{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:24:10Z","timestamp":1783571050478,"version":"3.55.0"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T00:00:00Z","timestamp":1696291200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T00:00:00Z","timestamp":1696291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["CS-2011-020"],"award-info":[{"award-number":["CS-2011-020"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009324","name":"Tommy's","doi-asserted-by":"publisher","award":["Maternal"],"award-info":[{"award-number":["Maternal"]}],"id":[{"id":"10.13039\/501100009324","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009324","name":"Tommy's","doi-asserted-by":"publisher","award":["Fetal Health Research Centre Grant"],"award-info":[{"award-number":["Fetal Health Research Centre Grant"]}],"id":[{"id":"10.13039\/501100009324","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Reprod. Sci."],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Oral supplementation with L-citrulline, which is sequentially converted to L-arginine then nitric oxide, improves vascular biomarkers and reduces blood pressure in non-pregnant, hypertensive human cohorts and pregnant mice with a pre-eclampsia-like syndrome. This early-phase randomised feasibility trial assessed the acceptability of L-citrulline supplementation to pregnant women with chronic hypertension and its effects on maternal BP and other vascular outcomes. Pregnant women with chronic hypertension were randomised at 12\u201316 weeks to receive 3-g L-citrulline twice daily (<jats:italic>n<\/jats:italic>\u2009=\u200924) or placebo (<jats:italic>n<\/jats:italic>\u2009=\u200912) for 8 weeks. Pregnant women reported high acceptability of oral L-citrulline. Treatment increased maternal plasma levels of citrulline, arginine and the arginine:asymmetric dimethylarginine ratio, particularly in women reporting good compliance. L-citrulline had no effect on diastolic BP (L-citrulline:\u2009\u2212\u20091.82 <jats:italic>95% CI<\/jats:italic> (\u2212\u20095.86, 2.22) vs placebo:\u2009\u2212\u20095.00 <jats:italic>95% CI<\/jats:italic> (\u2212\u200912.76, 2.76)), uterine artery Doppler or angiogenic biomarkers. Although there was no effect on BP, retrospectively, this study was underpowered to detect BP changes\u2009&lt;\u20099 mmHg, limiting the conclusions about biological effects. The increase in arginine:asymmetric dimethylarginine ratio was less than in non-pregnant populations, which likely reflects altered pharmacokinetics of pregnancy, and further pharmacokinetic assessment of L-citrulline in pregnancy is advised.<\/jats:p><jats:p><jats:bold>Trial Registration\u00a0<\/jats:bold>EudraCT 2015-005792-25 (2017-12-22) and ISRCTN12695929 (2018-09-20)<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>\n                <jats:p>In pregnant women with chronic hypertension, L-citrulline is an acceptable intervention which increased plasma L-citrulline bioavailability but did not affect BP, potentially due to altered pharmacokinetics of pregnancy.<\/jats:p>","DOI":"10.1007\/s43032-023-01335-4","type":"journal-article","created":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T17:01:31Z","timestamp":1696352491000},"page":"560-568","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy"],"prefix":"10.1007","volume":"31","author":[{"given":"Laura","family":"Ormesher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Worton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Best","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna R.","family":"Dodd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Dempsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Cottrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Glossop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Chmiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoi Yee","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Hardwick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Hennessy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward D.","family":"Johnstone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny E.","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,3]]},"reference":[{"key":"1335_CR1","unstructured":"National Institute for Health and Care Excellence. Hypertension in pregnancy: diagnosis and management. NICE guideline (NG133). 2019;1\u201341. http:\/\/www.nice.org.uk\/guidance\/ng133."},{"key":"1335_CR2","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/0002-9378(94)90276-3","volume":"171","author":"E Rey","year":"1994","unstructured":"Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol. 1994;171:410\u201316. https:\/\/doi.org\/10.1016\/0002-9378(94)90276-3.","journal-title":"Am J Obstet Gynecol"},{"key":"1335_CR3","doi-asserted-by":"publisher","first-page":"g2301","DOI":"10.1136\/bmj.g2301","volume":"348","author":"K Bramham","year":"2014","unstructured":"Bramham K, Parnell B, Nelson-Piercy C, Seed PT, Poston L, Chappell LC. Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis. BMJ. 2014;348:g2301. https:\/\/doi.org\/10.1136\/bmj.g2301.","journal-title":"BMJ"},{"key":"1335_CR4","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1053\/plac.2002.0819","volume":"23","author":"JM Roberts","year":"2002","unstructured":"Roberts JM, Lain KY. Recent insights into the pathogenesis of pre-eclampsia. Placenta. 2002;23:359\u201372. https:\/\/doi.org\/10.1053\/plac.2002.0819.","journal-title":"Placenta"},{"key":"1335_CR5","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1006\/NIOX.2000.0296","volume":"4","author":"DT Lowe","year":"2000","unstructured":"Lowe DT. Nitric oxide dysfunction in the pathophysiology of preeclampsia. Nitric Oxide. 2000;4:441\u201358. https:\/\/doi.org\/10.1006\/NIOX.2000.0296.","journal-title":"Nitric Oxide"},{"key":"1335_CR6","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1097\/00004872-199312000-00009","volume":"11","author":"WG Haynes","year":"1993","unstructured":"Haynes WG, Noon JP, Walker BR, Webb DJ. Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertens. 1993;11:1375\u201380. https:\/\/doi.org\/10.1097\/00004872-199312000-00009.","journal-title":"J Hypertens"},{"key":"1335_CR7","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/0006-291X(89)92517-5","volume":"160","author":"K Aisaka","year":"1989","unstructured":"Aisaka K, Gross SS, Griffith OW, Levi R. NG-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo? Biochem Biophys Res Commun. 1989;160:881\u20136. https:\/\/doi.org\/10.1016\/0006-291X(89)92517-5.","journal-title":"Biochem Biophys Res Commun"},{"key":"1335_CR8","doi-asserted-by":"publisher","unstructured":"Williams DJ, Vallance PJ, Neild GH, Spencer JA, Imms FJ. Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol. 1997;272. https:\/\/doi.org\/10.1152\/ajpheart.1997.272.2.H748.","DOI":"10.1152\/ajpheart.1997.272.2.H748"},{"key":"1335_CR9","doi-asserted-by":"publisher","unstructured":"Sladek SM, Magness RR, Conrad KP. Nitric oxide and pregnancy. Am J Physiol. 1997;272. https:\/\/doi.org\/10.1152\/AJPREGU.1997.272.2.R441.","DOI":"10.1152\/AJPREGU.1997.272.2.R441"},{"key":"1335_CR10","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/0140-6736(92)90865-Z","volume":"339","author":"A Leone","year":"1992","unstructured":"Leone A, Moncada S, Vallance P, Calver A, Collier J. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992;339:572\u20135. https:\/\/doi.org\/10.1016\/0140-6736(92)90865-Z.","journal-title":"Lancet"},{"key":"1335_CR11","doi-asserted-by":"publisher","unstructured":"Shin S, Thapa SK, Fung HL. Cellular interactions between L-arginine and asymmetric dimethylarginine: transport and metabolism. PLoS One. 2017;12:e0178710. https:\/\/doi.org\/10.1371\/JOURNAL.PONE.0178710.","DOI":"10.1371\/JOURNAL.PONE.0178710"},{"key":"1335_CR12","doi-asserted-by":"publisher","first-page":"179","DOI":"10.3109\/10641960903254505","volume":"32","author":"A Sonmez","year":"2010","unstructured":"Sonmez A, Celebi G, Erdem G, et al. Plasma apelin and ADMA levels in patients with essential hypertension. Clin Exp Hypertens. 2010;32:179\u201383. https:\/\/doi.org\/10.3109\/10641960903254505.","journal-title":"Clin Exp Hypertens"},{"key":"1335_CR13","doi-asserted-by":"publisher","unstructured":"Arlouskaya Y, Sawicka A, G\u0142owala M, et al. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations in patients with obesity and the risk of obstructive sleep apnea (OSA). J Clin Med. 2019;8:897. https:\/\/doi.org\/10.3390\/jcm8060897.","DOI":"10.3390\/jcm8060897"},{"key":"1335_CR14","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1016\/S0140-6736(03)13177-7","volume":"361","author":"MD Savvidou","year":"2003","unstructured":"Savvidou MD, Hingorani AD, Tsikas D, Frolich JC, Vallance P, Nicolaides KH. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet. 2003;361:1511\u20137. https:\/\/doi.org\/10.1016\/S0140-6736(03)13177-7.","journal-title":"Lancet"},{"key":"1335_CR15","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1080\/J.1600-0412.1998.770805.X","volume":"77","author":"A Pettersson","year":"1998","unstructured":"Pettersson A, Hedner T, Milsom I. Increased circulating concentrations of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, in preeclampsia. Acta Obstet Gynecol Scand. 1998;77:808\u201313. https:\/\/doi.org\/10.1080\/J.1600-0412.1998.770805.X.","journal-title":"Acta Obstet Gynecol Scand"},{"key":"1335_CR16","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1006\/BBRC.1996.0279","volume":"219","author":"SM Bode-B\u00f6ger","year":"1996","unstructured":"Bode-B\u00f6ger SM, B\u00f6ger RH, Kienke S, Junker W, Fr\u00f6lich JC. Elevated l-arginine\/dimethylarginine ratio contributes to enhanced systemic NO production by dietaryl-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun. 1996;219:598\u2013603. https:\/\/doi.org\/10.1006\/BBRC.1996.0279.","journal-title":"Biochem Biophys Res Commun"},{"key":"1335_CR17","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1172\/JCI115987","volume":"90","author":"MA Creager","year":"1992","unstructured":"Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992;90:1248\u20131253. https:\/\/doi.org\/10.1172\/JCI115987.","journal-title":"J Clin Invest"},{"key":"1335_CR18","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1038\/jhh.2013.100","volume":"28","author":"T Dorniak-Wall","year":"2014","unstructured":"Dorniak-Wall T, Grivell RM, Dekker GA, Hague W, Dodd JM. The role of L-arginine in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials. J Hum Hypertens. 2014;28:230\u201335. https:\/\/doi.org\/10.1038\/jhh.2013.100.","journal-title":"J Hum Hypertens"},{"key":"1335_CR19","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1113\/jphysiol.2006.126029","volume":"581","author":"MCG Van De Poll","year":"2007","unstructured":"Van De Poll MCG, Ligthart-Melis GC, Boelens PG, Deutz NEP, Van Leeuwen PAM, Dejong CHC. Intestinal and hepatic metabolism of glutamine and citrulline in humans. J Physiol. 2007;581:819\u201327. https:\/\/doi.org\/10.1113\/jphysiol.2006.126029.","journal-title":"J Physiol"},{"key":"1335_CR20","doi-asserted-by":"publisher","first-page":"1672","DOI":"10.1093\/ajcn\/85.1.167","volume":"85","author":"MCG Van De Poll","year":"2007","unstructured":"Van De Poll MCG, Siroen MPC, Van Leeuwen PAM, et al. Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism. Am J Clin Nutr. 2007;85:167\u201372. https:\/\/doi.org\/10.1093\/ajcn\/85.1.167.","journal-title":"Am J Clin Nutr"},{"key":"1335_CR21","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1046\/J.1432-1033.2003.03559.X","volume":"270","author":"A Husson","year":"2003","unstructured":"Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A. Argininosuccinate synthetase from the urea cycle to the citrulline\u2013NO cycle. Eur J Biochem. 2003;270:1887\u201399. https:\/\/doi.org\/10.1046\/J.1432-1033.2003.03559.X.","journal-title":"Eur J Biochem"},{"key":"1335_CR22","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1111\/j.1365-2125.2007.02990.x","volume":"65","author":"E Schwedhelm","year":"2007","unstructured":"Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2007;65:51\u20139. https:\/\/doi.org\/10.1111\/j.1365-2125.2007.02990.x.","journal-title":"Br J Clin Pharmacol"},{"key":"1335_CR23","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.ijcard.2010.10.004","volume":"155","author":"M Ochiai","year":"2010","unstructured":"Ochiai M, Hayashi T, Morita M, et al. Short-term effects of l-citrulline supplementation on arterial stiffness in middle-aged men. Int J Cardiol. 2010;155:257\u201361. https:\/\/doi.org\/10.1016\/j.ijcard.2010.10.004.","journal-title":"Int J Cardiol"},{"key":"1335_CR24","doi-asserted-by":"publisher","unstructured":"Gemmel M, Sutton EF, Brands J, Burnette L, Gallaher MJ, Powers RW. L-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia. Am J Physiol - Regul Integr Comp Physiol. 2021;321:R364\u201376. https:\/\/doi.org\/10.1152\/ajpregu.00115.2020.","DOI":"10.1152\/ajpregu.00115.2020"},{"key":"1335_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2014.10.011","author":"R Powers","year":"2015","unstructured":"Powers R, Weissgerber TL, McGonigal S, et al. Pregnancy Hypertens. 2015. https:\/\/doi.org\/10.1016\/j.preghy.2014.10.011.","journal-title":"Pregnancy Hypertens"},{"key":"1335_CR26","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/1471-0528.15393","volume":"126","author":"JE Myers","year":"2018","unstructured":"Myers JE, Myatt L, Roberts JM, Redman CWG. COLLECT, a collaborative database for pregnancy and placental research studies worldwide. BJOG. 2018;126:8\u201310. https:\/\/doi.org\/10.1111\/1471-0528.15393.","journal-title":"BJOG"},{"key":"1335_CR27","unstructured":"Barkhidarian B, Khorshidi M, Shab-Bidar S, Hashemi B. Effects of L-citrulline supplementation on blood pressure: a systematic review and meta-analysis. Avicenna J Phytomedicine. 2019;9:10\u201320. https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6369322\/."},{"key":"1335_CR28","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/J.PLACENTA.2006.03.015","volume":"28","author":"T Ishikawa","year":"2007","unstructured":"Ishikawa T, Harada T, Koi H, Kubota T, Azuma H, Aso T. Identification of arginase in human placental villi. Placenta. 2007;28:133\u20138. https:\/\/doi.org\/10.1016\/J.PLACENTA.2006.03.015.","journal-title":"Placenta"},{"key":"1335_CR29","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1017\/S0007114507841110","volume":"99","author":"C Moinard","year":"2008","unstructured":"Moinard C, Nicolis I, Neveux N, Darquy S, B\u00e9nazeth S, Cynober L. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. Br J Nutr. 2008;99:855\u201362. https:\/\/doi.org\/10.1017\/S0007114507841110.","journal-title":"Br J Nutr"}],"container-title":["Reproductive Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-023-01335-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s43032-023-01335-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s43032-023-01335-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T18:15:44Z","timestamp":1706638544000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s43032-023-01335-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,3]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,2]]}},"alternative-id":["1335"],"URL":"https:\/\/doi.org\/10.1007\/s43032-023-01335-4","relation":{},"ISSN":["1933-7191","1933-7205"],"issn-type":[{"value":"1933-7191","type":"print"},{"value":"1933-7205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,3]]},"assertion":[{"value":"24 February 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 October 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Ethical approval was obtained from North West Haydock Research Committee (16\/NW\/0557).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"No animal studies were carried out by the authors for this article.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Animal Studies"}},{"value":"Informed consent was obtained prospectively from all patients for being included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}