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Received Date : 14-May-2013 Revised Date: 10-Jun-2013 Revised Date : 21-Jul-2013 Accepted Date : 27-Jul-2013 Article type
:R
The role of orlistat combined with lifestyle changes in the management of overweight and obese patients with polycystic ovary syndrome
Short title: Orlistat in patients with PCOS
Dimitrios Panidis1, Konstantinos Tziomalos2, Efstathios Papadakis1, Panagiotis Chatzis1, Eleni A. Kandaraki1, Elena A. Tsourdi1, Ilias Katsikis1 1
Division of Endocrinology and Human Reproduction, Second Department of Obstetrics
and Gynecology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece,
2
First Propedeutic Department of Internal Medicine, Aristotle University of
Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
Corresponding author: Konstantinos Tziomalos, MD, PhD First Propedeutic Department of Internal Medicine, AHEPA Hospital 1 Stilponos Kyriakidi street, 546 36, Thessaloniki, Greece Tel. +30 2310994621 Fax. + 30 2310274434 e-mail: [email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cen.12305 This article is protected by copyright. All rights reserved.
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Keywords: Orlistat, polycystic ovary syndrome, obesity, insulin resistance, androgens Conflicts of interest: Nothing to declare.
Summary Objective: Obesity is frequently present in women with the polycystic ovary syndrome (PCOS) and aggravates insulin resistance (IR) and hyperandrogenemia. We aimed to assess the effects of orlistat combined with lifestyle changes in overweight and obese women with PCOS and body mass index (BMI)-matched controls. Design: Prospective study. Patients: We studied 101 women with PCOS (age 26.1±6.4 years, BMI 34.5±5.9 kg/m2) and 29 BMImatched women with normal ovulating cycles. All women were instructed to follow a lowcalorie diet, to exercise and were treated with orlistat 120 mg tid for 6 months. Measurements: Metabolic and endocrine characteristics of PCOS, blood pressure (BP) and lipid profile. Results: A significant and comparable reduction in BMI was observed in women with PCOS and controls. Systolic and diastolic BP decreased only in women with PCOS. Serum low density lipoprotein cholesterol levels decreased in both women with PCOS and controls; however, this reduction was greater in controls. In contrast, serum high density lipoprotein cholesterol levels did not change in women with PCOS and decreased in controls. Serum triglyceride levels decreased significantly and to a comparable degree in the two groups. Similarly, markers of IR improved significantly and to a comparable degree in women with PCOS and controls. Serum testosterone levels and the free androgen index decreased significantly in women with PCOS and did not change in controls. Conclusions: Orlistat combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvements in IR, hyperandrogenemia and cardiovascular risk factors.
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Introduction Obesity is frequently present in women with polycystic ovary syndrome (PCOS) and appears to play an important role in the manifestations of this syndrome1,2. Obesity contributes to the pathogenesis of the pivotal characteristics of PCOS, including infertility, hyperandrogenemia and insulin resistance (IR)1,2. In addition, weight loss has beneficial effects on the metabolic and endocrine abnormalities of PCOS3,4. In overweight and obese patients with PCOS, lifestyle changes represent first-line treatment3. However, weight loss is frequently small with lifestyle changes alone and many women eventually regain weight3,4. In these women, the combination of lifestyle changes with antiobesity agents might represent a useful option4. The only currently available antiobesity agent in most countries is orlistat, which does not have systemic adverse effects and appears to exert beneficial effects not only on body weight but also on other cardiovascular risk factors, including type 2 diabetes mellitus (T2DM), hypertension and dyslipidemia5,6. However, there are limited data on the effects of orlistat in women with PCOS7-10, a population at increased risk for both T2DM and cardiovascular disease11,12. We previously reported our experience with orlistat in this population in smaller studies13,14. The aim of the present larger report is to further evaluate the effects of orlistat combined with lifestyle changes on the metabolic and endocrine characteristics as well as on the cardiovascular risk profile of overweight and obese women with PCOS and body mass index (BMI)-matched women without PCOS.
Patients and methods Patients We studied 101 women with PCOS (age 26.1±6.4 years, BMI 34.5±5.9 kg/m2) and 29 BMI-matched healthy women with normal ovulating cycles (duration 28±2 days, serum
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progesterone levels > 10 ng/ml in 2 consecutive cycles), without clinical or biochemical signs of hyperandrogenism and without polycystic ovaries on ultrasound (control group). All women with PCOS were outpatients at the Gynecological Endocrinology Infirmary of the Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki. Women of the control group were healthy volunteers. Women with PCOS and controls who were studied in previous smaller reports on the effects of orlistat from our group were included in the present study13,14. Diagnosis of PCOS was based on the revised criteria of Rotterdam15. None of the studied women had galactorrhea or any endocrine or systemic disease that could possibly affect reproductive physiology. A Synachten test was performed with tetracosactide (Synachten 0.25 mg/1ml; Novartis Pharma, Rueil-Malmaison, France) in women with basal plasma 17α-hydroxyprogesterone (17α-OHP) levels > 1.5 ng/ml to exclude congenital adrenal hyperplasia. No woman reported use of any medication that could interfere with the normal function of the hypothalamic-pituitary-gonadal axis (including metformin and oral contraceptives) during the last semester. Except orlistat, no other medication was administered during the study period of 6 months. Informed consent was obtained from all women and the study was approved by the Institutional Review Board; the study met the requirements of the 1975 Helsinki guidelines.
Study protocol In all women, weight, height, waist circumference (W) and hip circumference (H) were measured. Body weight was measured with an analog scale and in light clothing; height was measured barefoot with a stadiometer. BMI was calculated by dividing weight (in kg) by height squared (in m) to assess obesity. The W was obtained at the smallest circumference at the level of the umbilicus and the H was measured at the level of the widest diameter around
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the buttocks. The W to H ratio (WHR) was calculated by dividing W by H. Systolic and diastolic blood pressure (BP) was measured with an automatic sphygmomanometer and the mean of three measurements was recorded.
Diagnosis of the metabolic syndrome (MetS) was based on the recent joint definition proposed by the International Diabetes Federation, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity, which requires the presence of at least three of the following features: a) abdominal obesity (W ≥ 80 cm), b) serum triglyceride (TG) levels ≥ 150 mg/dl, c) serum high-density lipoprotein cholesterol (HDL-C) levels < 50 mg/dl, d) systolic BP ≥ 130 mmHg or diastolic BP ≥ 85 mmHg, and, e) serum glucose levels ≥ 100 mg/dl16.
Baseline blood samples were collected between days 3 and 7 of the menstrual cycle in the control group and after a spontaneous bleeding episode in the PCOS group, after an overnight fast. The circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), total testosterone (T), Δ4-androstenedione (Δ4-A), dehydroepiandrosterone-sulfate (DHEA-S), 17α-OHP, sex hormone-binding globulin (SHBG), glucose, insulin, total cholesterol (TC), HDL-C and TG were measured. Lowdensity lipoprotein cholesterol (LDL-C) levels were calculated using Friedewald’s formula17. Immediately after the baseline blood sampling an oral glucose tolerance test (OGTT) was performed; 75 g of glucose were administered orally and serum glucose levels were determined after 30, 60, 90 and 120 min. At the same day transvaginal ultrasonography was performed and the volume of each ovary was determined as well as the number of follicles in each ovary.
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At baseline, the basal metabolic rate (in kcal/day) was calculated in all women and adjusted for moderate daily physical activity as follows: In women 18-30 years of age: (0.0621 x weight in kg + 2.0357) x 240 x 1.3 and in women > 30 years of age: (0.0342 x weight in kg + 3.5377) x 240 x 1.3. All women were prescribed a normal-protein, energy-restricted diet [basic metabolic rate - 600 kcal/day, consisting of 50% from carbohydrate, 30% from fat (10% saturated), and 20% from protein] and were instructed to exercise 3 days a week for 1 hour for a period of 6 months. Moderate intensity, aerobic exercise (e.g. brisk walking) was advised. Participants were educated and given diet and exercise advice at one session. No nutritionists or exercise specialists were involved in the study. All women were also given orlistat 120 mg tid before each meal for 6 months (Xenical®, Roche [Hellas] S.A., Greece). All baseline laboratory tests, the OGTT and the transvaginal ultrasonography were repeated at 3 months and at 6 months. Anthropometric and clinical parameters (weight, BMI, W, H, WHR, systolic and diastolic blood pressure) were recorded every month during the treatment period. Participants were also instructed to measure their weight every week. Adherence to lifestyle changes and orlistat was evaluated by the change in weight.
Methods Serum FSH, LH, PRL, androgens, 17α-OHP, SHBG, glucose, insulin, TC, HDL-C and TG concentrations were measured as previously described13. Free androgen index (FAI) was determined as follows: FAI = T (nmol/l) x 100 / SHBG (nmol/l)18. The homeostasis model assessment of insulin resistance (HOMA-IR) index was calculated as follows: HOMAIR = fasting insulin (μIU/ml) x fasting glucose (mg/dl) / 40519. The quantitative insulin sensitivity check index (QUICKI) was calculated according to the following formula: QUICKI = 1 / [logInsulin (μIU/ml) + logGlucose (mg/dl)]20.
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Transvaginal ultrasonography Transvaginal ultrasound scans of the ovaries were performed by an experienced sonographer in all women who participated in the study. Ovarian volume was calculated by the formula: V = (π/6) x Dlength x Dwidth x Dthickness, where D is dimension. The presence of polycystic ovaries was diagnosed by the presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume (> 10 cm3).
Statistical analysis Data analysis was performed with the statistical package SPSS (version 17.0; SPSS Inc., Chicago, IL). Results are reported as mean±SD. Changes between baseline and end-oftreatment were assessed with 2-way repeated measures analysis of variance. Correlations between changes in BMI and changes in other parameters were assessed with Pearson correlation. In all cases, a p value < 0.05 was considered significant.
Results Characteristics of women with PCOS and controls at baseline are shown at Table 1. Changes in weight and W during the study are shown in Graph 1. A significant reduction in both weight and W was observed in both women with PCOS and controls (p < 0.001 for all changes); changes in these parameters were comparable in the two groups (Graph 1). Mean weight loss was 12.9% and 14.9% in women with PCOS and controls, respectively. Similarly, BMI and WHR decreased in both groups (p < 0.001 for the changes in BMI in both groups and for the change in WHR in women with PCOS, p = 0.021 for the change in WHR in controls) and these reductions did not differ between the two groups. Systolic and diastolic BP decreased only in women with PCOS (p < 0.001 for both changes) and did not change in
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controls; however, the change in systolic and diastolic BP did not differ between women with PCOS and controls. Changes in metabolic and endocrine parameters are shown in Tables 2 and 3. Serum TC and LDL-C levels decreased in both women with PCOS and controls; however, these reductions were greater in controls (p < 0.001 and p = 0.001, respectively). In contrast, serum HDL-C levels did not change in women with PCOS and decreased in controls (p = 0.006). Serum TG levels decreased significantly and to a comparable degree in the two groups. Similarly, most markers of IR (glucose/insulin, HOMA-IR and QUICKI) improved significantly in both women with PCOS and controls and changes in these parameters did not differ between the two groups. On the other hand, the area of serum glucose levels under the OGTT curve (AUC OGTT) decreased in women with PCOS and did not change in controls, but the change in the two groups was not significantly different. Among androgens, serum T levels and the FAI declined significantly in women with PCOS and did not change in controls. In contrast, serum Δ4-A levels did not change in either group. Serum DHEA-S levels decreased in women with PCOS and did not change in controls, but the change in the two groups was not significantly different. The prevalence of MetS decreased by 54.4% in women with PCOS (from 43.2% at baseline to 19.7% at 6 months; p = 0.003) and by 48.3% in controls (from 52.4% at baseline to 26.1% at 6 months; p = NS). The prevalence of MetS did not differ between the two groups neither at baseline nor at 6 months. In women with PCOS, the change in BMI during the study correlated with the change in FAI (r = 0.332, p = 0.001), in serum 17α-OHP (r = 0.225, p = 0.024), SHBG (r = -0.407, p < 0.001) and insulin levels (r = 0.274, p < 0.001), in HOMA-IR (r = 0.262, p = 0.001) and QUICKI (r = -0.203, p = 0.043). In controls, the change in BMI correlated with the change in FAI (r = 0.433, p = 0.021) and in serum T (r = 0.431, p = 0.022), LH (r = 0.377, p = 0.044) and SHBG levels (r = -0.504, p = 0.006).
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Discussion In the present study, treatment with orlistat combined with diet and exercise resulted in substantial 12.9% weight loss in women with PCOS. Previous smaller studies in obese women with PCOS (n = 21-80) reported considerably smaller weight reductions, ranging between 3.9% and 5.7%7-10. However, in some of the former studies a 2-month run-in period of diet preceded the administration of orlistat and patients were asked not to modify their diet during orlistat treatment7,8. In addition, advice regarding exercise was not provided in most studies7,8,10 and a lower dose of orlistat (120 mg twice daily) was used in another study9. Moreover, participants in our study were relatively younger and less obese than patients in previous reports7-10 and therefore might have been more motivated to adhere to lifestyle changes. Therefore, orlistat combined with diet and exercise appears to induce considerably greater weight loss than orlistat alone in obese women with PCOS.
We also observed an improvement in markers of IR after treatment with orlistat combined with lifestyle changes in women with PCOS. Other investigators also reported reduction of IR after lifestyle changes in women with PCOS21,22. In contrast, an early study that evaluated the effects of orlistat on IR in 21 obese women with PCOS reported no change in HOMA-IR7. Nevertheless, in a more recent study in 30 obese patients with PCOS, orlistat reduced the HOMA-IR8. It is possible that the first study was not powered to detect an improvement in IR7. It is also possible that the smaller weight loss observed in that study (by 4.7%) contributed to the lack of change in HOMA-IR7. Indeed, the change in BMI in our study correlated with the change in HOMA-IR. Moreover, in studies where lifestyle changes did not result in weight loss, there was also no improvement in markers of IR23-25. Interestingly, the AUC OGTT decreased only in women with PCOS in our study and did not change in controls whereas the other markers of IR (glucose/insulin, HOMA-IR and
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QUICKI) decreased in both women with PCOS and controls. Even though changes in all markers of IR (AUC OGTT, glucose/insulin, HOMA-IR and QUICKI) did not differ between women with PCOS and controls, it appears that the dynamic OGTT provides more helpful information regarding changes in glucose homeostasis during treatment with orlistat than HOMA-IR or QUICKI. Unfortunately, we did not measure serum insulin levels during OGTT and therefore we are not able to determine other markers of glucose homeostasis (e.g. the Matsuda index)26 that would allow more comprehensive evaluation of the changes in glucose metabolism during treatment with orlistat and lifestyle changes. Moreover, none of the previous studies that evaluated the effects of orlistat in women with PCOS performed an OGTT7-10.
In agreement with previous studies7-10, treatment with orlistat reduced circulating androgens in women with PCOS. This effect appears to be mostly due to weight loss, since the reduction in BMI correlated with the reduction in FAI. On the other hand, even though IR appears to contribute to the increased androgen levels in PCOS1, we did not identify any correlation between changes in markers of IR and circulating androgens in patients with PCOS in our study (data not shown).
Orlistat combined with lifestyle changes also improved the lipid profile and lowered BP in women with PCOS. In a previous study, orlistat reduced serum TG levels but changes in LDL-C and HDL-C levels were not reported10. In contrast, orlistat had no effect on the lipid profile in a smaller study (n = 21)7. Interestingly, serum HDL-C levels did not change in women with PCOS but decreased in obese women without PCOS, in agreement with previous reports in obese patients6,27. Low serum HDL-C levels appear to be related to underlying IR28. Therefore, the more pronounced IR in PCOS and its improvement after
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treatment with orlistat might explain the lack of change in serum HDL-C levels with orlistat in PCOS. It has also been reported that among the diagnostic criteria for MetS, low serum HDL-C levels is the one that best explains the higher prevalence of MetS in women with PCOS29. Indeed, in our study, serum HDL-C levels < 50 mg/dl was the second most frequently present diagnostic criterion of MetS, following abdominal obesity. Regarding BP, to the best of our knowledge, this is the first study that evaluated the effects of orlistat on BP in women with PCOS. In obese patients without PCOS, orlistat induces small reductions in BP6. Besides the BP-lowering effect of weight loss during treatment with orlistat, it has been reported that the orlistat-induced acceleration of gastric emptying might also result in BP reduction30. It is also possible that the increase in serum HDL-C levels might contribute to BP-lowering during treatment with orlistat, since HDL-C improves endothelial function and induces vasodilation by increasing nitric oxide bioavailability31,32. On the other hand, lifestyle changes also reduce BP both in women with PCOS and in hypertensive patients21,33. Therefore, it is possible that both orlistat and diet/exercise contributed to the reduction in BP in women with PCOS in our study.
Accumulating data suggest that mood disorders, which are frequently present in women with PCOS, might aggravate the endocrine and metabolic abnormalities of these patients34,35. Therefore, the involvement of psychologists as members of the therapeutic team might be associated with more favorable effects on these abnormalities. Furthermore, even though specific dietary instructions were provided in the present study, it is possible that the involvement of a dietitian could also have resulted in greater weight loss and more pronounced improvement in the metabolic and endocrine profile of the participants4,36.
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Our findings might have implications extending beyond weight loss in women with PCOS. Indeed, lifestyle changes aiming at achieving weight loss are recommended as first line intervention for the management of infertility in overweight and obese women with PCOS4,37. Therefore, the increased weight loss observed when lifestyle changes are combined with orlistat might increase pregnancy rates compared with lifestyle changes alone. Even though we did not evaluate the effects of orlistat on ovulation in the present study, two previous small randomized studies in obese women with PCOS (n = 40 and 80, respectively) reported similar ovulation and pregnancy rates during treatment with either orlistat or metformin9,10, which is also frequently used for ovulation induction37. In addition, weight loss frequently regulates menstrual cycles in obese women with PCOS and the addition of orlistat to lifestyle changes might improve the efficacy of lifestyle changes alone in restoring menstrual cyclicity4,38. Indeed, in a previous small randomized study, menstrual cyclicity improved to a similar degree in patients treated with orlistat and in those treated with metformin9. An additional advantage of orlistat in this context is its favorable metabolic effects compared with oral contraceptives, which are the current first line treatment for improving menstrual regularity in PCOS38. However, it is clear that larger studies are needed to evaluate whether orlistat could have a role in ovulation induction and restoration of menstrual cyclicity in women with PCOS.
In conclusion, orlistat combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvements in IR and hyperandrogenemia. In addition, orlistat combined with lifestyle changes has beneficial effects on other established cardiovascular risk factors, including BP and dyslipidemia. It remains to be established whether these effects will translate in reduced risk for type 2 diabetes mellitus5 and cardiovascular disease in this high-risk population.
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Table 1. Characteristics of women with polycystic ovary syndrome and controls at baseline.
Women with
Controls
polycystic ovary syndrome
(n = 29)
p
(n = 101) Age (years)
26.1±6.4
31.5±4.7
Received Date : 14-May-2013 Revised Date: 10-Jun-2013 Revised Date : 21-Jul-2013 Accepted Date : 27-Jul-2013 Article type
:R
The role of orlistat combined with lifestyle changes in the management of overweight and obese patients with polycystic ovary syndrome
Short title: Orlistat in patients with PCOS
Dimitrios Panidis1, Konstantinos Tziomalos2, Efstathios Papadakis1, Panagiotis Chatzis1, Eleni A. Kandaraki1, Elena A. Tsourdi1, Ilias Katsikis1 1
Division of Endocrinology and Human Reproduction, Second Department of Obstetrics
and Gynecology, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece,
2
First Propedeutic Department of Internal Medicine, Aristotle University of
Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
Corresponding author: Konstantinos Tziomalos, MD, PhD First Propedeutic Department of Internal Medicine, AHEPA Hospital 1 Stilponos Kyriakidi street, 546 36, Thessaloniki, Greece Tel. +30 2310994621 Fax. + 30 2310274434 e-mail: [email protected] This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cen.12305 This article is protected by copyright. All rights reserved.
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Keywords: Orlistat, polycystic ovary syndrome, obesity, insulin resistance, androgens Conflicts of interest: Nothing to declare.
Summary Objective: Obesity is frequently present in women with the polycystic ovary syndrome (PCOS) and aggravates insulin resistance (IR) and hyperandrogenemia. We aimed to assess the effects of orlistat combined with lifestyle changes in overweight and obese women with PCOS and body mass index (BMI)-matched controls. Design: Prospective study. Patients: We studied 101 women with PCOS (age 26.1±6.4 years, BMI 34.5±5.9 kg/m2) and 29 BMImatched women with normal ovulating cycles. All women were instructed to follow a lowcalorie diet, to exercise and were treated with orlistat 120 mg tid for 6 months. Measurements: Metabolic and endocrine characteristics of PCOS, blood pressure (BP) and lipid profile. Results: A significant and comparable reduction in BMI was observed in women with PCOS and controls. Systolic and diastolic BP decreased only in women with PCOS. Serum low density lipoprotein cholesterol levels decreased in both women with PCOS and controls; however, this reduction was greater in controls. In contrast, serum high density lipoprotein cholesterol levels did not change in women with PCOS and decreased in controls. Serum triglyceride levels decreased significantly and to a comparable degree in the two groups. Similarly, markers of IR improved significantly and to a comparable degree in women with PCOS and controls. Serum testosterone levels and the free androgen index decreased significantly in women with PCOS and did not change in controls. Conclusions: Orlistat combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvements in IR, hyperandrogenemia and cardiovascular risk factors.
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Introduction Obesity is frequently present in women with polycystic ovary syndrome (PCOS) and appears to play an important role in the manifestations of this syndrome1,2. Obesity contributes to the pathogenesis of the pivotal characteristics of PCOS, including infertility, hyperandrogenemia and insulin resistance (IR)1,2. In addition, weight loss has beneficial effects on the metabolic and endocrine abnormalities of PCOS3,4. In overweight and obese patients with PCOS, lifestyle changes represent first-line treatment3. However, weight loss is frequently small with lifestyle changes alone and many women eventually regain weight3,4. In these women, the combination of lifestyle changes with antiobesity agents might represent a useful option4. The only currently available antiobesity agent in most countries is orlistat, which does not have systemic adverse effects and appears to exert beneficial effects not only on body weight but also on other cardiovascular risk factors, including type 2 diabetes mellitus (T2DM), hypertension and dyslipidemia5,6. However, there are limited data on the effects of orlistat in women with PCOS7-10, a population at increased risk for both T2DM and cardiovascular disease11,12. We previously reported our experience with orlistat in this population in smaller studies13,14. The aim of the present larger report is to further evaluate the effects of orlistat combined with lifestyle changes on the metabolic and endocrine characteristics as well as on the cardiovascular risk profile of overweight and obese women with PCOS and body mass index (BMI)-matched women without PCOS.
Patients and methods Patients We studied 101 women with PCOS (age 26.1±6.4 years, BMI 34.5±5.9 kg/m2) and 29 BMI-matched healthy women with normal ovulating cycles (duration 28±2 days, serum
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progesterone levels > 10 ng/ml in 2 consecutive cycles), without clinical or biochemical signs of hyperandrogenism and without polycystic ovaries on ultrasound (control group). All women with PCOS were outpatients at the Gynecological Endocrinology Infirmary of the Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki. Women of the control group were healthy volunteers. Women with PCOS and controls who were studied in previous smaller reports on the effects of orlistat from our group were included in the present study13,14. Diagnosis of PCOS was based on the revised criteria of Rotterdam15. None of the studied women had galactorrhea or any endocrine or systemic disease that could possibly affect reproductive physiology. A Synachten test was performed with tetracosactide (Synachten 0.25 mg/1ml; Novartis Pharma, Rueil-Malmaison, France) in women with basal plasma 17α-hydroxyprogesterone (17α-OHP) levels > 1.5 ng/ml to exclude congenital adrenal hyperplasia. No woman reported use of any medication that could interfere with the normal function of the hypothalamic-pituitary-gonadal axis (including metformin and oral contraceptives) during the last semester. Except orlistat, no other medication was administered during the study period of 6 months. Informed consent was obtained from all women and the study was approved by the Institutional Review Board; the study met the requirements of the 1975 Helsinki guidelines.
Study protocol In all women, weight, height, waist circumference (W) and hip circumference (H) were measured. Body weight was measured with an analog scale and in light clothing; height was measured barefoot with a stadiometer. BMI was calculated by dividing weight (in kg) by height squared (in m) to assess obesity. The W was obtained at the smallest circumference at the level of the umbilicus and the H was measured at the level of the widest diameter around
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the buttocks. The W to H ratio (WHR) was calculated by dividing W by H. Systolic and diastolic blood pressure (BP) was measured with an automatic sphygmomanometer and the mean of three measurements was recorded.
Diagnosis of the metabolic syndrome (MetS) was based on the recent joint definition proposed by the International Diabetes Federation, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society and International Association for the Study of Obesity, which requires the presence of at least three of the following features: a) abdominal obesity (W ≥ 80 cm), b) serum triglyceride (TG) levels ≥ 150 mg/dl, c) serum high-density lipoprotein cholesterol (HDL-C) levels < 50 mg/dl, d) systolic BP ≥ 130 mmHg or diastolic BP ≥ 85 mmHg, and, e) serum glucose levels ≥ 100 mg/dl16.
Baseline blood samples were collected between days 3 and 7 of the menstrual cycle in the control group and after a spontaneous bleeding episode in the PCOS group, after an overnight fast. The circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), total testosterone (T), Δ4-androstenedione (Δ4-A), dehydroepiandrosterone-sulfate (DHEA-S), 17α-OHP, sex hormone-binding globulin (SHBG), glucose, insulin, total cholesterol (TC), HDL-C and TG were measured. Lowdensity lipoprotein cholesterol (LDL-C) levels were calculated using Friedewald’s formula17. Immediately after the baseline blood sampling an oral glucose tolerance test (OGTT) was performed; 75 g of glucose were administered orally and serum glucose levels were determined after 30, 60, 90 and 120 min. At the same day transvaginal ultrasonography was performed and the volume of each ovary was determined as well as the number of follicles in each ovary.
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At baseline, the basal metabolic rate (in kcal/day) was calculated in all women and adjusted for moderate daily physical activity as follows: In women 18-30 years of age: (0.0621 x weight in kg + 2.0357) x 240 x 1.3 and in women > 30 years of age: (0.0342 x weight in kg + 3.5377) x 240 x 1.3. All women were prescribed a normal-protein, energy-restricted diet [basic metabolic rate - 600 kcal/day, consisting of 50% from carbohydrate, 30% from fat (10% saturated), and 20% from protein] and were instructed to exercise 3 days a week for 1 hour for a period of 6 months. Moderate intensity, aerobic exercise (e.g. brisk walking) was advised. Participants were educated and given diet and exercise advice at one session. No nutritionists or exercise specialists were involved in the study. All women were also given orlistat 120 mg tid before each meal for 6 months (Xenical®, Roche [Hellas] S.A., Greece). All baseline laboratory tests, the OGTT and the transvaginal ultrasonography were repeated at 3 months and at 6 months. Anthropometric and clinical parameters (weight, BMI, W, H, WHR, systolic and diastolic blood pressure) were recorded every month during the treatment period. Participants were also instructed to measure their weight every week. Adherence to lifestyle changes and orlistat was evaluated by the change in weight.
Methods Serum FSH, LH, PRL, androgens, 17α-OHP, SHBG, glucose, insulin, TC, HDL-C and TG concentrations were measured as previously described13. Free androgen index (FAI) was determined as follows: FAI = T (nmol/l) x 100 / SHBG (nmol/l)18. The homeostasis model assessment of insulin resistance (HOMA-IR) index was calculated as follows: HOMAIR = fasting insulin (μIU/ml) x fasting glucose (mg/dl) / 40519. The quantitative insulin sensitivity check index (QUICKI) was calculated according to the following formula: QUICKI = 1 / [logInsulin (μIU/ml) + logGlucose (mg/dl)]20.
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Transvaginal ultrasonography Transvaginal ultrasound scans of the ovaries were performed by an experienced sonographer in all women who participated in the study. Ovarian volume was calculated by the formula: V = (π/6) x Dlength x Dwidth x Dthickness, where D is dimension. The presence of polycystic ovaries was diagnosed by the presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter and/or increased ovarian volume (> 10 cm3).
Statistical analysis Data analysis was performed with the statistical package SPSS (version 17.0; SPSS Inc., Chicago, IL). Results are reported as mean±SD. Changes between baseline and end-oftreatment were assessed with 2-way repeated measures analysis of variance. Correlations between changes in BMI and changes in other parameters were assessed with Pearson correlation. In all cases, a p value < 0.05 was considered significant.
Results Characteristics of women with PCOS and controls at baseline are shown at Table 1. Changes in weight and W during the study are shown in Graph 1. A significant reduction in both weight and W was observed in both women with PCOS and controls (p < 0.001 for all changes); changes in these parameters were comparable in the two groups (Graph 1). Mean weight loss was 12.9% and 14.9% in women with PCOS and controls, respectively. Similarly, BMI and WHR decreased in both groups (p < 0.001 for the changes in BMI in both groups and for the change in WHR in women with PCOS, p = 0.021 for the change in WHR in controls) and these reductions did not differ between the two groups. Systolic and diastolic BP decreased only in women with PCOS (p < 0.001 for both changes) and did not change in
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controls; however, the change in systolic and diastolic BP did not differ between women with PCOS and controls. Changes in metabolic and endocrine parameters are shown in Tables 2 and 3. Serum TC and LDL-C levels decreased in both women with PCOS and controls; however, these reductions were greater in controls (p < 0.001 and p = 0.001, respectively). In contrast, serum HDL-C levels did not change in women with PCOS and decreased in controls (p = 0.006). Serum TG levels decreased significantly and to a comparable degree in the two groups. Similarly, most markers of IR (glucose/insulin, HOMA-IR and QUICKI) improved significantly in both women with PCOS and controls and changes in these parameters did not differ between the two groups. On the other hand, the area of serum glucose levels under the OGTT curve (AUC OGTT) decreased in women with PCOS and did not change in controls, but the change in the two groups was not significantly different. Among androgens, serum T levels and the FAI declined significantly in women with PCOS and did not change in controls. In contrast, serum Δ4-A levels did not change in either group. Serum DHEA-S levels decreased in women with PCOS and did not change in controls, but the change in the two groups was not significantly different. The prevalence of MetS decreased by 54.4% in women with PCOS (from 43.2% at baseline to 19.7% at 6 months; p = 0.003) and by 48.3% in controls (from 52.4% at baseline to 26.1% at 6 months; p = NS). The prevalence of MetS did not differ between the two groups neither at baseline nor at 6 months. In women with PCOS, the change in BMI during the study correlated with the change in FAI (r = 0.332, p = 0.001), in serum 17α-OHP (r = 0.225, p = 0.024), SHBG (r = -0.407, p < 0.001) and insulin levels (r = 0.274, p < 0.001), in HOMA-IR (r = 0.262, p = 0.001) and QUICKI (r = -0.203, p = 0.043). In controls, the change in BMI correlated with the change in FAI (r = 0.433, p = 0.021) and in serum T (r = 0.431, p = 0.022), LH (r = 0.377, p = 0.044) and SHBG levels (r = -0.504, p = 0.006).
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Discussion In the present study, treatment with orlistat combined with diet and exercise resulted in substantial 12.9% weight loss in women with PCOS. Previous smaller studies in obese women with PCOS (n = 21-80) reported considerably smaller weight reductions, ranging between 3.9% and 5.7%7-10. However, in some of the former studies a 2-month run-in period of diet preceded the administration of orlistat and patients were asked not to modify their diet during orlistat treatment7,8. In addition, advice regarding exercise was not provided in most studies7,8,10 and a lower dose of orlistat (120 mg twice daily) was used in another study9. Moreover, participants in our study were relatively younger and less obese than patients in previous reports7-10 and therefore might have been more motivated to adhere to lifestyle changes. Therefore, orlistat combined with diet and exercise appears to induce considerably greater weight loss than orlistat alone in obese women with PCOS.
We also observed an improvement in markers of IR after treatment with orlistat combined with lifestyle changes in women with PCOS. Other investigators also reported reduction of IR after lifestyle changes in women with PCOS21,22. In contrast, an early study that evaluated the effects of orlistat on IR in 21 obese women with PCOS reported no change in HOMA-IR7. Nevertheless, in a more recent study in 30 obese patients with PCOS, orlistat reduced the HOMA-IR8. It is possible that the first study was not powered to detect an improvement in IR7. It is also possible that the smaller weight loss observed in that study (by 4.7%) contributed to the lack of change in HOMA-IR7. Indeed, the change in BMI in our study correlated with the change in HOMA-IR. Moreover, in studies where lifestyle changes did not result in weight loss, there was also no improvement in markers of IR23-25. Interestingly, the AUC OGTT decreased only in women with PCOS in our study and did not change in controls whereas the other markers of IR (glucose/insulin, HOMA-IR and
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QUICKI) decreased in both women with PCOS and controls. Even though changes in all markers of IR (AUC OGTT, glucose/insulin, HOMA-IR and QUICKI) did not differ between women with PCOS and controls, it appears that the dynamic OGTT provides more helpful information regarding changes in glucose homeostasis during treatment with orlistat than HOMA-IR or QUICKI. Unfortunately, we did not measure serum insulin levels during OGTT and therefore we are not able to determine other markers of glucose homeostasis (e.g. the Matsuda index)26 that would allow more comprehensive evaluation of the changes in glucose metabolism during treatment with orlistat and lifestyle changes. Moreover, none of the previous studies that evaluated the effects of orlistat in women with PCOS performed an OGTT7-10.
In agreement with previous studies7-10, treatment with orlistat reduced circulating androgens in women with PCOS. This effect appears to be mostly due to weight loss, since the reduction in BMI correlated with the reduction in FAI. On the other hand, even though IR appears to contribute to the increased androgen levels in PCOS1, we did not identify any correlation between changes in markers of IR and circulating androgens in patients with PCOS in our study (data not shown).
Orlistat combined with lifestyle changes also improved the lipid profile and lowered BP in women with PCOS. In a previous study, orlistat reduced serum TG levels but changes in LDL-C and HDL-C levels were not reported10. In contrast, orlistat had no effect on the lipid profile in a smaller study (n = 21)7. Interestingly, serum HDL-C levels did not change in women with PCOS but decreased in obese women without PCOS, in agreement with previous reports in obese patients6,27. Low serum HDL-C levels appear to be related to underlying IR28. Therefore, the more pronounced IR in PCOS and its improvement after
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treatment with orlistat might explain the lack of change in serum HDL-C levels with orlistat in PCOS. It has also been reported that among the diagnostic criteria for MetS, low serum HDL-C levels is the one that best explains the higher prevalence of MetS in women with PCOS29. Indeed, in our study, serum HDL-C levels < 50 mg/dl was the second most frequently present diagnostic criterion of MetS, following abdominal obesity. Regarding BP, to the best of our knowledge, this is the first study that evaluated the effects of orlistat on BP in women with PCOS. In obese patients without PCOS, orlistat induces small reductions in BP6. Besides the BP-lowering effect of weight loss during treatment with orlistat, it has been reported that the orlistat-induced acceleration of gastric emptying might also result in BP reduction30. It is also possible that the increase in serum HDL-C levels might contribute to BP-lowering during treatment with orlistat, since HDL-C improves endothelial function and induces vasodilation by increasing nitric oxide bioavailability31,32. On the other hand, lifestyle changes also reduce BP both in women with PCOS and in hypertensive patients21,33. Therefore, it is possible that both orlistat and diet/exercise contributed to the reduction in BP in women with PCOS in our study.
Accumulating data suggest that mood disorders, which are frequently present in women with PCOS, might aggravate the endocrine and metabolic abnormalities of these patients34,35. Therefore, the involvement of psychologists as members of the therapeutic team might be associated with more favorable effects on these abnormalities. Furthermore, even though specific dietary instructions were provided in the present study, it is possible that the involvement of a dietitian could also have resulted in greater weight loss and more pronounced improvement in the metabolic and endocrine profile of the participants4,36.
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Our findings might have implications extending beyond weight loss in women with PCOS. Indeed, lifestyle changes aiming at achieving weight loss are recommended as first line intervention for the management of infertility in overweight and obese women with PCOS4,37. Therefore, the increased weight loss observed when lifestyle changes are combined with orlistat might increase pregnancy rates compared with lifestyle changes alone. Even though we did not evaluate the effects of orlistat on ovulation in the present study, two previous small randomized studies in obese women with PCOS (n = 40 and 80, respectively) reported similar ovulation and pregnancy rates during treatment with either orlistat or metformin9,10, which is also frequently used for ovulation induction37. In addition, weight loss frequently regulates menstrual cycles in obese women with PCOS and the addition of orlistat to lifestyle changes might improve the efficacy of lifestyle changes alone in restoring menstrual cyclicity4,38. Indeed, in a previous small randomized study, menstrual cyclicity improved to a similar degree in patients treated with orlistat and in those treated with metformin9. An additional advantage of orlistat in this context is its favorable metabolic effects compared with oral contraceptives, which are the current first line treatment for improving menstrual regularity in PCOS38. However, it is clear that larger studies are needed to evaluate whether orlistat could have a role in ovulation induction and restoration of menstrual cyclicity in women with PCOS.
In conclusion, orlistat combined with lifestyle changes induces substantial weight loss in women with PCOS, resulting in improvements in IR and hyperandrogenemia. In addition, orlistat combined with lifestyle changes has beneficial effects on other established cardiovascular risk factors, including BP and dyslipidemia. It remains to be established whether these effects will translate in reduced risk for type 2 diabetes mellitus5 and cardiovascular disease in this high-risk population.
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Table 1. Characteristics of women with polycystic ovary syndrome and controls at baseline.
Women with
Controls
polycystic ovary syndrome
(n = 29)
p
(n = 101) Age (years)
26.1±6.4
31.5±4.7
