Ijcb.co.in

Ind J Clin Biochem (Oct-Dec 2010) 25(4):367–370 Effect of Metformin on Hormonal and Biochemical Profilein PCOS Before and After Therapy Bratati Singh • Suchismita Panda • Rachita Nanda •Sanghamitra Pati • Manaswini Mangaraj •Pratima Kumari Sahu • Prakash Chandra Mohapatra Received: 18 September 2009 / Accepted: 24 September 2010 / Published online: 19 November 2010Ó Association of Clinical Biochemists of India 2010 Insulin resistance and the resultant hyperinsuli- nemia exacerbate the reproductive abnormalities of Poly-cystic Ovarian Syndrome by increasing ovarian androgen Polycystic Ovarian Syndrome is the most common repro- productions and decreasing serum sex hormone binding ductive endocrine disorder among women of reproductive globulin. The present study was conducted to estimate age, affecting 5–10% of population worldwide []. It is the serum insulin and testosterone level in 44 PCOS cases and commonest multisystem endocrinopathy having diverse eti- 32 control patients. Simultaneously the role of metformin opathogenesis in women, causing menstrual irregularities, (an insulin sensitizing agent) in modulating insulin resis- hirsutism and anovulatory infertility. In Indian population the tance and serum androgen level was also analyzed. A sig- incidence has been estimated to be between 4 and 11% among nificant rise in serum insulin and testosterone (P \ 0.001) women of reproductive age group []. PCOS is associated was observed in cases in comparison to control. Fasting with insulin resistance, obesity, dyslipidemia and infertility Plasma Glucose to insulin ratio, a marker of insulin resis- Recently some theories depict genetic and intraovarian tance revealed a significant fall in PCOS group. Follow up of origin associated with environmental factors such as diet and cases with metformin for 3 months revealed a significant altered life style ]. Several data support the hypothesis fall in serum insulin (P \ 0.05) with improvement in insulin that insulin resistance and associated hyperinsulinemia play a resistance along with a nonsignificant fall in testosterone pathogenic role in PCOS ]. Hyperinsulinemia may promote level. Serum insulin registered a significant positive corre- abnormal ovarian androgen secretion and therewith abnormal lation (P \ 0.05) with serum testosterone revealing its follicular development leading to dysfunctional ovarian and etiological association. Thus administration of drugs ame- menstrual activity []. These observations suggested the role liorating insulin levels is expected to provide new thera- of insulin sensitizing agents like metformin in improving these manifestations []. Some researchers demonstratedimprovement in reproductive abnormalities in their group of patients while others failed to observe any clinical or This discrepancy in the above observations created an interest for evaluating the role of insulin resistance for var-ious biochemical & pathological manifestations of PCOS as B. Singh Á S. Panda Á R. Nanda Á S. Pati Á M. Mangaraj Á well as the role of metformin as an insulin sensitizing agent for altering these manifestations in these cases.
Department of Biochemistry, SCB Medical College,Cuttack 753007, Orissa, India Department of Biochemistry, IMS & SUM Hospital,Siksha O Anusandhan University, Bhubaneswar, The study was conducted in the Department of Biochemistry, Orissa 751003, Indiae-mail: bratati.singh76@yahoo.co.in S.C.B. Medical College, Cuttack from February 2006 to July Ind J Clin Biochem (Oct-Dec 2010) 25(4):367–370 2007. 44 PCOS patients within age group 15–35 years patients had BMI C 25 kg/m2 showing obesity, whereas attending the OPD & indoor of O&G Department of S.C.B only 25% of controls had obesity with BMI C 25 kg/m2.
Medical College, Cuttack & 32 age matched healthy female Table revealed no significant difference in FPG & 2 h controls from hospital staffs were included in this study PGPG in PCOS patients as compared to control. That may be due to relatively young age group patients in this study, The diagnosis of PCOS was made from the history of because b-cell dysfunction worsens with age ]. Marked chronic oligomenorrhoea (cycle length [ 35 days, or less dyslipidemia was obvious in these patients in comparison to than 9 cycles per year), amenorrhoea (cycle length [ control, which may be attributed to insulin resistance ].
12wks), infertility with hirsutism or acne, and with an ultr- The hormone profile reveals a marked rise in fasting asonographic findings of polycystic ovaries [ serum insulin in these PCOS cases in comparison to control Women with prior history of glucose intolerance (P \ 0.001), which was in agreement with other workers (including gestational diabetes) or NIDDM, hyperprolac- showing the role of hyperinsulinemia in the pathogenesis tinemia, thyroid dysfunction, late onset congenital adrenal of PCOS ]. Marked rise in serum total testosterone in hyperplasia, cushing’s syndrome or patients taking medi- these cases (P \ 0.001) may be due to excess ovarian cations to alter the hormonal or biochemical profiles were production of androgens, which is central to the diagnosis excluded from the study. All patients included in the study of PCOS [Yet some researchers have shown appar- ently normal testosterone concentrations in their PCOS Blood was collected from both controls and cases and was cases, which may be attributed to their low to normal sex estimated for routine biochemical parameters (Fasting plasma glucose, 2 h PGPG & lipid profile) using automated Mean value of fasting plasma glucose to insulin ratio analyzer Flexor-XL. Specific tests for serum Insulin and (G/I), a good measure of insulin sensitivity was observed serum Testosterone were also performed using ELISA to be 4.34 in PCOS cases. Taking this fasting G/I ratio of B4.5 as abnormal [50% of cases and 9.4% of Out of these 44 PCOS patients, 22 women were admin- controls were determined as insulin resistant, having this istered with metformin (an insulin sensitizing agent) at a dose of 500 mg tds for a period of 3 months. After com- After administration of metformin to 22 PCOS cases at a pletion of treatment, the biochemical parameters, serum dose of 500 mg TDS for a period of 3 months, only 10% of insulin and serum testosterone values were analyzed again PCOS patients revealed improvement in glucose tolerance, and compared with their pre-intervention values respec- whereas no significant alteration was noted in mean FPG & tively. The results obtained were analyzed by student’s t PGPG values. Serum HDL registered a significant rise test, Wilcoxon signed ranks test and Mann–Whitney U test, (P \ 0.05) in these cases after metformin therapy. All Pearson correlation coefficient using SPSS-15. This study other lipid parameters documented no marked difference protocol has been approved by the institutional ethical after therapy. Similar observations have been registered by committee, S.C.B Medical College Cuttack.
other workers [who were in agreement that metforminreduces insulin resistance which in turn modifies dyslipi-demia in PCOS cases (Table ).
Overall change in BMI was statistically insignificant after therapy. However percentage of patients presented In the present study about 43.2% of PCOS cases were in with obesity having BMI C 25 kg/m2 was reduced from the age group of 21–25 years. 38.6% of these PCOS 36.4 to 27.3%. Obesity was worsened with increase in BMI Ind J Clin Biochem (Oct-Dec 2010) 25(4):367–370 hormonal changes before andafter therapy in 22 pcos cases only in one patient, which might have been due to decreased physical activity during treatment period.
After 3 months of metformin therapy, serum hormone status documented a marked fall in fasting serum insulin(P \ 0.001), similar to the results of other researchers [and was in concurrence with the opinion that beingan insulin sensitizer, metformin exerts its effect by pro- moting peripheral glucose utilization. Others have docu-mented no significant change in serum insulin level after therapy [Study of Barbieri et al. ] demonstrated thedirect stimulatory effect of insulin on ovarian androgen production in PCOS women. Insulin infusion studies haveshown a clear association existing between serum insulin Serum Testosterone in ng/ml
and testosterone levels in cases of PCOS, suggestive of acause and effect relationship. The present study alsorevealed a decline in serum testosterone level, yet it was Serum insulin in µIU/ml
Our study also revealed insulin resistance measured as fasting glucose to insulin ratio to be reduced from 77.27% Fig. 1 Correlation of serum insulin with serum testosterone before of cases to 40.1% after metformin therapy, showing an improvement in insulin sensitivity. The median value ofthis ratio raised from 4.19 before therapy to 4.68 after 3 months of metformin therapy crossing the limit value of4.5 which was statistically significant (P \ 0.05) and in PCOS has been a subject of research and debate over past six decades. Insulin resistance accompanied by compen- Significant positive association (r = 0.44, P \ 0.05) satory hyperinsulinemia is a common feature of PCOS and between fasting serum insulin and serum total testosterone both obese and non-obese women with the syndrome are before metformin therapy in PCOS cases in the present more insulin resistant and hyperinsulinemic than age and study (Fig. shows the etiological role of hyperinsuli- weight matched normal women ]. Insulin resistance in nemia in stimulating ovarian androgen production muscles and adipose tissues increases plasma FFA and However following metformin therapy the association was insulin concentration, that stimulate synthesis and secretion though positive, yet it was not significant.
of VLDL in the liver resulting in hypertriglyceridemia,which in turn enhances post-prandial accumulation of Table 3 FPG/insulin ratio before and after therapy (n = 22) lipoproteins (LDL, VLDL) in plasma with lowering of HDL cholesterol , ]. Hyperinsulinemia plays a path- ogenetic role in PCOS cases by increasing ovarian andro-gen production and decreasing the serum sex hormone binding globulin concentration [Insulin may directly stimulate ovarian cytochrome P450c17a, resulting in increased 17-a hydroxylase and to a lesser extent, 17, Ind J Clin Biochem (Oct-Dec 2010) 25(4):367–370 20-lyase activity. This would lead to increased production criteria and long-term health risks related to polycystic ovary of androstenedione, which is then converted to testosterone syndrome (PCOS). Fertile Steril 2004;81:19.
12. Sacks BD. Carbohydrate. In: Burtis CA, Ashwood AR, editors.
by the enzyme 17b reductase resulting in higher levels of Tietz textbook of clinical chemistry. 2nd ed. Philadelphia: W.B.
free testosterone with dysfunctional ovarian and menstrual activity. Insulin may also stimulate ovarian androgen pro- 13. Turkes AO, Turkes A, Read GF, Fahmy DR. A sensitive fiu- duction by enhancing serum luteinizing hormone pulses orometric enzyme immunoassay for testosterone in plasma andsaliva. J Endocrinol. 1979;81(2):165.
and activity that enhances ovarian cytochrome P450c17a 14. Chiu KC, Lee NP, Cohan P, Chuang LM. Beta cell function activity in PCOS women as evidenced by identification of declines with age in glucose tolerant Caucasians. Clin Endocri- insulin receptors in human pituitary tissue ].
Administration of metformin an insulin sensitizing agent 15. Talbott E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, et al. Coronary heart disease risk factors in women with poly- has beneficial role in lowering serum testosterone level by cystic ovary syndrome. Arterioscler Thromb Vasc Biol. 1995; exerting its action over serum insulin and increasing insulin sensitivity of tissues in PCOS [There is mild 16. Richardson MR. Current perspectives in polycystic ovary Syn- clinical improvement in terms of regularity of menstrual drome. Am Fam Physician. 2003;68:697–704.
17. Wajchenberg BL, Achando SS, Okada H, Czeresnia CE, Peixoto cycle. It may have the added benefit of improving at least S, Lima SS, et al. Determination of the sources(s) of androgen some features of syndrome X; such as dyslipidemia, overproduction in hirsutism associated with polycystic ovary hypertension and obesity However the definitive syndrome by simultaneous adrenal and ovarian venous catheter- clinical improvement as characterized by reduction of ization. Comparison with the dexamethasone suppression test.
J Clin Endocrinol Metab. 1986;63:1204–10.
hirsutism, acne, and increased fertility can be assessed if 18. Boots LR, Potter S, Potter HD, Azziz R. Measurement of total the follow up study will be continued still longer.
serum testosterone levels using commercially available kits: highdegree of between-kit variability. Fertil Steril. 1998;69:286–92.
19. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is useful measure of insulin sensitivity in women withpolycystic ovary syndrome. J Clin Endocrinol Metab. 1998; 20. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, 1. Franks S. Polycystic ovary syndrome. N Engl J Med. 1995;333: et al. Metformin effects on clinical features, endocrine and met- abolic profiles and insulin sensitivity on polycystic ovary syn- 2. Norman RJ, Mahabeer S, Masters S. Ethnic differences in insulin drome: a randomized, double-blind, placebo-controlled 6-month and glucose response to glucose between white and Indian trial, followed by open–long term clinical evaluation. J Clin women with polycystic ovary syndrome. Fertil Steril. 1995;63: Endocrinol Metab. 2000;85(1):139–46.
21. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Met- 3. Dunaif A. Insulin resistance and the polycystic ovary syndrome: formin therapy in Polycystic Ovary Syndrome reduces hyperin- mechanism and implications for pathogenesis. Endocr Rev.
sulinemia, insulin resistance, hyperandrogenemia and systolic blood pressure, while facilitating normal menses and pregnancy.
4. Webber LJ, Stubbs S, Stark J, Trew GH, Margara R, Hardy K, Franks S. Formation and early development of follicles in the 22. Eisenhardt S, Schwarzmann N, Henschel V, Germeyer A, Von polycystic ovary. Lancet. 2003;362:1017–21.
Wolff M, Hamann A, et al. Early effects of Metformin in women 5. Norman RJ. Metformin—comparison with the other therapies in with Polycystic Ovary Syndrome: a prospective Randomized, ovulation induction in polycystic ovary syndrome. J Clin Endo- Double-Blind, Placebo-Controlled Trial. J Clin Endocrinol 6. Burghen GA, Givens JR, Judd HL, Kitabchi AE, Kaplan SA.
23. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Correlation of hyper androgenism with hyperinsulinism in Poly- Ryan KJ. Insulin stimulates androgen accumulation in incuba- cystic ovaries. J Clin Endocrinol Metabol. 1980;50:113–6.
tions of ovarian stroma obtained form women with hyperan- 7. Chang JR, Nakamura RM, Howard LJ, Kaplan SA. Insulin drogenism. J Clin Endocrinol Metab. 1986;62:904–10.
resistance in nonobese patients with polycystic ovarian disease.
24. Diamanti Kandarakis E, Kouli C, Tsianateli T, Bergiele A.
J Clin Endocrinol Metab 1983;356–9.
Therapeutic effects of metformin on insulin resistance and hy- 8. Bailey CJ, Path MRC, Turner RC. Metformin. N Engl J Med.
perandrogenism in polycystic ovary syndrome. Eur J Endocrinol.
9. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of 25. Hadziomerovic D, Wildt L. Correlation between fasting insulin, metformin on spontaneous and clomiphene-induced ovulation in AUC insulin and HOMA—index in PCOS—patients. Exp Clin the polycystic ovary syndrome. N Eng J Med. 1998;338:1876–80.
10. Ehrmann DA, Cavaghan MK, Imperial J, Sturia J, Rosenfield RL, 26. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome Polonsky KS. Effects of metformin on insulin secretion, insulin P450c17a activity and serum free testosterone after reduction of action and ovarian steroidogenesis in women with polycystic insulin secretion in polycystic ovary syndrome. New Engl J Med.
ovary syndrome. J Clin Endocrinol Metab. 1997;82:524–30.
11. The Rotterdam ESHRE/ASRM—sponsored PCOS Consensus Workshop Group 2004 Revised 2003. Consensus on diagnostic

Source: http://www.ijcb.co.in/october%20issue/367-370.pdf