Cemil AKGÜL, Pervin VURAL, Vatandaş Gülnar GÜLAÇTI

Effects of menopause and postmenopausal hormone replacement therapy on plasma nitrate/nitrate and endothelin-1 levels

Amaç: Bu çalışmanın amacı menopoz sonrası (postmenopozda) plazma nitrat/nitrit (NOx) ve endotelin-1 (ET-1) düzeylerinde meydana gelen değişiklikleri, ve farklı hormon replasman tedavilerinin (HRT) bu vazoaktif maddeler üzerindeki etkisini incelemekti. Gereç ve yöntem: Çalışmaya 50 sağlıklı postmenopozal (PMW) ve 25 sağlıklı premenopozal kadın dahil edildi. Postmenopozal kadınlar rastgele iki alt gruba ayrıldı: siklik HRT ve kesintisiz HRT alan alt gruplar. 1. grup (siklik HRT) 2 ay boyunca siklüsün 1-28 günleri arasında 0,625mg konjuge estojen (CEE) + 18-28 günleri arasında 5mg medroksiprogesteron asetat (MPA) alan kadınlardan oluşturuldu. 2. grup (kesintisiz HRT) ise 2 ay boyunca siklüsün 1-28 günleri arasında 0,625mg CEE + 2,5mg MPAalan kadınlardan oluşturuldu. Sonuçların istatiksel değerlendirilmesinde Kruskal-Wallis, Mann-Whitney U, Wilcoxon signed ranks, ve Spearman korelasyon testleri kullanıldı.Bulgular: Premenopozal olanlara kıyasla postmenopozal kadınlarda NOx konsantrasyonları azalırken, ET-1 kon- santrasyonları artmaktadır. Premenopozal kadınlarda NOx ve ET-1 arasında görülen pozitif korelasyon, bu iki parametre arasında bir denge olduğunu göstermektedir. Bu denge menopozda değişmektedir. İki aylık HRT menopozla azalan NOx'nın artmasına neden olurken, ET-1 üzerine bir etkisi yoktur, böylece HRT NOx ve ET-1 arasındaki dengeyi düzenlemektedir. Siklik HRT'ye kıyasla kesintisiz HRT endotel fonksiyonu ve NOx/ET-1 arasındaki kritik dengenin sürdürülmesinde daha başarılı olduğunu söyleyebiliriz.Sonuç: Sonuçlarımızdan da görüldüğü gibi, HRT'ye cavaben postmenopozal kadınların bir kısmında (3/4) plazma NOx düzeyleri artmakta, bir kısmında ise (1/4) azalmaktadır; bu da, hepsi olmasa da postmenopozal kadınların çoğunun HRT'nin pozitif etkilerinden yararlandığını söyleyebiliriz.

Menopozun ve hormon replasman tedavisinin plazma nitrat/nitrit ve endotelin-1 düzeylerine etkisi

Objective: The aim of this study was to investigate the changes of plasma nitrate/nitrite (NOx) and endothelin-1 (ET-1) in postmenopause in comparison with premenopausal state and assess the effects of different hormone replacement regimens on these vasoactive substances. Materials and methods: The study involved 50 healthy postmenopausal (PMW), and 25 healthy premenopausal women. PMW were randomly divided into two subgroups: women receiving cyclic hormone replacement therapy (HRT) [0,625mg conjugated estrogen (CEE) from day 1 to day 28 + 5mg medroxyprogesterone acetate (MPA) from day 18 to day 28] (n=25); second subgroup consisted of women receiving continuous HRT [0.625mg CEE + 2,5mg MPAfrom day 1 to day 28] (n=25) for two months. Statistical significance was analysed by Kruskal-Wallis, Mann-Whitney U, Wilcoxon signed ranks, and Spearman correlation tests.Results: Compared with premenopausal individuals, PMW have decreased NOx and increased ET-1. There is a positive correlation between NOx and ET-1 in premenopausal women, suggesting that there is a balance between NOx and ET-1. This balance is changed with menopause. Two month durated HRT significantly elevates NOx that is diminished with menopause and does not change ET-1, thereby improves the NOx/ET-1 balance.Conclusion: Continuous HRT is more successful than cyclic HRT in improving the endothelial function and maintaining the critical balance between NOx and ET-1. Our data provide evidence for the existence of increased (3/4 of subjects) and reduced (1/4 of subjects) NOx levels in response to HRT, which suggest that a significant number (but not all) of the HRT receiving postmenopausal women profit from the beneficial effects of HRT.

PDF

___

1) Akgul C, Canbaz M, Vural P. Effects of tibolone on endogenous nitric oxide (nitrite/nitrate levels) in postmenopausal women. Int J fertil 2002; 47: 13-17.
2) Akgul C, Canbaz M, Vural P, Yildirim A, Geren N. Hormone replacement therapy and urinary prostaglandins in postmenopausal women. Maturitas 1998; 30: 79-83.
3) Balci H, Altunyurt S, Acar B, Fadiloglu M, Kirkali G, Onvural B. Effects of transdermal estrogen therapy on plasma levels of nitric oxide and plasma lipids in postmenopausal women. Maturitas 2005; 50: 289-293.
4) Best PJM, Beger PB, Miller VM, Lerman A. The effect of estrogen replacement therapy on nitric oxide and endothelin-1 levels in postmenopausal women. Ann Intern Med 1998; 128: 285-288
5) Busse R, Fleming I. Endothelial dysfunction in atherosclerosis. J Vasc Res 1996; 33: 181-194.
6) Cagnacci A, Tarquini R, Perfetto F, Arangino S, Zanni AL, Facchinetti F. Endothein-1 and nitric oxide are related cardiovascular risk dactors but are not modified by estradiol replacement in healthy postmenopausal women. A crossectional and randomised cross-over study. Maturitas 2003; 44: 117-124.
7) Christodoulakos G, Panoulis C, Kouskouni E, Chondros C, Dendrinos S, Cretsas G. Effects of estrogen-progestin and raloxifene therapy on nitric oxide, prostacyclin and endothelin-1 synthesis. Gynecol Endocrinol 2002; 16: 9-17.
8) De Nucci G, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, Vane JR. Pressor effects of endothelin are limited by its removal in the pulmonary circulation and by release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 1998; 85: 9797-9800.
9) Dubey RK. Vasodilator-derived nitric oxide inhibits fetal calf serum and angiotensin-II-induced growth of renal arteriolar smooth muscle cells. J Pharmacol Exp Ther 1994; 269: 402-408.
10) Giaid A, Gibson SJ, Ibrahim BN, Legon S, Bloom SR, Yanagisawa M, Masaki T, Varndell IM, Polak JM. Endothelin 1, an endothelium- derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia. Proc Natl Acad Sci USA 1989; 86: 7634-7638.
11) Gisclard V, Miller VM, Vanhoutte PM. Effect of 17 beta-estradiol on endothelium-dependent responses in the rabbit. J Pharmacol Exp Ther 1988; 244: 19-22.
12) Grisham MB, Johnson GG, Lancaster JR. Quantitation of nitrate and nitrite in extracellular fluids. Methods Enzymol 1996; 268: 237-246.
13) Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Up-regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Leett 1995; 360: 291-293.
14) Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B,Vittinghoff E. Randomised trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and estrogen/progestin replacement study (HERS) research group. J Am Med Assoc 1998; 280: 605-613.
15) Imthurn B, Roselli M, Jaeger AW, Keller PJ, Dubey RK. Differential effects of hormone-replacement therapy on endogenous nitric oxide (nitrite/nitrate) levels in postmenopausal women sobstituted with 17_-estradiol valerate and cyprosterone acetate or medroxyprogesterone acetate. J Clin Endocrinol Metab 1997; 82: 388-394.
16) Isomura H, Fujie K, Shibata K, Inoue N, Iizuka T, Takebe G, Takahashi K, Nishihara J, Ixumi H, Sakamoto W. Bone metabolism and oxidative stress in postmenopausal rats with iron overload. Toxicology 2004; 197: 93-100.
17) Kesim MD, Aydin Y, Erdemir M, Atis A. Nitric oxide in postmenopausal women taking three different HRT regimens. Maturitas 2005; 50: 52-57.
18) Khoram O, Garthwaite M, Magness RR. Endometrial and miometrial expression of nitric oxide synthase isoforms in pre-and postmenopausal women. J Clin Endocrinol Metab 1999; 84: 2226-2232.
19) Kuller LH. Hormone replacement therapy and coronary heart disease. Med Clin Nort Am 2000; 84: 181-198.
20) Lip GY, Blann AD, Jones AF, Baavers DG. Effects of hormone replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: implications for prevention of atherosclerosis. Am Heart J 1997; 134: 764-771.
21) Loscalzo J, Welch G. Nitric oxide and its role in cardiovascular system. Prog cardiovasc Dis 1995; 38: 87-104.
22) Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM. Variable expression of the estrogen receptor in normal and atherosclerotic arteries in postmenopausal women. Circulation 1994; 89: 1501-1510.
23) Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Gushman M. Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Eng J Med 2003; 349: 519-521.
24) Mathew V, Hasdai D, Lerman A. The role of endothelin in coronary atherosclerosis. Mayo Clin Proc 1996; 71: 769-777.
25) Pacifici R, Rifas L, McCraken R, Vered I, McMurty C, Avioli LV, Peck WA. Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release. Proc Natl Acad Sci USA 1989; 86: 2398-2402.
26) Roselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17_-estradiol and norethisterone acetate. A two-year follow-up study. Hypertension 1995; 25: 848-853.
27) Saitta A, Altavilla D, Cucinotta D, Morabito N, Frisina N, Corrado F, D'Anna R, Lasco A, Squadrito G, Gaudio A, Cancellieri F, Arcoraci V, Squadrito F. Randomized, double-blind, placebocontrolled study on effects of raloxifene and hormone replacement therapy on plasma NO concentrations, endothelin-1 levels, and endothelium-dependent vasodialatation in postmenopausal women. Arterioscler Thromb Vasc Biol 2001; 21: 1512-1519.
28) Sanada M. The effect of hormone replacement therapy on metabolism of lipoprotein remnants in postmenopausal women. Maturitas 2000; 34: 75-82.
29) Silvestri A, Gambacciani M, Vitale C, Monteleone P, Ciaponi M, Fini M, Genazzani AR, Mercuro C, Rosano GMC. Different effect of hormone replacement therapy, DHEAS and tibolone on endothelial function in postmenopausal women with increased cardiovascular risk. Maturitas 2005; 50: 305-311.
30) Van-Buren GA, Yang DS, Clark KE. Estrogen-induced uterine vasodilatation is antagonised by L-nitroarginine methyl ester, an inhibitor of nitric oxide synthesis. Am J Obstet Gynecol 1992; 167: 828-833.
31) Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium N Engl J Med 1990; 323: 27-36.
32) Vural P. Nitric oxide/endothelin-1 in preeclampsia. Clinica Chimica Acta 2002; 317: 65-70.
33) Vural P, Akgul C, Canbaz M. Effects of menopause and tibolone on antioxidants in postmenopausal women. Ann Clin Biochem 2005; 42: 220-223.
34) Vural P, Akgul C, Canbaz M: Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacological Research 2006; 54: 298-302.
35) Wang Y, Walsh SW, Kay HH. Placental lipid peroxides and thromboxane are increased and prostacyclin is decreased in women with preeclampsia. Am J Obstet Gynecol 1992; 167: 946- 949.
36) Wilcox CG, Hatch HE, Gentzschein E, Stanczyk F, Lobo RA. Endothelin levels decrease after oral and nonoral estrogen in postmenopausal women with increased cardiovascular risk factors. Fertil Steril 1997; 67: 273-277.
37) Wimalawansa SJ. Rationale for using nitric oxide donor therapy for prevention of bone loss and treatment of osteoporosis in humans. Ann N YAcad Sci 2007; 1117: 283-297.
38) Ylikorkala O, Cacciatore B, Paakkari I, Tikkanen MJ, Viinikka L, Tivonen J. The long-term effects of oral and transdermal postmenopausal hormone replacement therapy on nitric oxide, endothelin- 1, prostecyclin, and thromboxane. Fertil Steril 1998; 69: 8883-8888.