-
Tierarztliche Praxis. Ausgabe G,... Oct 2020The pituitary gonadotrophins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play a prominent role in the control of gonadal functions. Therefore, their... (Review)
Review
The pituitary gonadotrophins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play a prominent role in the control of gonadal functions. Therefore, their use in the treatment of fertility disorders (e. g. anovulatory anestrus) as well as in biotechnology (e. g. superovulation, hormone programs for cycle synchronization) is of substantial interest. Preparations of FSH or LH are relatively expensive due to the laborious extraction from pituitary tissue and are therefore reserved for special indications. In primates and equids, the chorionic epithelium expresses an LH-like molecule (chorionic gonadotrophin, CG). Equine CG (eCG) selectively binds to LH receptors in equids. In all other domestic mammalian species, equine CG (eCG) shows an extraordinarily high FSH activity in addition to its LH activity ("dual activity"). Since its market launch, this has therefore gained considerable importance as a comparatively inexpensive FSH analogue, mainly for use in ruminants and pigs. In contrast to the human CG (hCG), which may be isolated non-invasively from the urine of pregnant women and is widely used as LH analogue, eCG must be extracted from the blood of pregnant donor mares, as eCG concentrations in urine are only minimal. Following reports of deaths and suffering of donor mares associated with eCG collection in South American settings, the current practice of eCG production has given rise to increasing public criticism. This has recently led to calls for a general production ban. Primary aim of this review is therefore to summarize the current state of knowledge concerning the properties and biology of this molecule, which is also highly interesting from the point of view of basic science.
Topics: Animal Welfare; Animals; Chorionic Gonadotropin; Female; Gonadotropins, Equine; Horses; Pregnancy; Veterinary Drugs
PubMed: 33080658
DOI: 10.1055/a-1235-7973 -
Domestic Animal Endocrinology Jan 2017Leptin is involved in various reproductive processes in humans and rodents, including placental development and function. The specific ways that leptin influences...
Leptin is involved in various reproductive processes in humans and rodents, including placental development and function. The specific ways that leptin influences placental development and function in cattle are poorly understood. This work was completed to explore how leptin regulates hormone, cytokine and metalloprotease transcript abundance, and cell proliferation in cultured bovine trophoblast cells. In the first set of studies, cells were cultured in the presence of graded recombinant bovine leptin concentrations (0, 10, 50, 250 ng/mL) for 6 or 24 h. Transcript profiles were examined from extracted RNA. Leptin supplementation did not affect abundance of the maternal recognition of pregnancy factor, interferon-tau (IFNT), but leptin increased (P < 0.05) abundance of chorionic somatomammotropin hormone 2 (CSH2; ie, placental lactogen) at both 6 and 24 h at each concentration tested. At 24 h, the greatest CSH2 abundance (P < 0.05) was detected in cells supplemented with 50 ng/mL leptin. Transcript abundance of the remodeling factor, metalloprotease 2 (MMP2), was greater (P < 0.05) in leptin-treated cells at 24 h but not at 6 h. The 24 h MMP2 response was greatest (P < 0.05) at 250 ng/mL. Transcript abundance for MMP9 was not altered by leptin treatment. In a separate set of studies, cell proliferation assays were completed. Leptin supplementation did not affect bovine trophoblast cell line proliferation at any dose tested. In conclusion, leptin supplementation did not affect bovine trophoblast cell proliferation or IFNT expression, but leptin increases CSH2 and MMP2 transcript abundance. Both of these factors are involved with peri-implantation and postimplantation placental development and function, and this implicates leptin as a potential mediator of early placental development and function in cattle.
Topics: Animals; Cattle; Cell Proliferation; Cells, Cultured; Female; Gene Expression; Interferon Type I; Leptin; Matrix Metalloproteinase 2; Placenta; Placental Lactogen; Pregnancy; Pregnancy Proteins; RNA, Messenger; Recombinant Proteins; Trophoblasts
PubMed: 27743526
DOI: 10.1016/j.domaniend.2016.09.001 -
Reproductive Biology and Endocrinology... Aug 2020It is widely known that luteinising hormone (LH) and human chorionic gonadotrophin (hCG) are integral in the female reproductive lifecycle. Due to the common binding... (Review)
Review
It is widely known that luteinising hormone (LH) and human chorionic gonadotrophin (hCG) are integral in the female reproductive lifecycle. Due to the common binding site and similarity in molecular structure, they were previously thought to have overlapping roles. However, with the development of both purified urinary-derived and recombinant gonadotrophins, the individual characteristics of these molecules have begun to be defined. There is evidence to suggest that LH and hCG preferentially activate different signalling cascades and display different receptor-binding kinetics. The data generated on the two molecules have led to an improved understanding of their distinct physiological functions, resulting in a debate among clinicians regarding the most beneficial use of LH- and hCG-containing products for ovarian stimulation (OS) in assisted reproductive technologies (ARTs). Over the past few decades, a number of trials have generated data supporting the use of hCG for OS in ART. Indeed, the data indicated that hCG plays an important role in folliculogenesis, leads to improved endometrial receptivity and is associated with a higher quality of embryos, while presenting a favourable safety profile. These observations support the increased use of hCG as a method to provide LH bioactivity during OS. This review summarises the molecular and functional differences between hCG and LH, and provides an overview of the clinical trial data surrounding the use of products for OS that contain LH bioactivity, examining their individual effect on outcomes such as endometrial receptivity, oocyte yield and embryo quality, as well as key pregnancy outcomes.
Topics: Chorionic Gonadotropin; Female; Humans; Infertility; Ovulation Induction; Pregnancy; Pregnancy Outcome; Reproductive Techniques, Assisted; Treatment Outcome
PubMed: 32762698
DOI: 10.1186/s12958-020-00639-3 -
Advances in Experimental Medicine and... 2015The dialogue between the mammalian conceptus (embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the... (Review)
Review
The dialogue between the mammalian conceptus (embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients, collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of Developmental Origins of Health and Disease (DOHAD). Although mechanisms responsible for differential growth and development of the conceptus resulting in DOHAD phenomena remain unclear, epigenetic events involving methylation of DNA are likely mechanisms. Histotroph includes serine and methionine which can contribute to the one carbon pool, and arginine, lysine and histidine residues which may be targets of methylation. It is also clear that supplementing the diet with arginine enhances fetal-placental development in rodents, swine and humans through mechanisms that remain to be elucidated. However, molecules secreted by conceptuses such as interferon tau in ruminants, estrogens and interferons in pigs and chorionic gonadotrophin, along with progesterone, regulate expression of genes for nutrient transporters. Understanding mechanisms whereby select nutrients regulate expression of genes in cell signaling pathways critical to conceptus development, implantation and placentation is required for improving successful establishment and maintenance of pregnancy in mammals.
Topics: Amino Acids; Animals; Chorionic Gonadotropin; DNA Methylation; Embryo Implantation; Embryo, Mammalian; Epigenesis, Genetic; Female; Fetus; Humans; Placenta; Placental Circulation; Pregnancy; Progesterone; Signal Transduction; Uterus
PubMed: 25956294
DOI: 10.1007/978-1-4939-2480-6_2 -
Molecular Immunology Aug 2016Antigenic domains are defined to contain a limited number of neighboring epitopes recognized by antibodies (Abs) but their molecular relationship remains rather elusive.... (Review)
Review
Antigenic domains are defined to contain a limited number of neighboring epitopes recognized by antibodies (Abs) but their molecular relationship remains rather elusive. We thoroughly analyzed the antigenic surface of the important pregnancy and tumor marker human chorionic gonadotropin (hCG), a cystine knot (ck) growth factor, and set antigenic domains and epitopes in molecular relationships to each other. Antigenic domains on hCG, its free hCGα and hCGβ subunits are dependent on appropriate inherent molecular features such as molecular accessibility and protrusion indices that determine bulging structures accessible to Abs. The banana-shaped intact hCG comprises ∼7500Å(2) of antigenic surface with minimally five antigenic domains that encompass a continuum of overlapping non-linear composite epitopes, not taking into account the C-terminal peptide extension of hCGβ (hCGβCTP). Epitopes within an antigenic domain are defined by specific Abs, that bury nearly 1000Å(2) of surface accessible area on the antigen and recognize a few up to 15 amino acid (aa) residues, whereby between 2 and 5 of these provide the essential binding energy. Variability in Ab binding modes to the contact aa residues are responsible for the variation in affinity and intra- and inter-species specificity, e.g. cross-reactions with luteinizing hormone (LH). Each genetically distinct fragment antigen binding (Fab) defines its own epitope. Consequently, recognition of the same epitope by different Abs is only possible in cases of genetically identical sequences of its binding sites. Due to combinatorial V(D)J gene segment variability of heavy and light chains, Abs defining numerous epitopes within an antigenic domain can be generated by different individuals and species. Far more than hundred Abs against the immuno-dominant antigenic domains of either subunit at both ends of the hCG-molecule, the tips of peptide loops one and three (Ł1+3) protruding from the central ck, encompassing hCGβŁ1+3 (aa 20-25+64+68-81) and hCGαŁ1 (aa 13-22; Pro16, Phe17, Phe18) plus hCGαŁ3 (Met71, Phe74), respectively, have been identified in the two "ISOBM Tissue Differentiation-7 Workshops on hCG and Related Molecules" and in other studies. These Abs recognize distinct but overlapping epitopes with slightly different specificity profiles and affinities. Heterodimeric-specific epitopes involve neighboring αŁ1 plus βŁ2 (hCGβ44/45 and 47/48). Diagnostically important Abs recognize the middle of the molecule, the ck (aa Arg10, Arg60 and possibly Gln89) and the linear hCGβCTP "tail" (aa 135-145; Asp139, Pro144, Gln145), respectively. Identification of antigenic domains and of specific epitopes is essential for harmonization of Abs in methods that are used for reliable and robust hCG measurements for the management of pregnancy, pregnancy-related disease and tumors.
Topics: Antigens; Chorionic Gonadotropin; Crystallography, X-Ray; Epitopes, B-Lymphocyte; Humans; Models, Molecular
PubMed: 27450517
DOI: 10.1016/j.molimm.2016.06.015 -
Molecular and Cellular Endocrinology Dec 2021Vasoinhibin is an antiangiogenic, profibrinolytic peptide generated by the proteolytic cleavage of the pituitary hormone prolactin by cathepsin D, matrix...
Vasoinhibin is an antiangiogenic, profibrinolytic peptide generated by the proteolytic cleavage of the pituitary hormone prolactin by cathepsin D, matrix metalloproteinases, and bone morphogenetic protein-1. Vasoinhibin can also be generated when placental lactogen or growth hormone are enzymatically cleaved. Here, it is investigated whether plasmin cleaves human prolactin and placental lactogen to generate vasoinhibin-like peptides. Co-incubation of prolactin and placental lactogen with plasmin was performed and analyzed by gel electrophoresis and Western blotting. Mass spectrometric analyses were carried out for sequence validation and precise cleavage site identification. The cleavage sites responsible for the generation of the vasoinhibin-like peptides were located at K170-E171 in prolactin and R160-T161 in placental lactogen. Various genetic variants of the human prolactin and placental lactogen genes are projected to affect proteolytic generation of the vasoinhibin-like peptides. The endogenous counterparts of the vasoinhibin-like peptides generated by plasmin may represent vasoinhibin-isoforms with inhibitory effects on vasculature and coagulation.
Topics: Cell Cycle Proteins; Fibrinolysin; Genetic Variation; HEK293 Cells; Humans; Mass Spectrometry; Peptides; Placental Lactogen; Prolactin; Proteolysis
PubMed: 34601001
DOI: 10.1016/j.mce.2021.111471 -
The Journal of Physiology Apr 2023Maternal obesity and gestational diabetes mellitus (GDM) are associated with insulin resistance and health risks for mother and offspring. Obesity is also characterized...
Obesity and gestational diabetes independently and collectively induce specific effects on placental structure, inflammation and endocrine function in a cohort of South African women.
Maternal obesity and gestational diabetes mellitus (GDM) are associated with insulin resistance and health risks for mother and offspring. Obesity is also characterized by low-grade inflammation, which in turn, impacts insulin sensitivity. The placenta secretes inflammatory cytokines and hormones that influence maternal glucose and insulin handling. However, little is known about the effect of maternal obesity, GDM and their interaction, on placental morphology, hormones and inflammatory cytokines. In a South African cohort of non-obese and obese pregnant women with and without GDM, this study examined placental morphology using stereology, placental hormone and cytokine expression using real-time PCR, western blotting and immunohistochemistry, and circulating TNFα and IL-6 concentrations using ELISA. Placental expression of endocrine and growth factor genes was not altered by obesity or GDM. However, LEPTIN gene expression was diminished, syncytiotrophoblast TNFα immunostaining elevated and stromal and fetal vessel IL-6 staining reduced in the placenta of obese women in a manner that was partly influenced by GDM status. Placental TNFα protein abundance and maternal circulating TNFα concentrations were reduced in GDM. Both maternal obesity and, to a lesser extent, GDM were accompanied by specific changes in placental morphometry. Maternal blood pressure and weight gain and infant ponderal index were also modified by obesity and/or GDM. Thus, obesity and GDM have specific impacts on placental morphology and endocrine and inflammatory states that may relate to pregnancy outcomes. These findings may contribute to developing placenta-targeted treatments that improve mother and offspring outcomes, which is particularly relevant given increasing rates of obesity and GDM worldwide. KEY POINTS: Rates of maternal obesity and gestational diabetes (GDM) are increasing worldwide, including in low-middle income countries (LMIC). Despite this, much of the work in the field is conducted in higher-income countries. In a well-characterised cohort of South African women, this study shows that obesity and GDM have specific impacts on placental structure, hormone production and inflammatory profile. Moreover, such placental changes were associated with pregnancy and neonatal outcomes in women who were obese and/or with GDM. The identification of specific changes in the placenta may help in the design of diagnostic and therapeutic approaches to improve pregnancy and neonatal outcomes with particular significant benefit in LMICs.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Diabetes, Gestational; Placenta; Tumor Necrosis Factor-alpha; Interleukin-6; Obesity, Maternal; South Africa; Obesity; Inflammation; Cytokines; Insulin Resistance
PubMed: 36849131
DOI: 10.1113/JP284139 -
Reproductive Biology and Endocrinology... Oct 2014Gonadotropins extracted from the urine of post-menopausal women have traditionally been used to stimulate folliculogenesis in the treatment of infertility and in... (Comparative Study)
Comparative Study Review
Gonadotropins extracted from the urine of post-menopausal women have traditionally been used to stimulate folliculogenesis in the treatment of infertility and in assisted reproductive technology (ART). Products, such as human menopausal gonadotropin (hMG), consist not only of a mixture of the hormones, follicle-stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotropin (hCG), but also other biologically active contaminants, such as growth factors, binding proteins and prion proteins. The actual amount of molecular LH in hMG preparations varies considerably due to the purification process, thus hCG, mimicking LH action, is added to standardise the product. However, unlike LH, hCG plays a different role during the natural human menstrual cycle. It is secreted by the embryo and placenta, and its main role is to support implantation and pregnancy. More recently, recombinant gonadotropins (r-hFSH and r-hLH) have become available for ART therapies. Recombinant LH contains only LH molecules. In the field of reproduction there has been controversy in recent years over whether r-hLH or hCG should be used for ART. This review examines the existing evidence for molecular and functional differences between LH and hCG and assesses the clinical implications of hCG-supplemented urinary therapy compared with recombinant therapies used for ART.
Topics: Animals; Chorionic Gonadotropin; Drug Contamination; Drug Industry; Evidence-Based Medicine; Female; Fertility Agents, Female; Humans; Infertility, Female; Luteinizing Hormone; Recombinant Proteins; Reproductive Techniques, Assisted
PubMed: 25280580
DOI: 10.1186/1477-7827-12-95 -
Fiziologiia Cheloveka Jan 2017The last two decade discoveries shift the accent from consideration of human chorionic gonadotripin (hCG) as a hormone, that controls progesterone production by corpus... (Review)
Review
The last two decade discoveries shift the accent from consideration of human chorionic gonadotripin (hCG) as a hormone, that controls progesterone production by corpus luteum cells, to a powerful paracrine regulator which'in the tandem with its hyperglycozilated analog (hCG-H) induces successful implantation and coordinated dialog between blastocyst and uterus tissues. Ability of hCG to interact with TSH receptor and hCG-H with TGF-beta-RII extend significantly the spectrum of processes controlled by these molecules. Differences between intracellular pathways of signal transduction between hCG and LH mediated by the same receptor (LH/hCG-R) impugn unity of their effector mechanisms previously considered as obvious. Paracine properties-of hCG comprise control of fusing of trophoblasts into syncytiotrophoblasts, angiogenesis, immunity regulation and endometrium predisposition to implantation. Angiogenesis is associated with LH/hCG-R expressed on mural cells of uterine spiral arteries as well as induced secretion of soluble VEGF type by endometrial cells. hCG.regulates ratio between different forms of T-helper cells in maternal organism on the initial gestation stage determining high level of Th2 cells. hCG supports local immunotolerance acting as chemoattractant for T-suppressors (T-Treg) and apoptotic factor for T-lymphocytes. Endometrial susceptibility arises from activation of osteopantin secretion and decline of mucin secretion by epithelial cells. hCG-H acts on the same tissues as hCG as a paracrine agent regulating multiple cascades of cytokines. hCG-H plays the key role in trophoblast invasion into,uterine decidua as a result of gelatinase secretion by these cells.The degree of angiogenic effect of hCG-H is compatiblewith hCG but its signal transduction is mediated by TGF-beta signal transduction pathway that stimulates mural cell proliferation. hCG-H acts as mitogen on NK-cells and is able to activate them and direct to angiogenesis maintenance. In this article the attempt was made to elucidate the most important discoveries about the role of hCG and its hyperglycosylated analog yet accomplished and still upcoming.
Topics: Autoimmune Diseases; Chorionic Gonadotropin; Corpus Luteum; Endometrium; Female; Humans; Killer Cells, Natural; Mitogens; Mucin-1; Placenta; Placentation; Pregnancy; Progesterone; Signal Transduction
PubMed: 29509368
DOI: No ID Found -
Neuropharmacology May 2020Mammalian pregnancy and lactation is accompanied by a period of infertility that takes place in the midst of a sustained increase in food intake. Indeed, successful... (Review)
Review
Mammalian pregnancy and lactation is accompanied by a period of infertility that takes place in the midst of a sustained increase in food intake. Indeed, successful reproduction in females is dependent on co-ordination of the distinct systems that regulate reproduction and metabolism. Rather than arising from different mechanisms during pregnancy and lactation, we propose that elevations in lactogenic hormones (predominant among these being prolactin and the placental lactogens), are ideally placed to influence both of these systems at the appropriate time. We review the literature examining the impacts of lactogens on fertility and energy homeostasis in the virgin state, during pregnancy and lactation and potential long-term impacts of reproductive experience. Taken together, the literature indicates that duration and pattern of lactogen exposure is a vital factor in the ability of these hormones to alter reproduction and food intake. Transient increases in prolactin, as typically seen in healthy virgin females and males, are unable to exert lasting impacts. Importantly, both suppression of fertility and increased food intake are only observed following exposure to chronically-elevated levels of lactogens. Physiologically, the only time this pattern of lactogenic secretion is maintained in the healthy female is during pregnancy and lactation, when co-ordination between these regulatory systems emerges. This article is part of the special issue on 'Neuropeptides'.
Topics: Animals; Appetite Regulation; Energy Metabolism; Female; Fertility; Humans; Lactation; Male; Placental Lactogen; Pregnancy; Prolactin; Reproduction
PubMed: 32058177
DOI: 10.1016/j.neuropharm.2019.107911