Effects of the Progestagen-only Contraceptive Implant Implanon^® on Transforming Growth Factor β1 and Endothelin-1

Abstract

Progestagen-only contraceptives are often prescribed to women with an increased cardiovascular risk, despite the fact that only few data are available on the effect of these contraceptives on circulating biomarkers of inflammation and endothelial function. In our prospective case-control study, we aimed to investigate the influence of the low-dose etonogestrel-releasing contraceptive implant Implanon^® on endothelin-1 and cytokine transforming growth factor β (TGF-β1), both factors involved in the early phases of atherogenesis. We also were interested in searching for an interrelation between changes in these two parameters and changes in female hormones and plasma lipids. Cases (n=20) were women using Implanon^® for contraception, and controls (n=20) were females not using hormonal contraception. Baseline blood samples were taken during the early follicular phase of cycle 1 in both groups. A second sample was taken 12 weeks after Implanon^® insertion or, for controls, in the early follicular phase of cycle 4. In both groups no significant change in endothelin-1 or TGF-β1 was observed. In Implanon^® users, cholesterol, high-density lipoprotein, low-density lipoprotein, sex hormone-binding globulin, and testosterone decreased significantly. No correlations were found between endothelin-1 or TGF-β1 and the investigated parameters. The results suggest that Implanon^® does not exert a clinically relevant negative effect on endothelin-1 or TGF-β.

Key words

Implanon^® - endothelin-1 - transforming growth factor β - contraception - progestagen-only pill - cardiovascular risk - atherogenesis

References

• 1 Feinberg MW, Watanabe M, Lebedeva MA, Depina AS, Hanai J, Mammoto T, Frederick JP. et al . Transforming growth factor-beta1 inhibition of vascular smooth muscle cell activation is mediated via Smad3.  J Biol Chem. 2004;  279 16388-16393
• 2 Miller AP, Chen YF, Xing D, Feng W, Oparil S. Hormone replacement therapy and inflammation: interactions in cardiovascular disease.  Hypertension. 2003;  42 657-663
• 3 The ESHRE Capri Workshop Group. . Hormones and cardiovascular health in women.  Hum Reprod Update. 2006;  12 483-497
• 4 Merki-Feld GS. Cardiovascular risks associated with low-dose combined oral contraceptives.  Ther Umsch. 2001;  58 564-569
• 5 Merki-Feld GS, Imthurn B, Keller PJ. The effect of the menstrual cycle and of ethinylestradiol on nitric oxide, endothelin-1 and homocysteine plasma levels.  Horm Metab Res. 2000;  32 288-293
• 6 Merki-Feld GS, Imthurn B, Keller PJ. Effects of two oral contraceptives on plasma levels of nitric oxide, homocysteine, and lipid metabolism.  Metabolism. 2002;  51 1216-1221
• 7 Doring A, Frohlich M, Lowel H, Koenig W. Third generation oral contraceptive use and cardiovascular risk factors.  Atherosclerosis. 2004;  172 281-286
• 8 Heinemann LA, Assmann A, DoMinh T, Garbe E. Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women.  Eur J Contracept Reprod Health Care. 1999;  4 67-73
• 9 Ghosh J, Murphy MO, Turner N, Khwaja N, Halka A, Kielty CM, Walker MG. The role of transforming growth factor beta1 in the vascular system.  Cardiovasc Pathol. 2005;  14 28-36
• 10 Cipollone F, Fazia M, Mincione G, Iezzi A, Pini B, Cuccurullo C, Ucchino S. et al . Increased expression of transforming growth factor-beta1 as a stabilizing factor in human atherosclerotic plaques.  Stroke. 2004;  35 2253-2257
• 11 Grainger DJ. Transforming growth factor beta and atherosclerosis: so far, so good for the protective cytokine hypothesis.  Arterioscler Thromb Vasc Biol. 2004;  24 399-404
• 12 Luscher TF, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs.  Circulation. 2000;  102 2434-2440
• 13 Komuro I, Kurihara H, Sugiyama T, Yoshizumi M, Takaku F, Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells.  FEBS Lett. 1988;  238 249-252
• 14 Gonzalez W, Chen Z, Damon DH. Transforming growth factor-beta regulation of endothelin expression in rat vascular cell and organ cultures.  J Cardiovasc Pharmacol. 2001;  37 219-226
• 15 Rodriguez-Vita  Jr  OM, Ruperez M, Esteban V, Sanchez-Lopez E, Plaza JJ, Egido J. Endothelin-1, via ETA-receptor and independently of transfroming growth factor-beta, increases the connective tissue growth factor in vascular smooth muscle cells.  Circ Res. 2005;  22 125-134
• 16 Fakhouri F, Placier S, Ardaillou R, Dussaule JC, Chatziantoniou C. Angiotensin II activates collagen type I gene in the renal cortex and aorta of transgenic mice through interaction with endothelin and TGF-beta.  J Am Soc Nephrol. 2001;  12 2701-2710
• 17 Merki-Feld GS, Keller PJ. Decrease in endothelin-1 plasma levels during the menstrual cycle and after ethinylestradiol treatment.  Ann Intern Med. 1999;  131 394
• 18 Djurovic S, Os I, Hofstad AE, Abdelnoor M, Westheim A, Berg K. Increased plasma concentrations of TGF-beta1 after hormone replacement therapy.  J Intern Med. 2000;  247 279-285
• 19 Makarainen L, Beek A van, Tuomivaara L, Asplund B, Coelingh Bennink H. Ovarian function during the use of a single contraceptive implant: Implanon^® compared with Norplant.  Fertil Steril. 1998;  69 714-721
• 20 Biswas A, Viegas OA, Roy AC. Effect of Implanon^® and Norplant subdermal contraceptive implants on serum lipids: a randomized comparative study.  Contraception. 2003;  68 189-193
• 21 Baal WM Van, Emeis JJ, Kenemans P, Kessel H, Peters-Muller ER, Schalkwijk CG, Mooren MJ van der. et al . Short-term hormone replacement therapy: reduced plasma levels of soluble adhesion molecules.  Eur J Clin Invest. 1999;  29 913-921
• 22 Silvestri A, Gambacciani M, Vitale C, Monteleone P, Ciaponi M, Fini M, Genazzani AR. et al . Different effect of hormone replacement therapy, DHEAS and tibolone on endothelial function in postmenopausal women with increased cardiovascular risk.  Maturitas. 2005;  50 305-311
• 23 Wiegratz I, Kutschera E, Lee JH, Moore C, Mellinger U, Winkler UH, Kuhl H. Effect of four oral contraceptives on thyroid hormones, adrenal and blood pressure parameters.  Contraception. 2003;  67 361-366
• 24 Polderman KH, Stehouwer CD, Kamp GJ van, Dekker GA, Verheugt FW, Gooren LJ. Influence of sex hormones on plasma endothelin levels.  Ann Intern Med. 1993;  118 429-432
• 25 Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky VE, Daemen MJ. Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression.  Arterioscler Thromb Vasc Biol. 2002;  22 975-982
• 26 Grainger DJ, Kemp PR, Metcalfe JC, Liu AC, Lawn RM, Williams NR, Grace AA. et al . The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis.  Nat Med. 1995;  1 74-79
• 27 Tashiro H, Shimokawa H, Sadamatu K, Yamamoto K. Prognostic significance of plasma concentrations of transforming growth factor-beta in patients with coronary artery disease.  Coron Artery Dis. 2002;  13 139-143
• 28 Grainger DJ, Wakefield L, Bethell HW, Farndale RW, Metcalfe JC. Release and activation of platelet latent TGF-beta in blood clots during dissolution with plasmin.  Nat Med. 1995;  1 932-937
• 29 Shirai Y, Kawata S, Ito N, Tamura S, Takaishi K, Kiso S, Tsushima H. et al . Elevated levels of plasma transforming growth factor-beta in patients with hepatocellular carcinoma.  Jpn J Cancer Res. 1992;  83 676-679
• 30 Eilertsen AL, Hoibraaten E, Os I, Andersen TO, Sandvik L, Sandset PM. The effects of oral and transdermal hormone replacement therapy on C-reactive protein levels and other inflammatory markers in women with high risk of thrombosis.  Maturitas. 2005;  52 111-118
• 31 Fraccarollo D, Galuppo P, Bauersachs J, Ertl G. Collagen accumulation after myocardial infarction: effects of ETA receptor blockade and implications for early remodeling.  Cardiovasc Res. 2002;  54 559-567
• 32 Fukuda G, Khan ZA, Barbin YP, Farhangkhoee H, Tilton RG, Chakrabarti S. Endothelin-mediated remodeling in aortas of diabetic rats.  Diabetes Metab Res Rev. 2005;  21 367-375
• 33 Lawn RM, Pearle AD, Kunz LL, Rubin EM, Reckless J, Metcalfe JC, Grainger DJ. Feedback mechanism of focal vascular lesion formation in transgenic apolipoprotein(a) mice.  J Biol Chem. 1996;  271 31367-31371
• 34 Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice.  Nature. 1994;  370 460-462
• 35 O'Neil CH, Boffa MB, Hancock MA, Pickering JG, Koschinsky ML. Stimulation of vascular smooth muscle cell proliferation and migration by apolipoprotein(a) is dependent on inhibition of transforming growth factor-beta activation and on the presence of kringle IV type 9.  J Biol Chem. 2004;  279 55187-55195
• 36 Grainger DJ, Kirschenlohr HL, Metcalfe JC, Weissberg PL, Wade DP, Lawn RM. Proliferation of human smooth muscle cells promoted by lipoprotein(a).  Science. 1993;  260 1655-1658
• 37 Barkfeldt J, Virkkunen A, Dieben T. The effects of two progestogen-only pills containing either desogestrel (75 microg/day) or levonorgestrel (30 microg/day) on lipid metabolism.  Contraception. 2001;  64 295-299
• 38 Macy PA. Homocysteine: predictor of thrombotic disease.  Clin Lab Sci. 2001;  14 272-275
• 39 Bennink HJ. The pharmacokinetics and pharmacodynamics of Implanon^®, a single-rod etonogestrel contraceptive implant.  Eur J Contracept Reprod Health Care. 2000;  5 ((Suppl 2)) 12-20

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