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Increased serum ghrelin in preeclampsia: is ghrelin a friend or a foe?

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(5) . DOI: 10.17772/gp/57852. P R A C E. O R Y G I N A L N E po ł o ż n i c t wo. Increased serum ghrelin in preeclampsia: Is ghrelin a friend or a foe? Podwyższony poziom greliny w stanie przedrzucawkowym: czy grelina jest przyjacielem czy wrogiem? Onur Erol1 

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(16) #( 1. Department of Obstetrics and Gynecology, Antalya Training and Research Hospital, Antalya, Turkey Department of Biochemistry, Antalya Training and Research Hospital, Antalya, Turkey 3 Department of Obstetrics and Gynecology, Antalya Training and Research Hospital, Antalya, Turkey 4 Department of Obstetrics and Gynecology, Antalya Training and Research Hospital, Antalya, Turkey 5 Department of Obstetrics and Gynecology, Antalya Training and Research Hospital, Antalya, Turkey 6 Department of Biochemistry, Antalya Training and Research Hospital, Antalya, Turkey 7 Department of Biochemistry, Antalya Training and Research Hospital, Antalya, Turkey 2. Abstract Objectives: To investigate maternal serum ghrelin levels in pregnancies complicated by preeclampsia and to explore the relationship between ghrelin level and disease severity. Materials and methods: This case–control study included 40 healthy pregnant women, 42 women with mild preeclampsia, and 40 women with severe preeclampsia. The groups were matched in terms of maternal and gestational age and body mass index. Serum ghrelin levels were measured via enzyme immunoassay. Results: Serum ghrelin levels were significantly higher in women with mild and severe preeclampsia than in healthy controls (p<0.001). Although serum ghrelin levels were somewhat higher in the severe compared to the mild preeclampsia group, the difference was not statistically significant (p>0.05). In the control group, no significant correlation was observed between ghrelin level and any other parameter, but in the preeclampsia group, serum ghrelin levels were negatively correlated with uterine artery Doppler index values and both systolic and diastolic blood pressure (all p-values <0.05). Multivariate stepwise linear regression analysis revealed that systolic blood pressure (` = 0.493, p = 0.023) was independently associated with serum ghrelin level. Conclusion: Elevated blood ghrelin levels were correlated with disease severity in pregnancies complicated by preeclampsia.. Key words: ghrelin / pregnancy / preeclampsia /. Corresponding author: Onur Erol Department of Obstetrics and Gynecology, Antalya Training and Research Hospital, Antalya, Turkey Phone: 90-242-2494400 e-mail: dronurerol@hotmail.com. Nr 4/2016. © Polskie Towarzystwo Ginekologiczne. Otrzymano: 20.02.2015 Zaakceptowano do druku: 31.05.2015. 277.

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(21) . Onur Erol et al. Increased serum ghrelin in preeclampsia: Is ghrelin a friend or a foe?. Streszczenie Cel pracy: Ocena poziomu greliny w surowicy kobiet w ciąży powikłanej stanem przedrzucawkowym i określenie związku między poziomem greliny a ciężkością choroby. Materiał i metoda: Do badania włączono 40 zdrowych kobiet w ciąży, 42 z łagodnym stanem przedrzucawkowym i  40 z  ciężkim stanem przedrzucawkowym. Grupy były dobrane pod względem wieku ciążowego, wieku matek i wskaźnika masy ciała. Poziom greliny w surowicy był mierzony metodą immunoenzymatyczną. Wyniki: Poziom greliny w surowicy był istotnie wyższy u kobiet z łagodnym i ciężkim stanem przedrzucawkowym niż w  grupie kontrolnej (p<0.001). Chociaż poziom greliny w  surowicy był wyższy w  grupie z  ciężkim stanem przedrzucawkowym niż w  grupie z  łagodnym stanem przedrzucawkowym, to ta różnica nie była istotna statystycznie (p>0.05). W grupie kontrolnej nie obserwowano żadnych istotnych związków pomiędzy poziomem greliny a jakimkolwiek innym parametrem, ale w grupie ze stanem przedrzucawkowym poziom greliny w surowicy był ujemnie skorelowany z indeksami przepływów Dopplera w tętnicy macicznej oraz ciśnieniem krwi skurczowym i rozkurczowym (all p-values <0.05). Wieloczynnikowa analiza regresji liniowej wykazała, że skurczowe ciśnienie krwi było niezależnym czynnikiem związanym z poziomem greliny w surowicy (` = 0.493, p = 0.023). Wnioski: Podwyższony poziom greliny we krwi był związany z ciężkością choroby w ciążach powikłanych stanem przedrzucawkowym.. Słowa kluczowe: grelina / / stan przedrzucawkowy /. Introduction )'

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(420) . DOI: 10.17772/gp/57852. Onur Erol et al. Increased serum ghrelin in preeclampsia: Is ghrelin a friend or a foe?. Tabl e I . Comparison of clinical characteristics and Doppler parameters of the study groups.. Variables. Control (n=40). Mild preeclampsia (n=42). Severe preeclampsia (n=40). p. Age. 28.1±3.7. 27.7±4.8. 28.2±2.8. 0.284. Gestational age (week). 38.9±0.5. 38.6±2.2. 38.5±2.5. 0.245. BMI (kg/m2). 30.6±1.1. 30.8±2.2. 30.7±2.4. 0.467. 3 (1-5). 2 (1-4). 2 (1-5). 0.164. Systolic blood pressure (mmHg). 100.1±7.4. 147.9±6.4. 166.4±8.2. Diastolic blood pressure (mmHg). 70±7.4. 96.6±5.5. 0.65±0.12. Umbilical artery RI Uterine artery PI Uterine artery RI Birth weight (g). Gravidity. Umbilical artery PI. p1. p2. p3. <0.001. <0.001. <0.001. <0.001. 110.2±7.9. <0.001. <0.001. <0.001. <0.001. 0.70±0.14. 1.28±0.23. <0.001. 0.445. <0.001. <0.001. 0.41±0.11. 0.47±0.15. 0.70±0.18. <0.001. 0.255. <0.001. 0.002. 0.59±0.19. 0.63±0.18. 1.25±0.11. 0.001. 0.131. <0.001. <0.001. 0.36±0.14. 0.42±0.11. 0.67±0.12. 0.01. 0.335. 0.001. <0.001. 3548±232. 3307±410. 2768±312. <0.001. 0.035. <0.001. <0.001. Values are given as mean ± SD ( standart deviation ) or median (range). p – between three groups; p1 – between mild preeclampsia and control; p2 – between severe preeclampsia and controls; p3 – between severe preeclampsia and mild preeclampsia. BMI – body mass index, PI – pulsatility index, RI – resistance index.. Ta bl e I I . Correlations between serum ghrelin levels and other variables assessed in the control and preeclampsia groups. Control group. Gestational age BMI. Preeclampsia group. r. p. r. p. 0.183. 0.362. 0.025. 0.862. 0.37. 0.058. 0.11. 0.441. Systolic blood pressure. -0.113. 0.576. -0.591. <0.001*. Diastolic blood pressure. -0.177. 0.377. -0.541. <0.001*. Umbilical artery PI. -0.143. 0.478. 0.187. 0.105. Umbilical artery RI. -0.217. 0.277. 0.118. 0.302. Uterine artery PI. -0.093. 0.645. -0.334. 0.003*. Uterine artery RI. -0.143. 0.476. -0.362. 0.015*. Birth weight. 0.152. 0.448. 0.039. 0.27. BMI – body mass index, PI – pulsatility index, RI – resistance index, * Significant difference. $

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(661) * . Authors’ contribution: 1. Onur Erol – study design, analysis, assumptions , interpretation of data, corresponding author. 2. Hamit Y. Ellidağ – study design, acquisition of data. 3. Hülya Ayık – concept, assumptions, study design. 4. Gül A. Bülbül – acquisition of data. 5. Aysel U. Derbent – revised article critically. 6. Sibel Kulaksızoğlu – acquisition of data. 7. Necat Yılmaz – revised article critically. Authors’ statement ³. This is to certify, that the publication will not violate the copyrights of a third party, as understood according to the Act in the matter of copyright and related rights of 14 February 1994, Official Journal 2006, No. 90, Clause 63, with respect to the text, data, tables and illustrations (graphs, figures, photographs); ³. there is no ‘conflict of interests’ which occurs when the author remains in a financial or personal relationship which unjustly affects his/her actions associated with the publication of the manuscript; ³. any possible relationship(s) of the author(s) with the party/parties interested in the publication of the manuscript are revealed in the text of the article; ³. the manuscript has not been published in or submitted to any other journal. Source of financing: None.. References 1. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005, 365,785–799. 2. Kornacki J, Skrzypczak J. Preeclampsia – two manifestations of the same disease. Ginekol Pol. 2008,79,432-437. 3. Miehle K, Stepan H, Fasshauer M. Leptin, adiponectin and other adipokines in gestational diabetes mellitus and pre-eclampsia. Clin Endocrinol (Oxf). 2012, 76,2-11. 4. Kojima M, Hosoda H, Date Y, [et al.]. Ghrelin is a growth hormone releasing acylated peptide from stomach. Nature 1999,402, 656-660. 5. Khatib N, Gaidhane S, Gaidhane AM, [et al.]. Ghrelin: ghrelin as a regulatory peptide in growth hormone secretion. J Clin Diagn Res. 2014,8,MC13-7.. Conclusions " -.

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(705) *''. 6. Iwakura H, Kangawa K, Nakao K. The regulation of circulating ghrelin – with recent updates from cell-based assays [Review]. Endocr J. 2014,2. 7. Lin Y, Matsumura K, Fukuhara M, [et al.]. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 2004,43,977-982. 8. Shimizu Y, Nagaya N, Teranishi Y, [et al.]. Ghrelin improves endothelial dysfunction through growth hormone independent mechanisms in rats. Biochem Biophys Res Commun. 2003,310, 830-835.. © Polskie Towarzystwo Ginekologiczne. 281.

(706) P R A C E O R Y G I N A L N E poł ożn i ct wo. DOI: 10.17772/gp/57852.  

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(710) . Onur Erol et al. Increased serum ghrelin in preeclampsia: Is ghrelin a friend or a foe?. 9. Brown MA, Lindheimer MD, de Swiet M, [et al.]. The classification and diagnosis of the hypertensive disorders of pregnancy: Statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 2001, 20, IX–XIV 10. Gualillo O, Caminos J, Blanco M, [et al.]. Ghrelin, a  novel placental derived hormone. Endocrinology 2001,142,788-794. 11. Kedzia A, Tarka A, Petriczko E, [et al.]. Placental growth hormone (PGH), pituitary growth hormone (GH1), insulin-like growth factor (IGF-I) and ghrelin in pregnant women’s blood serum. Ginekol Pol. 2013, 84,620-623. 12. Cortelazzi, D, Cappiello V, Morpurgo PS, [et al.]. Circulating levels of ghrelin in human fetuses. Eur J Endocrinol. 2003,149, 111-116. 13. Farquhar J, Heiman M, Wong AC, [et al.]. Elevated umbilical cord ghrelin concentrations in small for gestational age neonates. J Clin Endocrinol Metab 2003, 88, 4324–4327. 14. Makino Y, Hosoda H, Shibata K, [et al.]. Alteration of plasma ghrelin levels associated with the blood pressure in pregnancy. Hypertension 2002, 39,781-784. 15. Aydin S, Guzel SP, Kumru S, [et al.]. Serum leptin and ghrelin concentrations of maternal serum, arterial and venous cord blood in healthy and preeclamptic pregnant women. J Physiol Biochem. 2008, 64,51-59. 16. Mao Y, Tokudome T, Kishimoto I. Ghrelin  as a  treatment  for  cardiovascular diseases. Hypertension. 2014, 64,450-454. 17. Enomoto M, Nagaya N, Uematsu M, [et al.]. Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci (Lond). 2003, 105,431–435. 18. Pöykkö SM, Kellokoski E, Horkko S, [et al.]. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003,52,2546-2553. 19. Huppertz B. Placental origins of preeclampsia challenging the current hypothesis. Hypertension 2008,51,970-975. 20. Silva LA, Klein C, Ealy AD, [et al.]. Conceptus-mediated endometrial vascular changes during early pregnancy in mares: an anatomic, histomorphometric, and vascular endothelial growth factor receptor system immunolocalization and gene expression study. Reproduction 2011,142,593–603. 21. Sudo N, Shimizu T, Kawashima C, [et al.]. Insulin-like growth factor-I (IGF-I) system during follicle development in the bovine ovary: relationship among IGF-I, type 1 IGF receptor (IGFR-1) and pregnancy-associated plasma protein-A (PAPP-A). Mol Cell Endocrinol. 2007, 264,197–203. 22. Milewicz T, Krzysiek J, Rogatko I, [et al.]. Bimodal influence of plasma estradiol on relation between insulin-like growth factor-I  (IGF-I) and estradiol in women. Neuro Endocrinol Lett. 2011,32,857–864. 23. Powers RW, Jeyabalan A, Clifton RG, [et al.]. Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network. Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies. PLoS One 2010,11,e13263. 24. Conti E, Zezza L, Ralli E, [et al.]. Growth factors in preeclampsia: a vascular disease model. A  failed vasodilation and angiogenic challenge from pregnancy onwards? Cytokine Growth Factor Rev. 2013, 24,411-425. 25. Chen JZ, Sheehan PM, Brennecke SP, [et al.]. Vessel remodelling, pregnancy hormones and extravillous trophoblast function. Mol Cell Endocrinol. 2012, 349,138-144. 26. Tropea A, Tiberi F, Minici F, [et al.]. Ghrelin affects the release of luteolytic and luteotropic factors in human luteal cells. J Clin Endocrinol Metab. 2007, 92,3239-3245. 27. Delgado M, Ganea D. Anti-inflammatory neuropeptides: a  new class of endogenous immunoregulatory agents. Brain Behav Immun. 2008, 22,1146-1151. 28. Fang F, Wang L, Zhang Y, [et al.]. Role of ghrelin on estrogen and progesterone secretion in the adult rat ovary during estrous cycle. Syst Biol Reprod Med. 2012 58,116-119. 29. Fernández-Fernández R, Tena-Sempere M, [et al.]. Ghrelin effects on gonadotropin secretion in male and female rats. Neurosci Lett. 2004,362,103-107. 30. Zaniolo K, Sapieha P, Shao Z, [et al.]. Ghrelin modulates physiologic and pathologic retinal angiogenesis through GHSR-1a. Invest Ophthalmol Vis Sci. 2011, 52, 5376-5386.. 282. © Polskie Towarzystwo Ginekologiczne. Nr 4/2016.

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