Pjs 26(1).indd

Eff ect of metformin therapy in patients with Polycystic
Ovary Syndrome

Abstract :
Objective: To determine the eff ect of 12 week of metformin therapy on clinical and
hormonal indices of patients with Polycystic Ovary Syndrome.
Study design: Prospective
Study sett ing: Th

e study was carried out at the outpatient Department of Obstetrics &
Gynaecology and Endocrinology from Sept. 2006 to April 2007. 30 women meeting
the eligibility criteria were enrolled. Th

ey were interviewed using standardized pro-
forma . Data was analyzed by using SPSS version 10. Paired t- test was used for com-
Intervention: Patients were treated with 500mg of tab.metformin three times daily for
12 weeks.
Main outcome measures: Hirsuitism, menstrual irregularities, BMI and fasting insulin
levels were assessed before and aft er treatment .
Results: In 21 of 30 patients(70%) normal menstrual cycle resumed. Th

ere was signifi -
cant reduction in the BMI (p< 0.000), and signifi cant reduction in the fasting insulin
Levels (p<0.000). 73.3% presented with hirsuitism and 33.3% showed improvement.
Conclusion: 12 week course of metformin is eff ective in the treatment of menstrual ir-
regularities ,in reducing weight, fasting insulin levels and improving hirsuitism.

Key words: PCOS,insulin resistance, hyperinsulinemia, hyperandrogenism, metform-

number of ways. At one end of the spectrum, the Polycystic ovary is the most common endocrine disease produces polycystic morphology and at disorder with incidence of 4% to 12% in the re- the other end there are symptoms like obesity, Department
productive age.1,2 Polycystic ovarian syndrome is hyperandrogenism, menstrual cycle disturbanc- of Obstetrics
considered a problem arising as a consequence es and infertility. Th &Gynaecology,
Liaquat National

of persistent anovulation with spectrum of eti- ther singly or in combination. It has been shown Hospital, Karachi
ologies and clinical manifestations that includes that insulin resistance is associated with PCOS.
insulin resistance as well as hyperandrogenism.
In addition, hyperandrogenism and insulin re- sistance may also be linked to each other.4 Correspondence:
Biochemical disturbances include elevated se- rum concentration of lutenizing hormones, Insulin resistance is defi ned as the decreased Department of Obstetrics &Gynaecology, testosterone, androstenedione and insulin. ability of insulin to stimulate glucose disposal in Hyperinsulinemia appears to be the key to the to target tissues, or a reduced glucose response to a given amount of insulin.5 In this situation, the blood insulin levels are chronically higher Polycystic ovary syndrome can manifest in which inhibits fat cells from giving up their en- Eff ect of metformin therapy in patients with polycystic ovary syndrome ergy stores, this in turn is associated with obe- sity, hypertension, abnormal triglycerides, glu- Reversed FSH:LH ratio in early follicular cose intolerance and type 2 diabetes mellitus. e discovery that insulin resistance has a key • role in the pathophysiology of PCOS has led to promising form of therapy in the form of insulin Exclusion criteria:sensitizing drugs. Metformin is an insulin sensi- tizer that reduces insulin resistance and insulin • secretion followed by a reduction of ovarian an- Other causes of obesity like hypothyroid- drogen production. Direct action of metformin on ovarian theca cells also reduces androgen Intervention: Patients were treated with 500 mg of metformin Metformin is an oral biguanide well established three times daily for 12 weeks. Th for the treatment of hyperglycemia, that does formin was fi xed in all the patients.
not cause hypoglycemia in normoglycemic sub- Clinical symptoms including hirsutism, men- e objective of the study was to determine the strual cycle, BMI,fasting insulin levels and fast- eff ect of twelve weeks of metformin therapy on ing blood glucose were assessed before and aft er clinical and hormonal indices of the women treatment with metformin.
with PCOS. It will not only help treating the Statistical analysis: presenting complaints but will also prevent the Data was collected on proforma; SPSS version long term health issues and will improve the 10 was used for analysis. Frequency and per- centage were used for categorical variables like Methodology
presenting complaints, family history of diabe- tes mellitus, menstrual irregularity. Mean and quat National Hospital Karachi with patients standard deviation were used for age, menstrual from Gynaecology and Endocrinology clinics cycle, BMI and hirsutism. Paired t- test was used for a period of 8 months. Th irty women who to compare the pre and post mean diff erences.
met the PCOS eligibility criteria were enrolled. Results:
e women were interviewed using proforma Th e study was done on 30 patients. All of the to keep the record. Data was analyzed by using patients completed the 12 week course of Met- SPSS version 10- statistical package. Paired t- formin. All of the patients belonged to reproduc- test was used to compare the results.
tive age group. Ages of the patients were between 18 to 37 years. 15 patients were with positive family history of diabetes mellitus. Of the 30 Sample technique: Non-probability purposive patients who completed the 12 week course of sampling metformin, 21 had normal menstrual cyclicity was restored (70%).
22 patients presented with hirsuitism (73.3%).
Inclusion criteria: Women fulfi lling any three According to Ferriman and Gallwey, hirsuitism out of the following criteria: score ranged from 7 to 18. Hirsutism was not completely treated in any of the patient although 10 patients (33.3%) showed some improvement. Treatment with metformin signifi cantly reduced fasting serum insulin levels from 8.72±3.43 mi- Figure 1: Menstrual Cycle (before treatment) like raised levels of LH, testosterone, andros- tenedione and insulin levels can over a period of time have serious eff ects.
Hyperinsulinemia in non diabetic patient is in- dependently associated with an increased risk of cardio vascular disease and metabolic abnor- malities that include glucose intolerance and hy-perlipidemia resulting in hypertension and type Also in PCOS menstrual irregularities are com- mon and because of chronic anovulation, infer-tility is a common problem in married couples. Figure 2: Menstrual Cycle (aft er treatment) Obesity by itself have long term consequences on the health of a person, these people are at higher risk of cardio vascular disease and diabe- So the objective of the study was to see the ef-fect of metformin on the clinical and hormonal indicies in a person suff ering from PCOS. Met-formin acts by reducing hepatic production of glucose, improves the tissue sensitivity to in-sulin, facilitating glucose utilization by skeletal muscles and adipocytes and reduced intestinal glucose absorption.9,10 Table 1: BMI before and aft er treatment with Metformin We gave 30 females who fulfi lled the criteria of De-
gree of

PCOS, metformin tablets 500 mg, three times a day for 12 weeks and studied its eff ects on men- Comparison
strual cyclicity, BMI, fasting insulin levels, hir- suitism and fasting blood glucose levels. It was seen that in 21(70%) out of 30 patients, normal menstrual cycle was restored aft er a 3 month course of metformin. Other investigators have cro units/ml to 6.91± 1.93 micro units/ml with p reported similar results where metformin use re- value <0.00, which is signifi cant. Metformin also sulted in decrease levels of androgens, increase reduced fasting blood sugar from 106.03±17.17 in the levels of sex hormone binding proteins to 97.40±10.12 with p value <0.00 which is also and resulting in restoration of normal menstrual cycles.11,12,13,14,15 Another study done in Services Hospital Lahore showed that females treated Patient also showed signifi cant decrease in their with metformin resumed their normal men- BMI (p<0.005) from 32.20±2.50 to30.67±2.51 strual cycle and started ovulating within 3 to 9 Discussion:
PCOS can manifest in a number of ways. Th ere Patient also showed signifi cant decrease in their is persistant state of anovulation which can BMI (p<0.000) from 32.20±2.50 to 30.67±2.51 manifest with both clinical and biochemical by improving tissue sensitivity to insulin and fa- Eff ect of metformin therapy in patients with polycystic ovary syndrome cilitating glucose utilization by skeletal muscles. References:
is result was similar to the fi ndings of a study 1. Balen AH, S secondary dysmenorrheal, In: Dewhurst J, DK, Edmonds. Dewhurst’s text book of obstetrics and gynaecol- ogy for postgraduates. 6th ed. Edinburgh ;Blackwell sciences improvement in menstrual cycle, fall in BMI due to improved tissue sensitivity to insulin. 2. Sheehan M T. Polycystic Ovarian Syndrome: Diagnosis and Management.Clin Med Res. 2004; 2 (1) : 13-27.
e third eff ect which was assessed in the study 3. Balen A H, Glas MR. What’s new in polycystic ovary syn- drome? In: Bonnar J, Dunlop W. Recent Advances in Obstet- was improvement in the fasting insulin levels and fasting blood glucose levels. It was seen that in all patients given metformin fasting insulin 4. Archard C, Th eirs J.Le virilisme pilaire et son association an l’ levels decreased signifi cantly (p-value <0.005). sance glycolytique (diabetes des femmes a barbe). Bull is was similar to the result of Moghatt i and 5. Haroush AB, Yogev Y, Fisch B. Insulin resistance and metformin co-workers 9 who conducted a double blind ran- in polycystic ovary syndrome. Eur J Of Obstet And Gynaecol domized study and it showed that Metformin And Reproductive Biology. 2004; 115: 125-133.
6. Homburg R.Polycystic ovary syndrome, Best Practice and Re- group had signifi cant reduction in fasting insu- search Clinical Obstet and Gynaecol 2007; 20: 1-4 lin levels.Similarly in another study, signifi cant 7. Speroff L, Glass RH, Kase GN. Anovulation and polycystic improvement was seen in the levels of fasting in- ovaries. Clinical gynaecology endocrinology and infertility. sulin levels and regular cycles in oligomenorrhic 8. Siddiq N M, Ghazi A, Jabbar S, Khan N H. Eff ect of metformin therapy on PCO induced infertility and menstrual distur-bances. Pakistan Journal Of Surgery. 2006; 22: 113-5.
Hirsutism is a common problem for women 9. Moghett i P, Castello R, Negri C,et al. Metformin eff ects on with PCOS and has potentially serious psycho- clinical features, endocrine and metabolic profi les, and insu- social sequelae18. In our study, 22 females had lin sensitivity in polycystic ovary syndrome: a randomized, double blind, placebo controlled 6-months trial, followed by hirsutism and aft er receiving Metformin for open ,long term clinical evaluation.J Clin Endocrinol Metab 12 weeks ,we saw some improvement in Ferri- man Galway score in 10(33.3%) patients. Litra- 10. asquali R, Gambineri A, Biscott i D, et al. Eff eat of long term treatment with Metformin added to hypocaloric diet on body ture also supports this. In a study, Christopher composition,fat distribution and androgen and insulin levels JG Kelly, Gorden19 demonstrated that when in abdominally obese women with and without the polycys- women treated with metformin for hirsutism, tic ovary syndrome. J Clin Endocrinol Metab 2000; 85:2767- showed signifi cant improvement in Ferriman 11. elazquez E M, Mendoza S, Hamer T, et al: Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, controlled study. Kolodziejyle et al also showed insulin resistance, hyperandrogenemia and systolic blood pressure, while facilitating normal menses and pregnancy, Metabolism 1994;43:647-54.
12. orin Papunen L C, Vauhkonen I, Koivunen R M, Ruokonen A, Marikainen HK,Tapanainen J S. Endocrine and metabolic From this study, we inferred that 500mg of met- eff ects of metformin versus ethinyl estradiol- cyproterone ac- formin given thrice daily to the patients of PCOS etate in obese women with polycystic ovary syndrome: J Clin will improve their menstrual cycle irregularity Endocrinol Metab. 2000; 85 (9) 3161-8.
g R, Hopkinson Z E, Wallace AM et al :Ovarian func- resulting in ovulation and pregnancy.It also has tion and metabolic factors in women with oligomenorrhea signifi cant eff ect on the BMI and fasting insulin treated with metformin in a randomizes double blind placebo- levels resulting in decreased risk of cardio vas- controlled trial.J Clin Endocrinol Metab 2002;87: 569-574.
cular disease and diabetes mellitus type 2. Not 14. l-Fadhli R, Tulendi T. Laproscopic treatment of PCOS:Is its place diminishing? In: Current opinion in obstet- a very signifi cant improvement was seen in the rics and gynaecology, Canada: Lilincott ,Williams hirsuits but maybe they require longer therapy. For this another study with large sample size and ck C J, Goldenberg N,Pranikoff J et al: Height,weight and of longer duration is required. We can conclude motor-social development during the fi rst 18 months of life in 126 infants born to 109 mothers with polycystic ovary syn- that metformin has a defi nite roll in the treat- drome who conceived on and continued metformin through pregnancy. Hum Reprod 2004;19:1323-1330.
16. mtiaz S A, Khan F A, Farid S, Yasmeen S, Nizami T. Metformin induced resumption of menses, ovulation and subsequent pregnancy in hyperinsulinemia polycystic ovarian disease. Annals of King Edward Medical College 2002; 8 (3) 177-78. polycystic ovary syndrome. Eur J Endocrinol 2002; 147:217- 17. banez L, Valls C,Ferrer A, Marcos MV, Rodriguez-Hierro F et al: Sensitization to insulin induces ovulation in non-obese yk, Duleba A J, Spaczynski RZ,Pawelczyk L. Met- adolescents with anovulatory hyperandrogenism. J Clin En-docrinol Metab 2001; 86:3595-8.
formin therapy decreases hyperandrogenism and hyperin- 18. arth JH, Catalan J, Cherry CA, Day A. Psychological morbid- sulinemia in women with polycystic ovary syndrome. Fertil ity in women referred for treatment of hirsutism.J of Psycho-

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