oligosaccharides of human luteinizing hormone and chorionic gonadotropin, do not support the generally accepted view of carbohydrates in hormone-receptor interactions and a further concept is proposed that invokes negative charges and changes in structured water.

Animals↗

PubMed1993

Multiple changes in chromatin structure precede the transcriptional activation of the human growth hormone locus in placental cells.

In addition to the growth hormone gene (hGH-N) itself, the human growth hormone (hGH) locus contains four related genes, namely hGH-V and hCS-L, -A and -B, which have appeared very recently in evolution and are specifically expressed in placenta. With the aim of identifying the regulatory elements responsible for this placental-specific expression, we have mapped the DNaseI hypersensitive sites present at the hGH gene cluster in a placental cell line (BeWo) that expresses the hGH-V and hCS genes. Our results reveal a complex pattern of hypersensitive sites distributed along the hGH locus, most of which appear to be cell type-specific. Thus, we have identified placental-specific hypersensitive sites within the first intron of the hGH-N and hGH-V genes, but not in the equivalent regions of the hCS genes. In addition, we have found several placental-specific hypersensitive sites downstream of the hCS-L and hCS-A genes, which might reflect the presence of enhancer elements similar to that located downstream of the hCS-B gene (Walker et al. (1990) J. Biol. Chem. 265, 12940). Comparison of BeWo cells with a placental cell line (JEG-3) which does not express the hGH-V and hCS genes revealed a very similar pattern of hypersensitive sites, suggesting that the sites detected are established before the onset of transcription. Our results indicate that the transition to an active hGH locus in placental cells requires multiple alterations in chromatin structure, and provide a framework for the molecular analysis of the regulatory elements and mechanisms mediating such processes.

Biological Evolution↗

PubMed1980

Acute changes in serum prolactin concentration have no effect on the secretion of progesterone, estradiol, or chorionic gonadotropin during early pregnancy.

The relationship between the circulating levels of PRL and progesterone, estadiol, and hCG was studied during the first half of pregnancy. The subjects were 1) nine hyperprolactinemic women who conceived during bromocriptine treatment and whose treatment was discontinued at the 7th to 11th weeks of gestation; 2) five women given chlorpromazine during the 11th to 12th weeks of pregnancy; and 3) four pregnant women give bromocriptine during the 11th to 12th weeks of pregnancy. In group 1, discontinuation of bromocriptine resulted in elevated serum PRL concentrations, but this was not associated with any significant changes in the circulating levels of estradiol, progesterone, and hCG. In group 2, chlorpromazine increased the serum PRL concentration but had no effect on serum estradiol, progesterone, or hCG concentrations. In group 3, bromocriptine decreased the serum PRL level, but this was not associated with any alteration in steroid hormone or hCG levels. Our results show that during early pregnancy acute moderate changes in the serum PRL concentration do not affect placental hormone secretion.

Bromocriptine↗

PubMedDate not supplied

Trophoblast viability in perfused term placental tissue and explant cultures limited to 7-24 hours.

Human term-placental culture techniques such as villous explant or dual perfusion are commonly used to study trophoblast function under control and experimentally manipulated conditions. We have compared trophoblast viability during perfusion and in explants cultured under various conditions by monitoring glucose consumption, protein synthesis and secretion, expression of differentiation-specific genes, induction of stress proteins and apoptotic cell death. The tissue was obtained from term-placentae of uncomplicated pregnancies after elective Caesarean delivery. We observed a severe loss of trophoblast viability in explants irrespective of the culture conditions used. Over 7 h of culture the amount of the differentiation specific placental hormones hCG, hPL and leptin accumulated in the medium dropped significantly. Analysis of their expression by semi-quantitative and real-time RT-PCR revealed that the down-regulation of expression occurred at the transcriptional level. This transcriptional repression was accompanied by induction of the stress-proteins RTP and BiP/GRP78. Analysis of apoptotic cell death by TUNEL assay and immunohistochemical detection of the caspase-3-specific degradation product of cytokeratin 18 revealed prominent cell death after 7 h of culture. These results are in contrast to the findings obtained in perfused placental tissue where, after 7 h of culture, hormone secretion, expression of stress proteins and cell death were similar as in native tissue. This difference between villous explant incubation and dual perfusion is also reflected by a significantly higher consumption of glucose in perfused tissue.

Apoptosis↗

PubMed1994

Growth hormone, insulin-like growth factor-I and somatostatin in human fetus, newborn, mother plasma and amniotic fluid.

During pregnancy, organism development and its differentiation are stimulated and modulated by fetal and placental hormones. However the exact role played by all the different growth factors has not been explained yet. This study summarizes knowledge about secretion, regulation and role of GH, IGF-1 and SRIF during perinatal age. It also reports the results of researches into GH, IGF-1 and SRIF in amniotic fluid, in mothers and in newborns at delivery and at four days of age. Amniotic fluid GH levels proved significantly higher during middle pregnancy that at delivery (p < 0.001); a significant difference was also found between mean GH concentrations observed in amniotic fluid collected at delivery in preterm and full-term pregnancies. In amniotic fluid, significant reductions of SRIF and IGF-1 concentrations correspond to a sudden decrease of GH concentration during the last months of pregnancy. Fetal serum GH levels resulted higher than venous cordonal GH concentration at birth (p < 0.001). High levels of IGF-1 were found in the amniotic fluid and in the maternal plasma. These values were higher than those observed in cord blood during pregnancy or at delivery. Preterm and full-term newborns showed similar serum GH levels at birth and at the age of 4 days. Mean GH values in newborns, both at birth and at the age of 4 days, proved to be significantly higher than the values of their mothers (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Amniotic Fluid↗

PubMed1992

Search for peptide immunogens of the beta-subunit of human chorionic gonadotropin (hCG) capable of eliciting hormone specific and neutralizing antisera. Identification of an undecapeptide eliciting hCG-specific antisera.

The work reported herein describes our attempts to identify peptide immunogens of the beta-subunit of the pregnancy-specific placental hormone, human chorionic gonadotropin (hCG), capable of eliciting hormone specific and neutralizing antisera. Hydrophilicity profiles of the beta-subunits of hCG and the homologous pituitary hormone, human luteinizing hormone (hLH) were compared and two sequences which are hydrophilic but unique to hCG-beta were identified. They are 6-12 and 109-119 of hCG-beta. Results of the studies with the undecapeptide 109-119 of hCG-beta are reported in this paper. The undecapeptide amide was synthesized using the p-(acyloxy) benzhydrylamine resin and antisera to the peptide were elicited in rabbits using the peptide-diphtheria toxoid conjugate. The peptide is highly immunogenic as both the rabbits responded with high titers of antibodies to the peptide. The antipeptide antibodies bound to hCG but not to hLH showing thereby that the region 109-119 of hCG-beta is a unique determinant of hCG. However, the antibodies were found not to neutralize the biological activity of hCG.

Amino Acid Sequence↗

PubMed1980

Effect of the placenta on the growth and function of artificially formed secondary corpora lutea of pregnancy in rats.

PMSG-induced prepubertal pregnant rats were injected with hCG on Day 7 of pregnancy to induce the formation of secondary corpora lutea (CL) in addition to the primary CL of pregnancy. The rats bearing two sets of CL were hypophysectomized on Day 11 of pregnancy (Day 3 of the secondary CL age) and their primary CL were removed on Day 13 of pregnancy (Day 5 of the secondary CL age). The operations did not affect the fetal growth until Day 18 of pregnancy when the weight of and progesterone secretion of the secondary CL rapidly increased. Hysterectomy on Day 18 of pregnancy (Day 10 of the secondary CL age), however, induced regression of CL and rapidly decreased the progesterone secretion. These results suggest that placentas between Days 15 and 18 of pregnancy could maintain the function of CL at Days 7-10 of CL age when LH is indispensable as a luteotropic hormone, and that placentas between Days 18 and 21 of pregnancy could support the rapid growth of CL at Days 10-13 of CL age. Placental hormones which would participate in these luteotropic events have been discussed.

Animals↗

PubMed2006

TGF-beta superfamily expression and actions in the endometrium and placenta.

Transforming growth factor beta (TGFbeta) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFbeta superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFbetas and activin beta subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFbetas, nodal and bone morphogenetic proteins (BMPs) in promoting pre- and post-implantation embryo development. TGFbeta superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFbeta and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFbeta superfamily members participate in modulating the extent of decidual invasion. Activins and TGFbetas have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down's syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

Activins↗

PubMedDate not supplied

Stimulation of ovine choriomammotrophin release, in vitro, by phospholipase C.

Phospholipid metabolites have previously been implicated in receptor-mediated stimulation of protein hormone secretion. As the factors which regulate the release of choriomammotrophin remain to be elucidated, we investigated the potential involvement of phospholipase C-induced phospholipid metabolism in the release of this placental hormone. Phospholipase C (PLC) caused a dose-dependent release of choriomammotrophin from ovine placenta, incubated in vitro. At a concentration of 0.2 units/ml (0.25 microgram protein/ml), PLC caused the release of choriomammotrophin from placental tissue to approximately double that observed in control incubations (7.08 +/- 0.4 micrograms/50 mg/h and 3.26 +/- 0.3 micrograms/50 mg/h, respectively). PLC treatment did not significantly alter plasma membrane permeability, as indicated by the release of lactate dehydrogenase and protein. PLC-stimulated release of oCM was completely abolished by incubation in calcium-free medium or by preincubation with the inorganic calcium-channel blocking agents cobalt chloride (4 mM) and lanthanum chloride (1 mM). The effects of PLC treatment on ovine choriomammotrophin (oCM) release were also inhibited by preincubation of placental tissue with inhibitors of arachidonic acid metabolism: ibuprofen (10(-5) M), naproxen (10(-4) M) or nordihydroguaiaretic acid (NDGA) 5 X 10(-6) M). These results suggest that the effects of PLC on the release of choriomammotrophin are mediated via metabolites of arachidonic acid.

Animals↗

PubMed2003

Resistin is expressed in the human placenta.

The mechanism for decreased insulin sensitivity in pregnant women is not fully clarified. Resistin, a novel peptide hormone, is specifically expressed in the adipose tissue and decreases insulin sensitivity in rodents. In the present study, we demonstrate resistin gene expression in the human placental tissue, mainly in trophoblastic cells. The resistin gene expression in term placental tissue was more prominent than was seen in the first trimester chorionic tissue. In contrast resistin gene expression in adipose tissue was rather weak and remained unchanged by pregnancy. Thus, resistin is a newly isolated placental hormone in humans which may modulate insulin sensitivity during pregnancy.

Blotting, Northern↗

PubMed1991

Comparative study of the influence of pregnancy and hormonal treatment on mammary carcinogenesis.

Since it has been shown that pregnancy protects the mammary gland from chemically induced carcinogenesis, this study was designed with the dual purpose of determining whether treatment of young virgin rats with the placental hormone chorionic gonadotropin (hCG) mimics pregnancy-induced changes in the tumourigenic response of the mammary gland and also whether the effect induced by both pregnancy and hormonal treatments was transitory, or a more permanent one, exerting the same effect when the period of time between delivery or termination of treatment and exposure to the carcinogen is lengthened. Virgin Sprague-Dawley rats were utilised in two experimental protocols. For protocol I, 50 day-old rats were either mated (Group II), or started receiving a daily intraperitoneal injection of 100 IU hCG (Group III) at age 50. Age-matched untreated virgin rats were used as controls (Group I). Twenty-one days after either delivery or termination of treatment all the animals received an intragastric dose of 8 mg DMBA/100 gbw. For the second protocol, 50 day-old virgin rats were also mated (Group V) or were treated with hCG for 21 days (Group VI); the resting period between delivery or termination of treatment was lengthened to 63 days, at which time they received a dose of DMBA. Age-matched controls (Group IV) received DMBA only. Tumourigenesis was evaluated 24 weeks post-carcinogen administration in all the groups. Pregnancy and hCG followed by the 21-day resting period significantly depressed mammary carcinogenesis to 11% and 6% respectively, compared with 63% in control animals. When the resting period was prolonged to 63 days there was also a significant depression in adenocarcinoma incidence to 9% in pregnancy (Group IV) in which it was observed that tumour incidence was also reduced as a consequence of aging at the time of exposure to the carcinogen. These results clearly indicate that hCG is as efficient as pregnancy and significantly reduces mammary carcinogenesis, and that the protective effect of both pregnancy and hCG treatment is long-lasting and both are more efficient than aging in reducing mammary carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1975

Human chorionic gonadotropin. Its inhibitory effect on cell-mediated immunity in vivo and in vitro.

An inhibitory effect of human chorionic gonadotropin (HCG) on delayed hypersensitivity skin test responses in guinea-pigs given 4000 i.u. of HCG intraperitoneally, 1--7 days prior to skin testing, is presented. The effect of HCG on skin test responses lasted for at least 3 weeks. Inhibition of lymphocyte response to PHA or PPD in the HCG-treated guinea-pigs was also observed. Guinea-pig peripheral blood lymphocyte response to mitogen or antigen is unequivocally inhibited by HCG in vitro. The effect of this hormone is not due to direct cytotoxicity, and its inhibitory effect seems to be dose related. These observations support the hypothesis that the HCG and possibly other placental hormones might play an important role in protecting the foetus against maternal rejection.

Animals↗

PubMed1993

[Pathology of the placenta. XIII. Pathological anatomy of the placenta and placental insufficiency].

An account is given of morphological issues relating to placental insufficiency. Variable manifestations of placental insufficiency in foetuses and newborns are described in some detail. Reference is made to morphological clues useful in diagnosing causes of placental insufficiency. It proved to be particularly difficult to find quantitatively recordable parameters for such diagnosis, comparable to morphological indicators resulting from various placental measurements or from determination of exchange area and thickness measurement of placental basal membranes. Most of these quantitative methods, after all, would not even be applicable to routine examination. All the other diagnostic criteria of placental insufficiency are part of obstetrics (placental hormone production, measurement of uterus circulation and of intervillous space). In a more specialized section of this paper, reference is made to various pathologico-anatomic patterns of placental disorders and their specific relevance to placental insufficiency. Circulatory disorders (maternal side), placental inflammation, impaired maturation and obliterative endarteriitis were the most common findings in this order.

Female↗