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RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas
BACKGROUND: Pheochromocytomas and paragangliomas (PPGL) are catecholamine-producing neuroendocrine tumors that arise from the adrenal medulla or ganglia and display the highest heritability rate among all human tumours. Genomic analyses allowed identification of molecular subgroups of PPGL which are...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624813/ http://dx.doi.org/10.1210/jendso/bvac150.292 |
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author | Lopez, Antoine-Guy Duparc, Céline Renouf, Sylvie Machevin, Elise Guillou, Vincent L Sabourin, Jean-Christophe Defortescu, Guillaume Buffet, Alexandre Gimenez-Roqueplo, Anne-Paule Dubessy, Christophe Lefebvre, Hervé Louiset, Estelle |
author_facet | Lopez, Antoine-Guy Duparc, Céline Renouf, Sylvie Machevin, Elise Guillou, Vincent L Sabourin, Jean-Christophe Defortescu, Guillaume Buffet, Alexandre Gimenez-Roqueplo, Anne-Paule Dubessy, Christophe Lefebvre, Hervé Louiset, Estelle |
author_sort | Lopez, Antoine-Guy |
collection | PubMed |
description | BACKGROUND: Pheochromocytomas and paragangliomas (PPGL) are catecholamine-producing neuroendocrine tumors that arise from the adrenal medulla or ganglia and display the highest heritability rate among all human tumours. Genomic analyses allowed identification of molecular subgroups of PPGL which are organized into 2 main clusters. Cluster 1 contains SDHx- and VHL-mutated tumors which do not produce epinephrine while cluster 2 includes the epinephrine-secreting PPGL related to RET, NF1, TMEM127 and MAX mutations. PPGL must be early diagnosed and treated to prevent adrenergic crises which can be life-threatening. Detection of PPGL is particularly important during pregnancy since PPGL are associated with a high risk of either maternal or fetal complications in this context. Reciprocally, pregnancy can favor adrenergic crises in patients with previously undiagnosed or silent pheochromocytoma (PCC). These dangerous events can be triggered by tumor compression resulting from fetus growth, or labor and delivery. However, it is known that surges in plasma catecholamines may also occur during early gestation suggesting that pregnancy may also activate the secretory activity of PPGL through the involvement of non-mechanical factors, such as gestational hormones. METHODS: In the present study, we report a case of silent PCC revealed in a pregnant woman by life-threatening adrenergic myocarditis occurring at 31 weeks of gestation. Analysis of PPGL susceptibility genes showed the presence of a heterozygous germline RET variant of uncertain significance. The fact that the first symptoms of catecholamine excess had appeared during the first trimester of pregnancy led us to conduct in vitro studies to investigate the effects of estradiol and the pregnancy hormone chorionic gonadotropin (hCG) on epinephrine secretion by cultured cells derived from the resected patient's tumor. Expression of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) was searched for in the tumor and an additional series of 12 PCC by RT-qPCR and immunohistochemistry. LHCGR expression was also analyzed in silico in the PPGL cohorts of the COMETE and The Cancer Genome Atlas (TCGA) databases. RESULTS: hCG stimulated epinephrine secretion by primary cultured PCC cells. The tumor expressed the LHCG receptor, which was colocalized with catecholamine-producing enzymes. A similar expression pattern of the LHCG receptor was also observed in 5 out of a series of 12 PCCs. Moreover, in silico studies revealed that PPGL display the highest expression levels of LHCGR mRNA among the 32 solid tumor types of TCGA cohort. Interestingly, expression of LHCGR was higher in cluster 2 than in cluster 1 PPGL. CONCLUSION: We show that PCC can express functional LHCG receptor. Consequently, pregnancy may activate catecholamine production by previously silent pheochromocytoma as early as the first trimester of gestation especially in women with gene mutations that predispose to cluster 2 epinephrine-secreting PCC. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:18 p.m. - 1:23 p.m. |
format | Online Article Text |
id | pubmed-9624813 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-96248132022-11-14 RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas Lopez, Antoine-Guy Duparc, Céline Renouf, Sylvie Machevin, Elise Guillou, Vincent L Sabourin, Jean-Christophe Defortescu, Guillaume Buffet, Alexandre Gimenez-Roqueplo, Anne-Paule Dubessy, Christophe Lefebvre, Hervé Louiset, Estelle J Endocr Soc Adrenal BACKGROUND: Pheochromocytomas and paragangliomas (PPGL) are catecholamine-producing neuroendocrine tumors that arise from the adrenal medulla or ganglia and display the highest heritability rate among all human tumours. Genomic analyses allowed identification of molecular subgroups of PPGL which are organized into 2 main clusters. Cluster 1 contains SDHx- and VHL-mutated tumors which do not produce epinephrine while cluster 2 includes the epinephrine-secreting PPGL related to RET, NF1, TMEM127 and MAX mutations. PPGL must be early diagnosed and treated to prevent adrenergic crises which can be life-threatening. Detection of PPGL is particularly important during pregnancy since PPGL are associated with a high risk of either maternal or fetal complications in this context. Reciprocally, pregnancy can favor adrenergic crises in patients with previously undiagnosed or silent pheochromocytoma (PCC). These dangerous events can be triggered by tumor compression resulting from fetus growth, or labor and delivery. However, it is known that surges in plasma catecholamines may also occur during early gestation suggesting that pregnancy may also activate the secretory activity of PPGL through the involvement of non-mechanical factors, such as gestational hormones. METHODS: In the present study, we report a case of silent PCC revealed in a pregnant woman by life-threatening adrenergic myocarditis occurring at 31 weeks of gestation. Analysis of PPGL susceptibility genes showed the presence of a heterozygous germline RET variant of uncertain significance. The fact that the first symptoms of catecholamine excess had appeared during the first trimester of pregnancy led us to conduct in vitro studies to investigate the effects of estradiol and the pregnancy hormone chorionic gonadotropin (hCG) on epinephrine secretion by cultured cells derived from the resected patient's tumor. Expression of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) was searched for in the tumor and an additional series of 12 PCC by RT-qPCR and immunohistochemistry. LHCGR expression was also analyzed in silico in the PPGL cohorts of the COMETE and The Cancer Genome Atlas (TCGA) databases. RESULTS: hCG stimulated epinephrine secretion by primary cultured PCC cells. The tumor expressed the LHCG receptor, which was colocalized with catecholamine-producing enzymes. A similar expression pattern of the LHCG receptor was also observed in 5 out of a series of 12 PCCs. Moreover, in silico studies revealed that PPGL display the highest expression levels of LHCGR mRNA among the 32 solid tumor types of TCGA cohort. Interestingly, expression of LHCGR was higher in cluster 2 than in cluster 1 PPGL. CONCLUSION: We show that PCC can express functional LHCG receptor. Consequently, pregnancy may activate catecholamine production by previously silent pheochromocytoma as early as the first trimester of gestation especially in women with gene mutations that predispose to cluster 2 epinephrine-secreting PCC. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:18 p.m. - 1:23 p.m. Oxford University Press 2022-11-01 /pmc/articles/PMC9624813/ http://dx.doi.org/10.1210/jendso/bvac150.292 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Adrenal Lopez, Antoine-Guy Duparc, Céline Renouf, Sylvie Machevin, Elise Guillou, Vincent L Sabourin, Jean-Christophe Defortescu, Guillaume Buffet, Alexandre Gimenez-Roqueplo, Anne-Paule Dubessy, Christophe Lefebvre, Hervé Louiset, Estelle RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas |
title | RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas |
title_full | RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas |
title_fullStr | RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas |
title_full_unstemmed | RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas |
title_short | RF33 | PSUN04 Luteinizing Hormone-Chorionic Gonadotrophin Receptor in Pheochromocytomas |
title_sort | rf33 | psun04 luteinizing hormone-chorionic gonadotrophin receptor in pheochromocytomas |
topic | Adrenal |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9624813/ http://dx.doi.org/10.1210/jendso/bvac150.292 |
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