Metformin treatment with or without life style changes in the 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) INTRODUCTION There has been no universally accepted therapeutic approach to the polycystic ovary syndrome (PCOS); even the most recent advice lists the treatment possibilities according to the patients’ symptoms that practically means treatment for complains. Treating infertility also often disregards the patient’s metabolic problems or other symptoms. On cessation of any kind of treatment, symptoms of PCOS usually recur. Since patients coming to us rarely complain about infertility (see the distribution of symptoms of our clientele in Fig. 1) we have been seeking for a general treatment approach to PCOS that addresses the underlying insulin sensitivity, can be used for long, and can also be continued during eventual pregnancies. DISCUSSION PCOS is a chronic condition affecting the whole body and leads to the deterioration of metabolism into diabetes and dyslipidaemia 5. To treat all symptoms and prevent the metabolic consequences, in lack of a final cure PCOS would require long-term, safe and cheap treatment that can be used independently from the actual symptoms and also during pregnancy and lactation; and which has no contraindications and side effects in the majority of patients. Metformin and life style changes seem to fulfil these expectations. Long-term safety of metformin has already been proved in diabetes, another chronic insulin resistance syndrome. Metformin improves all symptoms of PCOS even if it is not the best in certain aspects of the disease 6. The suggested life style is recommendable to everyone not only for those with insulin resistance. Not all patients responded the same way to the combined therapy. The efficacy of metformin is limited; and life style changes require patient compliance. Therefore in cases where certain symptoms do not improve satisfactorily, the introduction of other treatment modalities may become necessary. Our working hypothesis is that metformin, low glycaemic index diet and increased physical activity as a basal triple treatment is the initial treatment of choice for all patients with PCOS for the time being; to which additional drugs may be added if necessary like acarbose, contraceptive pill, clomiphene or IVF treatment – without stopping the basal therapy not to loose improvements already achieved. The time of introduction of any additional treatment should depend on the symptom not responding: in case of acne after six months; while hirsutism, irregular menses or infertility may require more patience. We hope that the long term triple basal treatment for PCOS may also increase those rather low live birth rate with clomiphene monotherapy in obese infertile women 7. Table 3. shows observed changes in the regularity of menstrual cycles during the six-month treatment period. The proportion of patients who changed from irregular to regular was not significantly different between treatment forms (Fisher’s exact test, P = 0.29). REFERENCES 1. Petrányi G, Zaoura M. End. Abstracts 2007, 14: P The Rotterdam ESHRE/ASRM PCOS consensus. Hum Reprod 2004, 19: Doshi A et al. Int J Dermatol 1997, 36: Rosenfield RL. Pediatr Clin North Am 1990, 37: Wang ET et al. Obstet Gynecol 2011, 117: Palomba S et al. Endocr Rev 2009, 30: Legro RS et al. N Engl J Med 2007, 356:551.7 Table 1. Changes of symptom severity during six months MET (n = 29) MET+LS (n = 34) Δ Acne 20 ± ± 9 25 ± ± 8 Δ = 7.9 ***Δ = 9.3 *** 1.4 n.s. F-G 15 ± ± 6 12 ± ± 3 Δ = 2.27 *** Δ = 2.48 *** 0.2 n.s. BMI 26.6 ± ± ± ± 6 Δ = 0.26 n.s.Δ = 0.88 *** 0.62 * W/H 0.74 ± ± ± ± 0.02 Δ = n.s. Δ = ** * Table 3. Changes of regularity of menstrual cycles MET (n = 29) MET+LS (n = 34) Irregular at start12 22 Became regular 8 14 Regular at start17 12 Became irregular 0 0 CONCLUSIONS The favourable improvement of symptoms related to hyperandrogenism and insulin resistance during the six-month combination treatment consisting of metformin, low glycaemic index diet and increased physical activity convinced us to continue this triple basal therapy; and to commence it in all new PCOS patients regardless of the severity and combination of actual symptoms to find out its long-term benefits until better universal treatment emerges. ECE 2011 Rotterdam Poster # ABSTRACT Metformin 500 mg three times daily had been advised to our patients suffering from the polycystic ovary syndrome by the Rotterdam criteria who did not want to take contraceptive pills. More recently, we have included life style changes to metformin taking: increased physical activity and low glycaemic index diet (with calorie restriction for the obese). The efficacy of the two treatment forms was compared. The metformin only group consisted of 29 patients (age 18 to 39 y, mean, 26); the metformin + life style changes group of 34 age-matched patients. The following parameters were registered at the beginning and the end of a six- month treatment period: global acne score, Ferriman-Gallwey hirsutism score (FG), body mass index (BMI), and the waist-hip circumference ratio (W/H). By the end of the treatment period, both acne and FG improved significantly in both treatment groups, without significant difference between treatment forms: acne 7.9±6.0 vs. 9.3±5.9 (P=0.37); FG 2.3±2.1 vs. 2.5±1.6 (P=0.75). BMI and WH remained practically unchanged in the metformin only group: 0.26±1.0 (n.s.) and 0.001±0.02 (n.s.). BMI improved in the metformin + life style group by 0.88±1.1 (P<0.001); and W/H by 0.019±0.03 (P<0.01). Life style changes did not show in additional improvement of hyperandrogenic symptoms compared to metformin only but diminished BMI and W/H. Based on these results we advise the continuation of the triple basal treatment consisting of metformin with low glycaemic index diet and increased physical activity to all patients with PCOS for long-term assessment. PATIENTS AND METHODS PCOS was diagnosed using the Rotterdam criteria 2 ; all patients had at least one hyperandrogenic symptom. The dose of metformin was 500 mg three times daily in all patients. Patients from the metformin monotherapy era served as historical control group (MET) consisting of 29 women (age 18 to 39 y, mean, 26) to whom we compared the recent metformin + life style changes group (MET+LS) consisting of 34 patients with comparable age distribution. The advice on life style changes included the low glycaemic index diet (with calorie restriction in the overweight ones) and increased physical activity. The following parameters were recorded every three months during the 6-month observation period: severity of acne estimated by the Global Acne Grading Score 3, hirsutism by the Ferriman-Gallwey score 4, body mass index (BMI), waist-to-hip ratio (WH), and the regularity of the menstrual periods. Patients with carbohydrate metabolic disorders (IFG, IGT, DM) or those who became pregnant during the six-month period were not included in the evaluation. RESULTS Table 1 shows the changes of the four easily measurable symptoms during the six-month observation period within MET and MET + LS therapy groups; and between the two treatment forms (Δ). MET improved acne and hirsutism but left BMI and W/H practically unchanged. MET+LS improved all four parameters. The improvement of BMI and W/H was the significant difference between the efficacy of the two treatment forms. Fig. 1 shows the acne score changes for each patient: all improved by three months and improved further by six months. Fig. 2 shows the F-G score changes for the hirsute patients. All improved by six months. In 2002 we introduced metformin to treat all PCOS patients who did not want to take the contraceptive pill. We demonstrated similar efficacy of metformin and the pill treatment on acne and hirsutism in this forum 1. In many patients, regularity of the menstrual cycle was also restored and spontaneous pregnancies with live birth occurred. Since 2006 we have combined metformin taking with advice on life style: the low glycaemic index diet and increased physical activity. Here we present our observations comparing these two treatment forms. Fig. 2. Individual changes: Hirsutism score. MET + LS, n = 21 Fig. 1. Individual changes: Acne score. MET + LS, n = 32