Effects of calcium-vitamin D and metformin on the menstrual cycle and ovulation in polycystic ovary syndrome patients in a tertiary care teaching hospital
DOI:
https://doi.org/10.18203/2320-1770.ijrcog20211117Keywords:
Calcium-Vitamin D, Ovulation, Menstrual cycle, Metformin, PCOSAbstract
Background: Polycystic ovary syndrome (PCOS) is a heterogeneous hormonal disorder of reproductive aged women characterized by chronic anovulation, irregular menstrual cycles and hyperandrogenism. The present study aimed to investigate the effects of metformin and calcium-vitamin D on follicular maturation and regularity of menstrual cycles in patients with PCOS.
Methods: A prospective, open-label, multiple arms, randomized clinical trial. Group 1 participants received 1,000 mg of calcium and 400 IU of vitamin D per day, orally, group 2 participants received 1,500 mg of metformin per day, orally and group 3 participants received combination of above drugs. The patients were treated for 3 months and followed up for a further 3 months. Menses regularity, number of dominant follicles (≥14 mm) and pregnancy rates were compared among the three groups.
Results: A total of sixty infertile women with PCOS were recruited. Calcium-vitamin D plus metformin treated patients showed highest percentage improvement (50%) menstrual regularity as compared to other two groups (p<0.001) also showed significant follicular response (p<0.014). Calcium-vitamin D plus metformin treated group showed better follicular response in the second and third month of follow-up and 30% of women showed high quality dominant large (≥14 mm) follicles at the end of follow-up period.
Conclusions: Calcium-vitamin D plus metformin combination is more effective in terms of follicle maturation and restoring menstrual disturbances as compared to individual drug treatment.
References
Ganie MA, Vasudevan V, Wani IA, Baba MS, Arif T, Rashid A. Epidemiology, pathogenesis, genetics and management of polycystic ovary syndrome in India. Indian J Med Res. 2019;150(4):333.
Witchel SF, Oberfield SE, Peña AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc. 2019;3(8):1545-73.
El Hayek S, Bitar L, Hamdar LH, Mirza FG, Daoud G. Poly cystic ovarian syndrome: an updated overview. Front Physiol. 2016;7.
Group TREP consensus workshop. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19(1):41-7.
Robinson S, Kiddy D, Gelding SV, Willis D, Niththyananthan R, Bush A, et al. The relationship of insulin insensitivity to menstrual pattern in women with hyperandrogenism and polycystic ovaries. Clin Endocrinol. 1993;39(3):351-5.
Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2010;122(1-3):42-52.
Rodriguez Paris V, Bertoldo MJ. The Mechanism of Androgen Actions in PCOS Etiology. Med Sci. 2019;7(9).
Asunción M, Calvo RM, San Millán JL, Sancho J, Avila S, Escobar-Morreale HF. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 2000;85(7):2434-8.
Kamalanathan S, Sahoo JP, Sathyapalan T. Pregnancy in polycystic ovary syndrome. Indian J Endocrinol Metab. 2013;17(1):37-43.
Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol. 1998;138(3):269-74.
Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338(26):1876-80.
Ledger WL. Non-reproductive consequences of polycystic ovary syndrome. Curr Obstet Gynaecol. 2003;13(6):350-4.
De Felici M, Dolci S, Siracusa G. An increase of intracellular free Ca2+ is essential for spontaneous meiotic resumption by mouse oocytes. J Exp Zool. 1991;260(3):401-5.
Steinhardt RA, Epel D, Carroll EJ, Yanagimachi R. Is calcium ionophore a universal activator for unfertilised eggs? Nature. 1974;252(5478):41-3.
Homa ST, Carroll J, Swann K. The role of calcium in mammalian oocyte maturation and egg activation. Hum Reprod Oxf Engl. 1993;8(8):1274-81.
Thys-Jacobs S, Donovan D, Papadopoulos A, Sarrel P, Bilezikian JP. Vitamin D and calcium dysregulation in the polycystic ovarian syndrome. Steroids. 1999;64(6):430-5.
Stumpf WE. Vitamin D sites and mechanisms of action: a histochemical perspective. Reflections on the utility of autoradiography and cytopharmacology for drug targeting. Histochem Cell Biol. 1995;104(6):417-27.
Bednarska S, Siejka A. The pathogenesis and treatment of polycystic ovary syndrome: What’s new. Adv Clin Exp Med. 2017;26(2):359-67.
Kaufman ML, Homa ST. Defining a role for calcium in the resumption and progression of meiosis in the pig oocyte. J Exp Zool. 1993;265(1):69-76.
Ullah G, Jung P, Machaca K. Modeling Ca2+ signaling differentiation during oocyte maturation. Cell Cal. 2007;42(6):556-64.
Lee JH, Yoon SY, Bae IH. Studies on Ca2+-channel distribution in maturation arrested mouse oocyte. Mol Reprod Dev. 2004;69(2):174-85.
Kitai H, Santulli R, Wright KH, Wallach EE. Examination of the role of calcium in ovulation in the in vitro perfused rabbit ovary with use of ethyleneglycol-bis (beta-aminoethyl ether)-n,n’-tetraacetic acid and verapamil. Am J Obstet Gynecol. 1985;152(6 Pt 1):705-8.
Lin MW, Wu MH. The role of vitamin D in polycystic ovary syndrome. Indian J Med Res. 2015;142(3):238-40.
Miao CY, Fang XJ, Chen Y, Zhang Q. Effect of vitamin D supplementation on polycystic ovary syndrome: a meta‑analysis. Exp Ther Med. 2020;19(4):2641-9.
Touyz RM, Jiang L, Sairam RM. Follicle-stimulating hormone mediated calcium signaling by the alternatively spliced growth factor type I receptor. Biol Reprod. 2000;62(4):1067-74.
Chen W, Xia WG, Ruan D, Wang S, Abouelezz KFM, Wang SL, et al. Dietary calcium deficiency suppresses follicle selection in laying ducks through mechanism involving cyclic adenosine monophosphate-mediated signaling pathway. Animal. 2020;14(10):2100-8.
Velázquez ME, Acosta A, Mendoza SG. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome. Obstet Gynecol. 1997;90(3):392-5.
Cormick G, Belizán JM. Calcium Intake and Health. Nutrients. 2019;11(7).
