Back
 JBM  Vol.7 No.8 , August 2019
Effects of Ethinylestradiol/Cyproterone Acetate and Ethinylestradiol/Desogestrel Alone and in Combination with Low-Dose Metformin on Glucose and Lipid Homeostasis and Androgenic Hormone Profile in Hirsute Women with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Triple-Dummy Study
Abstract: Background: The effects of combined oral contraceptive pills and metformin on glucose and lipid metabolism and androgenic hormone profile of hirsute women with polycystic ovary syndrome (PCOS) are not clearly known. Aims: To determine the effect of ethinylestradiol (35 microg)/cyproterone acetate (2 mg) (EE/CPA) and ethinylestradiol (20 microg)/desogestrel 0.15 mg (EE/DES) alone and in combination with metformin on glucose and lipid metabolism and androgenic hormone profile in hirsute women with PCOS. Settings and Design: This randomised, double-blind, triple dummy study was conducted at the Department of Pharmacology, Faulty of Science, University of Peradeniya, Sri Lanka. Methods and Material: A total of 107 patients with PCOS (Rotterdam Consensus Conference Criteria 2003) having hirsutism of 8 or more in the modified Ferriman-Gallwey Score (mFGS), were randomised to receive four drug therapies (arm A: EE/CPA, arm B: EE/DES, arm C: EE/CPA plus metformin, arm D: EE/DES plus metformin). Body mass index, fasting plasma glucose, area under the curve of the oral glucose tolerance test, fasting serum insulin, serum leptin, fasting lipids, serum total testosterone, serum sex hormone-binding globulin were determined at initiation and 12 months. Homeostasis model assessment of beta cell function (HOMA-β), homeostasis model assessment-estimated insulin resistance (HOMA-IR) and free androgen index were calculated. Statistical analysis was done with two ways ANOVA. Results: There was no significant difference in outcome measures at 12 months between the treatment arms. Within the treatment arms, there was reduction of HOMA-β in arm B, serum leptin in arm C, CHO/HDL ratio in arm D and an increase in total cholesterol and LDL-cholesterol in arms B and C. Conclusions: EE/DES and EE/CPA with and without low-dose metformin did not have a significant overall effect on glucose and lipid metabolism and androgenic hormonal profile in hirsute women with PCOS. However, desogestrel has reduced the beta-cell function and both desogestrel and cyproterone have adversely affected the lipids.
Cite this paper: Fonseka, S. , Bandara, D. , Wijeyaratne, C. , Gawarammana, I. , Kalupahana, N. , Rosairo, S. and Kumarasiri, R. (2019) Effects of Ethinylestradiol/Cyproterone Acetate and Ethinylestradiol/Desogestrel Alone and in Combination with Low-Dose Metformin on Glucose and Lipid Homeostasis and Androgenic Hormone Profile in Hirsute Women with Polycystic Ovary Syndrome: A Randomized, Double-Blind, Triple-Dummy Study. Journal of Biosciences and Medicines, 7, 13-26. doi: 10.4236/jbm.2019.78002.
References

[1]   Hardiman, P., Pillay, O.C. and Atiomo, W. (2003) Polycystic Ovary Syndrome and Endometrial Carcinoma. The Lancet, 361, 1810-1812.
https://doi.org/10.1016/S0140-6736(03)13409-5

[2]   Messer, C., Boston, R., Leroith, D., Geer, E., Miller, J.D., Messer, M. and Futterweit, W. (2012) Pancreatic Beta-Cell Dysfunction in Polycystic Ovary Syndrome: The Role of Metformin. Endocrine Practice, 18, 685-693.
https://doi.org/10.4158/EP11375.OR

[3]   Wallace, T.M., Levy, J.C. and Matthews, D.R. (2004) Use and Abuse of HOMA Modeling. Diabetes Care, 27, 1487-1495.
https://doi.org/10.2337/diacare.27.6.1487

[4]   Brzechffa, P.R., Jakimiuk, A.J., Agarwal, S.K., Weitsman, S.R., Buyalos, R.P. and Magoffin, D.A. (1996) Serum Immunoreactive Leptin Concentrations in Women with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism, 81, 4166-4169.
https://doi.org/10.1210/jcem.81.11.8923878

[5]   Moll, G.W. and Rosenfield, R.L. (1979) Testosterone Binding and Free Plasma Androgen Concentrations under Physiological Conditons: Chararacterization by Flow Dialysis Technique. The Journal of Clinical Endocrinology & Metabolism, 49, 730-736.
https://doi.org/10.1210/jcem-49-5-730

[6]   Miller, K.K., Rosner, W., Lee, H., Hier, J., Sesmilo, G., Schoenfeld, D., Neubauer, G. and Klibanski, A. (2004) Measurement of Free Testosterone in Normal Women and Women with Androgen Deficiency: Comparison of Methods. The Journal of Clinical Endocrinology & Metabolism, 89, 525-533.
https://doi.org/10.1210/jc.2003-030680

[7]   Falsetti, L. and Pasinetti, E. (1995) Effects of Long-Term Administration of an Oral Contraceptive Containing Ethinylestradiol and Cyproterone Acetate on Lipid Metabolism in Women with Polycystic Ovary Syndrome. Acta Obstetricia et Gynecologica Scandinavica, 74, 56-60.
https://doi.org/10.3109/00016349509009945

[8]   Legro, R.S., Kunselman, A.R., Dodson, W.C., Dunaif, A. (1999) Prevalence and Predictors of Risk for Type 2 Diabetes Mellitus and Impaired Glucose Tolerance in Polycystic Ovary Syndrome: A Prospective, Controlled Study in 254 Affected Women. The Journal of Clinical Endocrinology & Metabolism, 84, 165-169.
https://doi.org/10.1210/jcem.84.1.5393

[9]   World Health Organization (1999) Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications: Report of a WHO Consultation Part 1: Diagnosis and Classification of Diabetes Mellitus. 2nd Edition, World Health Organization, Geneva.

[10]   Bhattacharya, S.M. and Jha, A. (2012) Comparative Study of the Therapeutic Effects of Oral Contraceptive Pills Containing Desogestrel, Cyproterone Acetate, and Drospirenone in Patients with Polycystic Ovary Syndrome. Fertility and Sterility, 98, 1053-1059.
https://doi.org/10.1016/j.fertnstert.2012.06.035

[11]   Gaspard, U., Scheen, A., Endrikat, J., Buicu, C., Lefebvre, P., Gerlinger, C. and Heithecker, R. (2003) A Randomized Study over 13 Cycles to Assess the Influence of Oral Contraceptives Containing Ethinylestradiol Combined with Drospirenone or Desogestrel on Carbohydrate Metabolism. Contraception, 67, 423-429.
https://doi.org/10.1016/S0010-7824(02)00537-1

[12]   Klipping, C. and Marr, J. (2005) Effects of Two Combined Oral Contraceptives Containing Ethinyl Estradiol 20 Microg Combined with Either Drospirenone or Desogestrel on Lipids, Hemostatic Parameters and Carbohydrate Metabolism. Contraception, 71, 409-416.
https://doi.org/10.1016/j.contraception.2004.12.005

[13]   Sitruk-Ware, R. and Nath, A. (2011) Metabolic Effects of Contraceptive Steroids. Reviews in Endocrine and Metabolic Disorders, 12, 63-75.
https://doi.org/10.1007/s11154-011-9182-4

[14]   Cagnacci, A., Ferrari, S., Tirelli, A., Zanin, R. and Volpe, A. (2009) Insulin Sensitivity and Lipid Metabolism with Oral Contraceptives Containing Chlormadinone Acetate or Desogestrel: A Randomized Trial. Contraception, 79, 111-116.
https://doi.org/10.1016/j.contraception.2008.09.002

[15]   Shahnazi, M., Farshbaf-Khalili, A., Pourzeinali-Beilankouh, S. and Sadrimehr, F. (2016) Effects of Second and Third Generation Oral Contraceptives on Lipid and Carbohydrate Metabolism in Overweight and Obese Women: A Randomized Triple-Blind Controlled Trial. Iranian Red Crescent Medical Journal, 18, e36982.
https://doi.org/10.5812/ircmj.36982

[16]   Morin-Papunen, L.C., Vauhkonen, I., Koivunen, R.M., Ruokonen, A., Martikainen, H.K. and Tapanainen, J.S. (2000) Endocrine and Metabolic Effects of Metformin versus Ethinyl Estradiol-Cyproterone Acetate in Obese Women with Polycystic Ovary Syndrome: A Randomized Study. The Journal of Clinical Endocrinology & Metabolism, 85, 3161-3168.
https://doi.org/10.1210/jc.85.9.3161

[17]   Fruzzetti, F., Perini, D., Lazzarini, V., Parrini, D., Gambacciani, M. and Genazzani, A.R. (2010) Comparison of Effects of 3 mg Drospirenone plus 20 μg Ethinylestradiol Alone or Combined with Metformin or Cyproterone Acetate on Classic Metabolic Cardiovascular Risk Factors in Nonobese Women with Polycystic Ovary Syndrome. Fertility and Sterility, 94, 1793-1798.
https://doi.org/10.1016/j.fertnstert.2009.10.016

[18]   Unluhizarci, K., Kelestimur, F., Sahin, Y. and Bayram, F. (1999) The Treatment of Insulin Resistance Does Not Improve Adrenal Cytochrome P450c17alpha Enzyme Dysregulation in Polycystic Ovary Syndrome. European Journal of Endocrinology, 140, 56-61.
https://doi.org/10.1530/eje.0.1400056

[19]   Diamanti-Kandarakis, E., Kouli, C., Tsianateli, T. and Bergiele, A. (1998) Therapeutic Effects of Metformin on Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome. European Journal of Endocrinology, 138, 269-274.
https://doi.org/10.1530/eje.0.1380269

[20]   Moghetti, P., Castello, R., Negri, C., Tosi, F., Perrone, F., Caputo, M., Zanolin, E. and Muggeo, M. (2000) Metformin Effects on Clinical Features, Endocrine and Metabolic Profiles, and Insulin Sensitivity in Polycystic Ovary Syndrome: A Randomized, Double-Blind, Placebo-Controlled 6-Month Trial, Followed by Open, Long-Term Clinical Evaluation. The Journal of Clinical Endocrinology & Metabolism, 85, 139-146.
https://doi.org/10.1210/jcem.85.1.6293

[21]   Crave, J.C., Fimbel, S., Lejeune, H., Cugnardey, N., Dechaud, H. and Pugeat, M. (1995) Effects of Diet and Metformin Administration on Sex Hormone-Binding Globulin, Androgens, and Insulin in Hirsute and Obese Women. The Journal of Clinical Endocrinology & Metabolism, 80, 2057-2062.
https://doi.org/10.1210/jcem.80.7.7608255

[22]   Acbay, O. and Gundogdu, S. (1996) Can Metformin Reduce Insulin Resistance in Polycystic Ovary Syndrome? Fertility and Sterility, 65, 946-949.
https://doi.org/10.1016/S0015-0282(16)58266-1

[23]   Cullberg, G., Hamberger, L., Mattsson, L.-Å., Mobacken, H. and Samsioe, G. (1985) Effects of a Low-Dose Desogestrel-Ethinylestradiol Combination on Hirsutism, Androgens and Sex Hormone Binding Globulin in Women with a Polycystic Ovary Syndrome. Acta Obstetricia et Gynecologica Scandinavica, 64, 195-202.
https://doi.org/10.3109/00016348509155112

[24]   Wu, J., Zhu, Y., Jiang, Y. and Cao, Y. (2008) Effects of Metformin and Ethinyl Estradiol-Cyproterone Acetate on Clinical, Endocrine and Metabolic Factors in Women with Polycystic Ovary Syndrome. Gynecological Endocrinology, 24, 392-398.
https://doi.org/10.1080/09513590802217027

[25]   Elter, K., Imir, G. and Durmusoglu, F. (2002) Clinical, Endocrine and Metabolic Effects of Metformin Added to Ethinyl Estradiol-Cyproterone Acetate in Non-Obese Women with Polycystic Ovarian Syndrome: A Randomized Controlled Study. Human Reproduction, 17, 1729-1737.
https://doi.org/10.1093/humrep/17.7.1729

[26]   Morin-Papunen, L.C., Koivunen, R.M., Ruokonen, A. and Martikainen, H.K. (1998) Metformin Therapy Improves the Menstrual Pattern with Minimal Endocrine and Metabolic Effects in Women with Polycystic Ovary Syndrome. Fertility and Sterility, 69, 691-696.
https://doi.org/10.1016/S0015-0282(98)00011-9

[27]   Harborne, L., Fleming, R., Lyall, H., Norman, J. and Sattar, N. (2003) Descriptive Review of the Evidence for the Use of Metformin in Polycystic Ovary Syndrome. The Lancet, 361, 1894-1901.
https://doi.org/10.1016/S0140-6736(03)13493-9

[28]   Cusin, I., Sainsbury, A., Doyle, P., Rohner-Jeanrenaud, F. and Jeanrenaud, B. (1995) The ob Gene and Insulin. A Relationship Leading to Clues to the Understanding of Obesity. Diabetes, 44, 1467-1470.
https://doi.org/10.2337/diabetes.44.12.1467

[29]   Rouru, J., Anttila, L., Koskinen, P., Penttila, T.A., Irjala, K., Huupponen, R. and Koulu, M. (1997) Serum Leptin Concentrations in Women with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism, 82, 1697-1700.
https://doi.org/10.1210/jcem.82.6.3996

[30]   Morin-Papunen, L.C., Koivunen, R.M., Tomas, C., Ruokonen, A. and Martikainen, H.K. (1998) Decreased Serum Leptin Concentrations during Metformin Therapy in Obese Women with Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism, 83, 2566-2568.
https://doi.org/10.1210/jcem.83.7.4944

[31]   Sitruk-Ware, R. and Nath, A. (2013) Characteristics and Metabolic Effects of Estrogen and Progestins Contained in Oral Contraceptive Pills. Best Practice & Research: Clinical Endocrinology & Metabolism, 27, 13-24.
https://doi.org/10.1016/j.beem.2012.09.004

[32]   Cullberg, G., Hamberger, L., Mattsson, L.A., Mobacken, H. and Samsioe, G. (1985) Lipid Metabolic Studies in Women with a Polycystic Ovary Syndrome during Treatment with a Low-Dose Desogestrel-Ethinylestradiol Combination. Acta Obstetricia et Gynecologica Scandinavica, 64, 203-207.
https://doi.org/10.3109/00016348509155113

[33]   Porcile, A. and Gallardo, E. (1991) Long-Term Treatment of Hirsutism: Desogestrel Compared with Cyproterone Acetate in Oral Contraceptives. Fertility and Sterility, 55, 877-881.
https://doi.org/10.1016/S0015-0282(16)54291-5

[34]   Mastorakos, G., Koliopoulos, C. and Creatsas, G. (2002) Androgen and Lipid Profiles in Adolescents with Polycystic Ovary Syndrome Who Were Treated with Two Forms of Combined Oral Contraceptives. Fertility and Sterility, 77, 919-927.
https://doi.org/10.1016/S0015-0282(02)02993-X

[35]   DeFronzo, R.A. and Goodman, A.M. (1995) Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes Mellitus. The Multicenter Metformin Study Group. The New England Journal of Medicine, 333, 541-549.
https://doi.org/10.1056/NEJM199508313330902

[36]   Ehrmann, D.A., Barnes, R.B., Rosenfield, R.L., Cavaghan, M.K. and Imperial, J. (1999) Prevalence of Impaired Glucose Tolerance and Diabetes in Women with Polycystic Ovary Syndrome. Diabetes Care, 22, 141-146.
https://doi.org/10.2337/diacare.22.1.141

 
 
Top