METFORMIN IN POLYCYSTIC OVARY SYNDROME FIVE-YEAR TREATMENT EXPERIENCE WITH METFORMIN IN POLYCYSTIC OVARY SYNDROME Petrányi G 1 & Zaoura Maria 2 (1 private practice in Internal Medicine and Endocrinology, Limassol 2 Head, Skin Department, Nicosia General Hospital, Cyprus) Side effects. 122 patients opted for MET and 45 patients for PILL treatment. Initial side effects of MET occurred in 13 patients (11%): 6 experienced vertigo, 1 vomiting, 2 abdominal discomfort, 4 diarrhoea but only 4 women opted for a change to the PILL because of metformin intolerance (3.3%). No other adverse effects of MET were found, neither during nor on the outcome of pregnancy cases or babies delivered. In the PILL group, 2 patients experienced weight gain, 1 breast tension, and one woman developed vitamin B12 deficiency. Follow-up from 3 to 42 months was successful in 58 MET and 31 PILL cases (total of 1006 patient months). Significant improvement was detectable in the acne score in both treatment groups by three months and in hirsutism by six months. The improvement continued during further follow-up. Relapse was detected in cases where tablet taking was neglected; improvement recurred when therapy was continued. Evaluation of changes in the acne and hirsutism scores of patients who were treated for at least 12 months are summarized in Table 2 and individual changes of the same patients are shown in Figs. 2-3. Table 4. Pregnancies on metformin treatment Case Rx months at conc. Outcome 1 1 live birth 2 1 unknown 3 5 live birth 4/1 7 early loss 4/2 6 live birth 5 10 live birth 6 11 early loss 7 17 continuing (gr. s. 34) INTRODUCTION Despite the high frequency of the polycystic ovary syndrome (PCOS), it has had no uniform therapeutic approach in the world. Most patients receive temporary and/or symptomatic treatment for acne, hirsutism, menstrual disorder or infertility; the outcome is often disappointing and symptoms recur after cessation of treatment. Our standard treatment for PCOS used to be the anti-androgenic combined contraceptive pill. Upon the accumulating reports on the successful treatment of the underlying insulin resistance in PCOS with metformin1 we also started using it in January 2002. The preliminary assessment of the results in 2004 justified our decision2 and now a five-year treatment experience can be presented here. PATIENTS AND METHODS All women with symptoms suspect for PCOS on history taking and clinical examination underwent further evaluation using hormone profiles and pelvic ultrasound. Patients suffering from other endocrine diseases were not excluded from the study if they met the Rotterdam criteria of PCOS3 after controlling any concomitant disorder. A choice between two treatment forms was offered to all women with PCOS. The anti-androgenic combined contraceptive pill Diane 35® (PILL) was prescribed if the patient wanted contraceptive treatment. Metformin (MET) was given to all the others including those where the PILL caused side effects or it was contraindicated, or if the patient wanted to be pregnant. The benefits and probable side effects of both treatment options were discussed with the patients in detail. The final dose of MET was 500 mg three times daily after a stepwise build-up lasting at least for three weeks to minimize side-effects. Lifestyle changes (diet or physical activity) were not requested in these patients. The severity of acne estimated by the Global Acne Grading Score4, hirsutism by the Ferriman-Gallwey score5, body mass index (BMI), waist-to-hip ratio (WH), frequency of menstrual periods were recorded every three months. The use of MET during eventual pregnancies was discussed and encouraged throughout6. RESULTS 203 women met the Rotterdam criteria (mean age 25 y, 12-45); further 6 suspect cases were excluded during the evaluation including 2 late onset 21-hydroxylase-deficiency cases. 50/206 women had other endocrine disorders which were stabilized before treatment was commenced for PCOS (Table 1). DISCUSSION Relatively few patients with PCOS come to the medical practitioner with fertility problems, and most cases are detected after suspicion raised during the first visit. Drop-out and non-adherence to the therapeutic advice is a known phenomenon in private care; epidemiologic consequences cannot be drawn from observational studies, placebo control cannot be used. The efficacy of the two treatment forms cannot be compared directly because of obvious differences in the indication of treatment and in the different distribution of symptoms between groups: the MET group contained more severe and more obese cases; and obesity is a relative contraindication of the PILL. Changes in the hyperandrogenic symptoms were significant in both treatment groups, and MET proved to be useful to restore the regularity of menstrual cycles and increase fertility in many cases. The improvement of acne and/or menstrual cycles encourages the patient to continue tablet taking and wait for further benefits like the diminishing of hirsutism. Table 2. One-year changes in acne and hirsutism scores PILL (n = 17) MET (n = 19) Age (year) 24 (20-31) 23 (15-36) BMI 24.0 ± 6.4 - 23.7 ± 5.8 26.7 ± 7.8 - 25.4 ± 7.8 W/H ratio 0.73 ± 0.1 - 0.71±0.1 0.75 ± 0.1 – 0.74 ± 0.1 Acne score 16.9 ± 7.1 – 2.7±2.9 19.7 ± 11.2 – 6.6 ± 6.9 F-G score 15.2 ± 2.7 – 6.6 ± 3.5 16.4 ± 7.2 – 10.9 ± 6.0 Table 1. Concomitant endocrine disorders Hypothyroidism 35 (17%) Multinodular goitre (euthyroid) 5 Multinodular goitre (toxic) 2 Graves’ disease 2 De Quervain thyroiditis 1 Microprolactinoma 3 Type-1 diabetes 1 Type-2 diabetes 1 CONCLUSION AND OUTLOOK Metformin treatment proved to be a useful alternative to the anti-androgenic contraceptive pill in PCOS, especially for those women who want to conceive. Cases with partial effect or slow improvement warranted us to include lifestyle changes in the therapeutic advice to see if this could provide additional benefit. Starting last year, a “triple basal therapy” (diet of low glycaemic index food + increased physical activity + drug treatment) has been introduced for all new cases and for previous slow responders. The effect of MET on the irregular menstrual cycle is shown in Table 3; pregnancies and outcome results in Table 4. Patient No. 1 had five previous pregnancies with pre-ecclampsia (ended with two early pregnancy losses and three Caesarean sections), that did not present this time when conceived during the first month on MET and took it throughout. All these women in Table 4 had not been able to conceive at least for the previous three years. The distribution of clinical symptoms is shown in Fig. 1. Table 3. Effect of metformin on irregular menstrual cycles Before After 3 months No. of cases Irregular irregular 12 (21%) Irregular regular 15 (27%) Irregular gravidity 2 (4%) Regular regular 27 (48%) REFERENCES 1 Velasquez EM et al. Metabolism 1994; 43: 392. 2 Petrányi G. Orv Hetil 2005, 146: 1151. 3 The Rotterdam ESHRE/ASRM PCOS consensus. Hum Reprod 2004, 19: 41. 4 Doshi A et al. Int J Dermatol 1997, 36: 416. 5 Rosenfield RL. Pediatr Clin North Am 1990, 37: 1333. 6 Glueck CJ et al. Fertil Steril 2002, 77:520. ECE 2007 Budapest Poster #493 01.05.2007