期刊论文详细信息
BMC Endocrine Disorders
Ethinylestradiol30μg-drospirenone and metformin: could this combination improve endothelial dysfunction in polycystic ovary syndrome?
Carmen Emanuela Pepene2  Ileana Duncea2  Lucian Mocan3  Razvan Ilie4  Teodora Mocan1  Ioan Marian5  Ioana Rada Ilie2 
[1] Departmen of Physiology, University of Medicine and Pharmacy, Cluj-Napoca, Romania;Department of Endocrinology, University of Medicine and Pharmacy, 3-5 Louis Pasteur, 400349, Cluj-Napoca, Romania;3-rd Department of Surgery, University of Medicine and Pharmacy, Cluj-Napoca, Romania;Department of Obstetrics and Gynecology, University of Medicine and Pharmacy, Cluj-Napoca, Romania;Department of Internal Medicine-Cardiology, University of Medicine and Pharmacy, Cluj-Napoca, Romania
关键词: Polycystic ovary syndrome;    Metformin;    HsCRP;    Endothelial dysfunction;    Flow-mediated dilatation;    Ethinylestradiol30μg-drospirenone;   
Others  :  1086402
DOI  :  10.1186/1472-6823-12-9
 received in 2012-02-15, accepted in 2012-06-19,  发布年份 2012
【 摘 要 】

Background

We are hereby investigating for the first time the effect of the association ethinylestradiol30μg-drospirenone 3mg (DRP/EE30μg) plus metformin and weight loss on endothelial status and C-reactive protein (hsCRP) levels in polycystic ovary syndrome (PCOS).

Methods

25 young women with PCOS (mean age 22.76 ± 0.83 years, body mass index (BMI): 28.44 ± 6.23) who completed the study were prospectively evaluated. The oral contraceptive- DRP/EE30μg (21 days/month) and metformin (1700 mg daily) were administered for 6 months to the PCOS group. Additionally, the 15 overweight and obese patients (BMI > 25 kg/m2) were instructed in a diet of no more than 1500 cal daily. Primary outcome measures were surrogate markers of cardiovascular disease and included endothelial function, i.e. flow-mediated dilatation (FMD) on the brachial artery and endothelin-1 levels, as well as hsCRP concentrations, body composition (measured by whole-body dual-energy X-ray-absorptiometry) and insulin resistance. Variables were assessed at baseline, as well as after our medical intervention.

Results

The combination between DRP/EE30μg plus metformin combined with weight loss triggered a significant improvement in the FMD values (FMD-PCOSbasal 3.48 ± 1.00 vs FMD-PCOS6 months7.43 ± 1.04, p = 0.033), as well as body composition and insulin insensitivity (p < 0.05). Regarding hsCRP levels, there was no significant intragroup (PCOS6months – PCOSbasal) difference.

Conclusion

A 6-month course of metformin- DRP/EE30μg (associated with weight loss) improves the endothelial dysfunction in PCOS and shows neutral effects on hsCRP concentrations as an inflammation marker. These data demand for reevaluation of the medical therapy in PCOS, particularly in women with additional metabolic and cardiovascular risk factors (ClinicalTrials.gov Identifier: NCT01459445).

【 授权许可】

   
2012 Ilie et al.; licensee BioMed Central Ltd.

附件列表
Files Size Format View
Figure 1. 87KB Image download
【 图 表 】

Figure 1.

【 参考文献 】
  • [1]Pepene CE, Ilie IR, Marian I, Duncea I: Circulating osteoprotegerin and soluble receptor activator of nuclear factor {kappa}B ligand in polycystic ovary syndrome: relationships to insulin resistance and endothelial dysfunction. Eur J Endocrinol 2011, 164:61-8.
  • [2]Shaw LJ, Bairey Merz CN, Azziz R, Stanczyk FZ, Sopko G, Braunstein GD, Kelsey SF, Kip KE, Cooper-Dehoff RM, Johnson BD, Vaccarino V, Reis SE, Bittner V, Hodgson TK, Rogers W, Pepine CJ: Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation. J Clin Endocrinol Metab 2008, 93:1276-84.
  • [3]Ilie IR, Pepene CE, Marian I, Mocan T, Hazi G, Dragotoiu G, Ilie R, Mocan L, Duncea I: The polycystic ovary syndrome [pcos] status and cardiovascular risk in young women. Cent Eur J Med 2011, 6:64-75.
  • [4]Buzdugan E, Crisan S, Campean R, Donca V, Radulescu D, Duncea C: Cardiovascular event risk in relation to arterial stiffness in patients with subclinical peripheral atherosclerosis. HVM Bioflux 2009, 1:45-54.
  • [5]Diamanti-Kandarakis E, Alexandraki K, Piperi C, Protogerou A, Katsikis I, Paterakis T, Lekakis J, Panidis D: Inflammatory and endothelial markers in women with polycystic ovary syndrome. Eur J Clin Invest 2006, 36:691-697.
  • [6]Meyer C, McGrath BP, Teede HJ: Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease. J Clin Endocrinol Metab 2005, 90:5711-5716.
  • [7]Diamanti-Kandarakis E, Spina G, Kouli C, Migdalis I: Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy. J Clin Endocrinol Metab 2001, 86:4666-73.
  • [8]Agarwal N, Rice SP, Bolusani H, Luzio SD, Dunseath G, Ludgate M, Rees DA: Metformin reduces arterial stiffness and improves endothelial function in young women with polycystic ovary syndrome: a randomized, placebo-controlled, crossover trial. J Clin Endocrinol Metab 2010, 95:722-30.
  • [9]Meyer C, McGrath BP, Teede HJ: Effects of medical therapy on insulin resistance and the cardiovascular system in polycystic ovary syndrome. Diabetes Care 2007, 30:471-8.
  • [10]Diamanti-Kandarakis E, Alexandraki K, Protogerou A, Piperi C, Papamichael C, Aessopos A, Lekakis J, Mavrikakis M: Metformin administration improves endothelial function in women with polycystic ovary syndrome. Eur J Endocrinol 2005, 152:749-756.
  • [11]Teede HJ, Meyer C, Hutchison SK, Zoungas S, McGrath BP, Moran LJ: Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Fertil Steril 2010, 93:184-91.
  • [12]Diamanti-Kandarakis E, Paterakis T, Alexandraki K, Piperi C, Aessopos A, Katsikis I, Katsilambros N, Kreatsas G, Panidis D: Indices of low-grade chronic inflammation in polycystic ovary syndrome and the beneficial effect of metformin. Hum Reprod 2006, 21:1426-1431.
  • [13]Morin-Papunen L, Rautio K, Ruokonen A, Hedberg P, Puukka M, Tapanainen JS: Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003, 88:4649-54.
  • [14]Nader S, Diamanti-Kandarakis E: Polycystic ovary syndrome, oral contraceptives and metabolic issues: new perspectives and a unifying hypothesis. Hum Reprod 2007, 22:317-22.
  • [15]Mancini F, Cianciosi A, Persico N, Facchinetti F, Busacchi P, Battaglia C: Drospirenone and cardiovascular risk in lean and obese polycystic ovary syndrome patients: a pilot study. Am J Obstet Gynecol 2010, 202(169):e1-8.
  • [16]Battaglia C, Mancini F, Fabbri R, Persico N, Busacchi P, Facchinetti F, Venturoli S: Polycystic ovary syndrome and cardiovascular risk in young patients treated with drospirenone-ethinylestradiol or contraceptive vaginal ring. A prospective, randomized, pilot study. Fertil Steril 2010, 94:1417-1425.
  • [17]Azziz R, Carmina E, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Futterweit W, Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF: Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006, 91:4237-4245.
  • [18]Simoncini T, Caruso A, Giretti MS, Scorticati C, Fu XD, Garibaldi S, Baldacci C, Mannella P, Fornari L, Genazzani AR: Effects of dydrogesterone and of its stable metabolite, 20-alpha-dihydrodydrogesterone, on nitric oxide synthesis in human endothelial cells. Fertil Steril 2006, 86:1235-1242.
  • [19]Maeda S, Jesmin S, Iemitsu M, Otsuki T, Matsuo T, Ohkawara K, Nakata Y, Tanaka K, Goto K, Miyauchi T: Weight loss reduces plasma endothelin-1 concentration in obese men. Exp Biol Med (Maywood) 2006, 231:1044-1047.
  • [20]Raitakari M, Ilvonen T, Ahotupa M, Lehtimäki T, Harmoinen A, Suominen P, Elo J, Hartiala J, Raitakari OT: Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol 2004, 24:124-128.
  • [21]Hamdy O, Ledbury S, Mullooly C, Jarema C, Porter S, Ovalle K, Moussa A, Caselli A, Caballero AE, Economides PA, Veves A, Horton ES: Lifestyle modification improves endothelial function in obese subjects with the insulin resistance syndrome. Diabetes Care 2003, 26:2119-2125.
  • [22]Clifton PM, Keogh JB, Foster PR, Noakes M: Effect of weight loss on inflammatory and endothelial markers and FMD using two low-fat diets. Int J Obes (Lond) 2005, 29:1445-51.
  • [23]Keogh JB, Brinkworth GD, Clifton PM: Effects of weight loss on a low-carbohydrate diet on flow-mediated dilatation, adhesion molecules and adiponectin. Br J Nutr 2007, 98:852-9.
  • [24]Orio F, Palomba S, Cascella T, De Simone B, Manguso F, Savastano S, Russo T, Tolino A, Zullo F, Lombardi G, Azziz R, Colao A: Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study. J Clin Endocrinol Metab 2005, 90:6072-6076.
  • [25]Palomba S, Falbo A, Giallauria F, Russo T, Tolino A, Zullo F, Colao A, Orio F: Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome. Diabetes Care 2010, 33:246-251.
  • [26]English JL, Jacobs LO, Green G, Andrews TC: Effect of the menstrual cycle on endothelium-dependent vasodilation of the brachial artery in normal young women. Am J Cardiol 1998, 82:256-8.
  • [27]Williams MR, Westerman RA, Kingwell BA, Paige J, Blombery PA, Sudhir K, Komesaroff PA: Variations in endothelial function and arterial compliance during the menstrual cycle. J Clin Endocrinol Metab 2001, 86:5389-5395.
  • [28]Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL: Oral contraceptives improve endothelial function in amenorrheic athletes. J Clin Endocrinol Metab 2005, 90:3162-3167.
  • [29]Rickenlund A, Eriksson MJ, Schenck-Gustafsson K, Hirschberg AL: Amenorrhea in female athletes is associated with endothelial dysfunction and unfavorable lipid profile. J Clin Endocrinol Metab 2005, 90:1354-9.
  • [30]Wakatsuki A, Okatani Y, Ikenoue N, Fukaya T: Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen. Circulation 2001, 104:1773-1778.
  • [31]Faludi AA, Aldrighi JM, Bertolami MC, Saleh MH, Silva RA, Nakamura Y, Pereira IR, Abdalla DS, Ramires JA, Sousa JE: Progesterone abolishes estrogen and/or atorvastatin endothelium dependent vasodilatory effects. Atherosclerosis 2004, 177:89-96.
  • [32]Meendering JR, Torgrimson BN, Miller NP, Kaplan PF, Minson CT: A combined oral contraceptive containing 30 mcg ethinyl estradiol and 3.0 mg drospirenone does not impair endothelium-dependent vasodilation. Contraception 2010, 82:366-372.
  • [33]Ibanez L, Valls C, Cabre S, De Zegher F: Flutamide-metformin plus ethinylestradiol-drospirenone for lipolysis and antiatherogenesis in young women with ovarian hyperandrogenism: the key role of early, low-dose flutamide. J Clin Endocrinol Metab 2004, 89:4716-4720.
  • [34]Holte J, Bergh T, Berne C, Wide L, Lithell H: Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 1995, 80:2586-2593.
  • [35]Ibanez L, de Zegher F: Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women. Hum Reprod Update 2006, 12:243-252.
  • [36]Ibanez L, de Zegher F: Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity. J Clin Endocrinol Metab 2004, 89:1592-1597.
  • [37]Palep-Singh M, Mook K, Barth J, Balen A: An observational study of Yasmin in the management of women with polycystic ovary syndrome. J Fam Plann Reprod Health Care 2004, 30:163-165.
  • [38]Guido M, Romualdi D, Giuliani M, Suriano R, Selvaggi L, Apa R, Lanzone A: Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 2004, 89:2817-2823.
  • [39]Fruzzetti F, Perini D, Lazzarini V, Parrini D, Gambacciani M, Genazzani AR: Comparison of effects of 3 mg drospirenone plus 20 mug ethinyl estradiol alone or combined with metformin or cyproterone acetate on classic metabolic cardiovascular risk factors in nonobese women with polycystic ovary syndrome. Fertil Steril 2010, 94:1793-1798.
  • [40]Mohlig M, Spranger J, Osterhoff M, Ristow M, Pfeiffer AF, Schill T, Schlösser HW, Brabant G, Schöfl C: The polycystic ovary syndrome per se is not associated with increased chronic inflammation. Eur J Endocrinol 2004, 150:525-532.
  • [41]Shroff R, Kerchner A, Maifeld M, Van Beek EJ, Jagasia D, Dokras A: Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab 2007, 92:4609-4614.
  • [42]Tarkun I, Arslan BC, Canturk Z, Turemen E, Sahin T, Duman C: Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. J Clin Endocrinol Metab 2004, 89:5592-5596.
  • [43]Orio F, Palomba S, Cascella T, Di Biase S, Manguso F, Tauchmanovà L, Nardo LG, Labella D, Savastano S, Russo T, Zullo F, Colao A, Lombardi G: The increase of leukocytes as a new putative marker of low-grade chronic inflammation and early cardiovascular risk in polycystic ovary syndrome. J Clin Endocrinol Metab 2005, 90:2-5.
  • [44]Puder JJ, Varga S, Kraenzlin M, De Geyter C, Keller U, Muller B: Central fat excess in polycystic ovary syndrome: relation to low-grade inflammation and insulin resistance. J Clin Endocrinol Metab 2005, 90:6014-6021.
  • [45]Moran LJ, Noakes M, Clifton PM, Wittert GA, Belobrajdic DP, Norman RJ: C-reactive protein before and after weight loss in overweight women with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2007, 92:2944-2951.
  • [46]Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R, Giugliano D: Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 2003, 289:1799-1804.
  • [47]Jakubowska J, Bohdanowicz-Pawlak A, Milewicz A, Szymczak J, Bednarek-Tupikowska G, Demissie M: Plasma cytokines in obese women with polycystic ovary syndrome, before and after metformin treatment. Gynecol Endocrinol 2008, 24:378-384.
  • [48]Caballero AE, Delgado A, Aguilar-Salinas CA, Herrera AN, Castillo JL, Cabrera T, Gomez-Perez FJ, Rull JA: The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2004, 89:3943-8.
  • [49]Tan BK, Adya R, Chen J, Farhatullah S, Heutling D, Mitchell D, Lehnert H, Randeva HS: Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc Res 2009, 83:566-74.
  • [50]Lacut K, Oger E, Le Gal G, Blouch MT, Abgrall JF, Kerlan V, Scarabin PY, Mottier D, SARAH Investigators: Differential effects of oral and transdermal postmenopausal estrogen replacement therapies on C-reactive protein. Thromb Haemost 2003, 90:124-131.
  • [51]Puder JJ, Freda PU, Goland RS, Wardlaw SL: Estrogen modulates the hypothalamic-pituitary-adrenal and inflammatory cytokine responses to endotoxin in women. J Clin Endocrinol Metab 2001, 86:2403-8.
  • [52]Haarala A, Eklund C, Pessi T, Lehtimäki T, Huupponen R, Jula A, Viikari J, Raitakari O, Hurme M: Use of combined oral contraceptives alters metabolic determinants and genetic regulation of C-reactive protein. The Cardiovascular Risk in Young Finns Study. Scand J Clin Lab Invest 2009, 69:168-174.
  • [53]Lowe GD, Upton MN, Rumley A, McConnachie A, O'Reilly DS, Watt GC: Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI and C-reactive protein–a cross-sectional population survey. Thromb Haemost 2001, 86:550-6.
  • [54]Yang L, Wang L, Lin HK, Kan PY, Xie S, Tsai MY, Wang PH, Chen YT, Chang C: Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells. Biochem Biophys Res Commun 2003, 305:462-9.
  • [55]Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Klein J, Paschke R: Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2003, 301:1045-50.
  • [56]Hansen PR, Rieneck K, Bendtzen K: Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells. Immunol Lett 2004, 91:87-91.
  • [57]Ibanez L, Valls C, de Zegher F: Discontinuous low-dose flutamide-metformin plus an oral or a transdermal contraceptive in patients with hyperinsulinaemic hyperandrogenism: normalizing effects on CRP, TNF-alpha and the neutrophil/lymphocyte ratio. Hum Reprod 2006, 21:451-6.
  文献评价指标  
  下载次数:0次 浏览次数:7次