Clinical, metabolic, and endocrine parameters in response to
Transcript Of Clinical, metabolic, and endocrine parameters in response to
Gynecological Endocrinology, March 2010; 26(3): 173–178
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PCOS
Clinical, metabolic, and endocrine parameters in response to metformin and lifestyle intervention in women with polycystic ovary syndrome: A randomized, double-blind, and placebo control trial
CAROLINA FUX OTTA1, MYRIAM WIOR1, GABRIEL S. IRACI2, RAQUEL KAPLAN3, DIANA TORRES3, MARI´A ISABEL GAIDO4, & EDUARDO P. WYSE1
1Departamento de Endocrinolog´ıa, Centro Me´dico de Co´rdoba, Hospital Privado, Co´rdoba Capital, Argentina, 2Facultad de Ciencias Me´dicas, Ca´ tedra de Farmacolog´ıa, Hospital Nacional de Cl´ınicas, Universidad Nacional de Co´rdoba, Co´rdoba Capital, Argentina, 3Fundacio´n para el Progreso de la Medicina, Co´rdoba Capital, Argentina, and 4Laboratorio de Bioqu´ımica Cl´ınica, Centro Me´dico de Co´rdoba, Hospital Privado, Co´rdoba Capital, Argentina
(Received 19 July 2009; accepted 20 July 2009)
Abstract The aim of this study was to evaluate the effects of metformin in addition to diet and exercise on endocrine and metabolic disturbances in women with polycystic ovary syndrome (PCOS) in a prospective, double-blind, randomized, placebo (PBO) control trial. Thirty women with insulin resistance and PCOS received lifestyle modification and 1500 mg of metformin or placebo for 4 months. Before and after treatment, body mass index, waist/hip ratio, blood pressure, hirsutism, and menstrual patterns were evaluated. Serum concentrations of gonadotropins, androgens, progesterone, glucose, insulin, and lipids were measured. Lifestyle interventions resulted in similar weight and menstrual cycle’s improvements in both groups. A significant reduction in serum fasting insulin, HOMA index, waist and testosterone levels was only observed with metformin. There were no significant changes in androstenedione, dehydroepiandrosterone sulfate, gonadotropins, and lipids levels. No other changes were observed in hirsutism or blood pressure. These findings suggest that metformin has an additive effect to diet and exercise to improve parameters of hyperandrogenism and insulin resistance. Although, a small decrease in body weight trough lifestyle changes could be enough to improve menstrual cycles in insulin-resistant women with PCOS.
Keywords: Polycystic ovary syndrome, insulin resistance, lifestyle intervention, metformin
Introduction
Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder in women of reproductive age. Hyperandrogenism and chronic anovulation characterize it. Several studies in diverse populations estimate its prevalence at 5–10% [1–3]. Women present, in a high percentage of cases, with obesity, hirsutism, acne, menstrual irregularities and infertility [4]. Although the exact physiopathology of PCOS remains unknown, several studies tend to point to insulin resistance (IR) as the cause of the syndrome [5]. IR is present in 60–70% of the patients independent of obesity [6]. Compensatory hyperinsulinism has a pivotal role in the physiopathogenesis of PCOS. In vitro, insulin stimulates androgen synthesis
in thecal cells and decreases sex hormone-binding globulin (SHBG) synthesis in the liver, therefore increasing free androgen availability [7,8]. Because of the high prevalence of IR, PCOS shares components of metabolic syndrome like abdominal obesity, impaired glucose tolerance, gestational and type 2 diabetes, abnormalities in lipid profile, blood hypertension, endothelial dysfunction, and probably cardiovascular disease [9–18].
In the past, PCOS treatment was focused on ovulation induction for infertility, oral contraceptives for irregular bleeding or androgen antagonists for hirsutism and acne. In later years, insulin sensitizing agents have been used to reduce hyperinsulinemia, improve ovary function and associated metabolic abnormalities [19]. Metformin, a biguanide, usually
Correspondence: Carolina Fux Otta, Departamento de Endocrinolog´ıa, Hospital Privado, Centro Me´dico de Co´ rdoba, Co´ rdoba Capital, Argentina. E-mail: [email protected]
ISSN 0951-3590 print/ISSN 1473-0766 online ª 2010 Informa UK Ltd. DOI: 10.3109/09513590903215581
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174 C. F. Otta et al.
prescribed in obese patients with type 2 diabetes, inhibits glucose hepatic production, reduces fatty acids oxidation, and increases glucose uptake in peripheral tissues therefore reducing insulin secretion [20,21]. Some studies using metformin have reported an improvement in insulin sensitivity associated with reduction of hyperandrogenism and improvements in reproductive abnormalities. On the other hand, other authors failed to observe those changes. Prescribing metformin to treat PCOS has grown dramatically in later years. Despite metformin is ‘off label’ by the FDA for the treatment of this disorder and there is lack of large controlled trials to support its use [22,23].
In obese women with PCOS, weight loss ameliorates hyperandrogenism and metabolic disorders by improving IR. The present randomized double-blind and placebo-controlled study, was designed to test the effects of metformin in addition to lifestyle modifications on menstrual cycles, endocrine, and metabolic disturbances in women with PCOS.
Methods
Ethical approval
Every subject gave written informed consent before entering the study, which was conducted in accordance with the Declaration of Helsinki and approved by the institutional ethical committee.
Subjects
We enrolled 30 women who were 20–34 years old. They were outpatients attending the Department of Endocrinology of Hospital Privado Centro Me´dico de Co´ rdoba (Argentina). All women had PCOS, as defined by hyperandrogenemia (elevated serum testosterone concentrations) and oligomenorrhea (cycles of 35 days or longer) or amenorrhea (no menses in the last 6 months) after negative screening pregnancy test. Estimation of IR was derived from the HOMA index (basal glucose mmol/l 6 basal insulin mIU/ml/22.5) to 2. Other causes of hyperandrogenism (Cushing’s syndrome, late-onset congenital adrenal hyperplasia, and androgen-secreting tumors) were excluded with appropriate diagnostic tests. None of them had concomitant thyroid dysfunction, hyperprolactinemia, diabetes, severe infections, cardiovascular, renal, or hepatic abnormalities. And they have not taken any medications for atleast 3 months before enrollment in the study.
Study protocol
Gynecological history and pregnancy willing were addressed. Familial history of PCOS, type 2 diabetes,
hypertension, hyperlipidemias, obesity, cardiovascular diseases, and early coronal male androgenetic alopecia were also evaluated. Menstrual cycles were assessed by recording the last 6-month period before entering the study and during it. Body mass index, (weight in kilograms divided by the square of height in meters), waist circumference, waist/hip ratio, blood pressure, acanthosis nigricans, and clinical signs of androgen excess (hirsutism measured by a modification of the Ferriman-Gallwey method, acne, seborrheic skin, and androgenetic alopecia) were recorded by a single trained observer using standardized techniques [24]. During the follicular phase of the menstrual cycle or during amenorrhea, after a 12-h overnight fast, blood samples were drawn at 8:00 a.m. for measurement of androgens (total testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S)), gonadotropins, insulin, glucose, total cholesterol, HDL and LDL cholesterol and triglycerides. A standardized 75 g oral glucose tolerance test (OGTT) was performed with measurement of fasting insulin and glucose at 0 and 120 min. Every determination was done at baseline and at the end of the study. Serum progesterone was measured on Days 22–24 and ovulation was presumed to have occurred if the concentration exceeded 4 ng/ml (12.7 nmol/l). The women were randomly assigned through a computerized allocation software in a double-blind way to receive oral metformin or placebo for 4 months. Fifteen women received metformin and 15 placebo. To reduce gastrointestinal side effects of metformin, doses were tapered from 500 mg with lunch during the first week, then 500 mg with lunch and dinner during the second week, and finally 750 mg twice in day. Patients were also given a nutritional plan of 1500 calories daily, composed of 50% from carbohydrates, 20% from proteins, and 30% from fat. The women were advice to exercise (a minimum of 40 min of brisk walking per day, 4 times a week) and to use barrier contraceptives during the whole study. Monthly visits were arranged to evaluate clinical, anthropometrical parameters, treatment compliance and adverse events.
Assays
Androstenedione was measured with radioimmunoassay kit (Active Androstenedione RIA DSL3800. Diagnostic Systems Laboratories, Texas, Berthold LB 2111) with coefficient of variation of 5.6% intra-assay and 9.8% inter-assay. Testosterone, LH, FSH, DHEA-S, progesterone, and insulin were determined with electrochemiluminescent (Elecsys 2010 Roche, Germany). Glucose, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were measured with an analyzer (Hitachi 917 Roche, Germany).
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Statistical analysis
Normal distribution was tested with skewness and kurtosis. Symmetric variables were expressed with arithmetic mean and +1 standard deviation and asymmetric variables were expressed with median and interquartilic range (IqR). Percentiles 25 and 75 were estimated with Tukey’s Hinges method. Qualitative variables in treatment arms were contrasted with Chi square test and adjusted for continuity with Yates. Analysis of quantitative variables was performed with Student’s t-test in case of symmetric distribution and Mann–Whitney test for asymmetric distribution. Wilcoxon or Student t-test was used, when corresponding for contrasting variables before and after treatment in each arm. In normal distribution, the variables were calculated at a confidence interval of 95% (CI 95%) and the variables were considered statistically significant at a p value 50.05. Analysis was performed using SPSS Statistics 17.0 software.
Results
One woman in metformin group was withdrawn for lack of adherence to treatment, so 14 patients received metformin and 15 placebo to the end of the study. There were neither serious nor mild adverse events in both groups.
Baseline characteristics
The clinical, anthropometric, metabolic, and hormonal characteristics of the patients are depicted in Tables I–III. Overall, there were no significant differences in baseline features between treatment groups.
Table I. The baseline clinical parameters.
Variable
Metformin
Placebo
p
Age (years)* Systolic blood
pressure (mmHg) Diastolic blood
pressure (mmHg) F-G score Acne Androgenetic alopecia{ Seborrheic skin Acanthosis Nigricans Pregnancy willing Familiar history
Hypertension Obesity Diabetes Hyperlipidemias
25.47 [4.82] 119.3 [11.4]
77.1 [9.4]
11.73 [5.31] 8 (57.1) 4 (28.6)
11 (78.6) 7 (50) 3 (21.4)
11 (78.6) 9 (64.3)
10 (71.4) 8 (57.1)
24.7 [3.46] 120.7 [8.0]
79.7 [7.7]
13.5 [5.97] 10 (66.7)
5 (35.7) 10 (66.7)
9 (60) 2 (13.3)
11 (84.6) 9 (69.2) 8 (61.5) 7 (53.8)
0.510 0.707
0.426
0.4 0.885 1.00 0.763 0.867 0.932
1.000 1.000 0.892 1.000
*X [SD]: Student’s t-test. Data are arithmetic mean and standard
deviation between brackets. {n (%): Number of cases and percentage between parenthesis.
Metformin & lifestyle in PCOS 175
Effect on menstrual abnormalities
An improvement in menstrual cycling in both groups was observed. Baseline means of menstrual cycling were 120.33 + 81.05 days and 121.42 + 75.30 days in metformin and placebo groups, respectively. After treatment means significantly decreased to 66.35 + 47.09 days (p ¼ 0.003) with metformin and to 77.86 + 56.48 days (p ¼ 0.009) with placebo.
Eight patients experienced normalization of menstrual cycling (four metformin group and four in placebo) and the other 16 patients (nine in metformin group and seven in placebo) reported amelioration of menstrual cycle abnormalities. Forty-five percent of patients ovulated, 7 in metformin group and 6 in placebo group.
Effects on anthropometric variables
Both groups showed a non-significant small reduction in body mass index. Metformin group obtained a significant reduction in waist circumference compared pre to post treatment: 98.6 cm (IqR: 84.1–113.1 cm) to 93.7 cm (IqR: 77.6–109.8 cm) (p ¼ 0.007). However, metformin only showed a statistical positive trend in waist to hip ratio 0.88 (IqR: 0.82–0.94) to 0.85 (IqR: 0.78–0.92) (p ¼ 0.062). Women in placebo group did not show a statistical significant difference after treatment on those parameters (Table II).
Effects on serum insulin and glucose profiles
In metformin group, mean serum insulin concentration decreased from 14.2 + 4.03 to 9.42 + 5.13 mU per ml (p ¼ 0.003) and HOMA-IR decreased from 3.25 + 1.11 to 2.06 + 1.36 (p ¼ 0.01). None of these values significantly changed with placebo (Table II). The serum glucose concentration in fasting and 2 h after OGTT and insulin after 2-h OGTT did not change significantly in both groups. Nevertheless, five patients had pre-diabetes diagnosed (17%), (one in metformin group and four in placebo group) that became normal at the end of the study.
Effect on lipid profile
Both groups showed a favorable profile in total and LDL cholesterol at the end of the study, but none reached statistical significance (Table II).
Effect on clinical and biochemical androgen excess
The administration of metformin was associated with a statistically significant 18.06% reduction in serum total testosterone concentrations (93.2 + 22.02 to 76.36 + 13.59 ng/dl) (p ¼ 0.02); however, no significant changes were seen in the rest of the androgen
176 C. F. Otta et al.
Table II. Anthropometric and metabolic parameters at baseline and after 4 months of treatment.
Metformin
Placebo
Pre
Post
p
Pre
Post
p
BMI (kg/m2)*
32.4 + 6.7{
31.53 + 4.98
0.73
35.6 + 4.98
34.16 + 4.95
0.4
Waist (cm){
98.6 (84.1–113.1){ 93.7 (77.6–109.8) 0.007 106 (92.5–119.5) 103 (93.4–112.6) 0.59
Waist /hip ratio
0.88 (0.82–0.94){
0.85 (0.78–0.92) 0.062 0.91 (0.83–0.99)
0.92 (0.84–1)
0.59
Cholesterol (mg/dl)
159 + 33.17{
158.5 + 29.42
0.54
190 + 31.2
185 + 28.71
0.24
LDL-C (mg/dl)
93.2 + 27.1{
76.35 + 22.35
0.68
94.47 + 29.85
88.2 + 27.112 0.25
HDL-C (mg/dl)
48.27 + 9.38{
43.29 + 8.25
0.75
44.47 + 10.22
43.29 + 8.25
0.47
Triglycerides (mg/dl)
107.93 + 42.77{
115.28 + 70.5
0.73
124.8 + 64.53
124.25 + 61.92
0.98
Fasting glucose (mg/dl)
86.87 + 9.01{
85.14 + 11.12
0.65
89.33 + 13.96
89 + 10.82
0.94
2 h-OGTT glucose (mg/dl)
94.13 + 24.47{
86.57 + 20.73
0.27
100 + 23.08
94.93 + 16.9
0.49
Fasting insulin (mU/ml)
14.2 + 4.03{
9.42 + 5.13
0.003
17.18 + 6.73
15.31 + 5.36
0.4
2 h-OGGT insulin (mU/ml)
36.66 + 15.2{
30.6 + 18
0.13
58.39 + 41.1
50.8 + 34.6
0.32
HOMA-IR
3.25 + 1.11{
2.05 + 1.36
0.01
3.91 + 2.22
3.31 + 1.08
0.35
*X + SD: Student’s t-test. Data are arithmetic mean and standard deviation. {p ¼ NS vs. Placebo. {M (RI): Mann–Whitney. Median and percentiles 25–75% of interquartile range.
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Table III. Hormone results baseline and after 4 months of treatment.
Testosterone (ng/dl)* DHEA-S (mg/dl){ Androstenedione (ng/ml) LH (mUI/ml) LH/FSH ratio
Metformin
Pre
Post
93.2 + 22.01{ 342.5 [295–390]{
2.87 + 1.01{ 5.6 [4.1–6.1]{ 1.03 + 0.74{
76.36 + 13.59 344.5 [300–400]
2.58 + 1.21 5.1 [3.9–8.4] 1.11 + 0.57
p
0.02 0.61 0.466 0.470 0.76
Placebo
Pre
Post
94.47 + 18.22 376 [290.5–408.5]
2.98 + 1.27 6.2 [4.6–7.4] 1.06 + 0.48
88.2 + 24.83 350 [267–392] 2.96 + 1.44 4.8 [3.2–6.0] 1.07 + 0.48
*X [SD]: Student’s t-test. Data are arithmetic mean and standard deviation between brackets. {p ¼ NS vs. Placebo. {M [RI]: Mann–Whitney. Median and percentiles 25–75% of interquartile range.
p
0.43 0.955 0.927 0.112 0.97
profiles. No changes were observed in placebo group (Table III).
Hirsutism scores did not improve during the 4 months of treatment: 11.73 + 5.31 to 11.6 + 5.29 (p ¼ 0.47) with metformin vs. 13.5 + 5.97 to 13 + 5.95 (p ¼ 0.46) with placebo before and after treatment, respectively. We did not find changes in the rest of the signs of hyperandrogenism as acne, seborrheic skin, and androgenetic alopecia.
Effect on gonadotropin levels
LH levels and LH/FSH ratio did not substantially change in either group (Table III). However not an objective of the trial, we emphasize that the patients who were seeking pregnancy before enrollment (n ¼ 5), got pregnant after the study without medical intervention (two in placebo group and three in metformin).
Discussion
PCOS is an endocrine and metabolic dysfunction closely associated with IR. Many trials suggested that
weight loss could improve metabolic parameters and hyperandrogenism in obese patients with PCOS [25– 30]. These changes could be explained by the improvement in hyperinsulinism and insulin sensitivity. Our randomized, placebo-controlled study was designed to evaluate the clinical efficacy and metabolic effects of metformin in addition to lifestyle interventions in insulin-resistant women with PCOS.
In 1994, Velazquez et al. reported, in a noncontrolled study of 26 women with PCOS, a reduction in free testosterone plasma levels after 8 weeks of treatment with metformin. That study was designed to evaluate the endocrine and metabolic characteristics of PCOS after reduction of IR and hyperinsulinemia. Most patients in that study were obese and at the end of it, five patients got pregnant spontaneously and eight normalized their menstrual cycles. However, those benefits could also been explained due to weight loss [31]. In 1996, a study, in which women with PCOS received thiazolidinediones, demonstrated that these treatments decrease androgen levels in parallel with decrease in insulin levels and improvement in insulin sensitivity without changes in body weight [32]. Nestler and Jakubowicz
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studied 24 obese women with PCOS treated with metformin during 4–8 weeks and reported a significant reduction in serum levels of insulin, androgens and LH with increases in SHBG. Those changes were independent of weight reduction [33]. Similar findings were published in non-obese women with PCOS [34]. Those findings were promising and proposed the use of insulin sensitizing drugs (like metformin and thiazolidinediones) for PCOS treatment; but other trials evaluated the effects of metformin over androgens profile and could not confirm those results [35–37]. Possible reasons for those differences remained unclear. Changing definition of PCOS for lack of consensus about it over time, could be one possible reason. Anyway, the use of metformin in PCOS is accepted and widespread; but clinical practice is ahead of the evidence [22].
In our trial, independently of treatment allocation to metformin or placebo, diet and exercise helped patients to improve her menstrual cycles and the ones who were seeking pregnancy, got pregnant at the end of the study. However non-statistically significant, weight reduction could have effectively helped women to restore menstrual cycles and fertility. Similarly, other trials have demonstrated that a modest weight reduction of 5–10% was enough to get these favorable effects [26,38,39]. Metformin showed effectiveness to induce ovulation in women with PCOS [19], but in our study we found a high percentage of ovulation in both groups at the end of the study. Similar findings, with high rates of ovulation, were reported on patients treated with placebo [36,40].
We did not find important changes in serum androgen levels, except for a statistically significant reduction (18.06%) in total testosterone in metformin group. Other investigators reported greater reductions of 25–35% in androgen levels, in response to metformin [19]. Consistent with testosterone decrease, some trials have registered an improvement in hirsutism, although in our experience we did not find changes due to the insufficient duration of the study to detect a difference in hair growth cycle [22].
Our patients were moderately obese, hirsute and presented irregular menses. In obese women with PCOS, weight loss improves IR and leads to an effective amelioration of hyperandrogenism and metabolic disorders [41]. Physical activity and lifestyle modifications are thought to be the most effective interventions to reduce visceral fat, which is associated with metabolic syndrome and cardiovascular disease [42]. As metformin demonstrated benefits in patients with impaired glucose tolerance, it resulted in the increase in prescribing metformin for women with PCOS [43]. In our studied population, a reduction in waist circumference after 4 months of metformin treatment was observed. Our results were consistent
Metformin & lifestyle in PCOS 177
with findings in others trials. There is also evidence that metformin may enhance the degree of visceral fat loss when taken concomitant with an hypocaloric diet and also an associated improvement in cardiovascular risk factors [44,45].
Five patients had pre-diabetes at baseline and it was normalized at the end of the study irrespective of allocation. We observed in this subset of patients that they had more first grade family members with type 2 diabetes than the normal ones (80% in pre-diabetes subgroup and 50% in normal ones).
In summary, our findings suggest that lifestyle changes help to improve menstrual cycling in obese, insulin-resistant women with PCOS. And metformin offers an additive benefit to lifestyle, leading to modest improvements in hyperandrogenism and abdominal fat, independently of weight reduction. Besides, other trials with similar design are being needed to increase the evidence on the efficacy of adding metformin to lifestyle modifications in women with PCOS.
Acknowledgment
This trial was done with a grant from National Institutes of Health (NCT00679679).
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fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism 1995;44:611– 616. 30. Moran L, Noakes M, Clifton P, Tomlinson L, Norman R. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003;88:812–819. 31. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 1994;43:647–654. 32. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R. The insulin sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;81:3299–3306. 33. Nestler J, Jakubowicz D. Decreases in ovarian cytochrome P 450c 17a activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996;335:617–623. 34. Jakubowicz D, Nestler J. Lean woman with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian cytochrome P 450c a activity and serum androgens. J Clin Endocrinol Metab 1998;82:4075–4079. 35. Ehrmann D, Cavaghan M, Imperial J, Sturis J, Rosenfield R, Polonsky K. Effects of metformin on insulin secretion, insulin action and ovarian steroidogenesis in woman with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82: 524–530. 36. Fleming R, Hopkinson Z, Wallace R. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002;87:569–574. 37. Akbay J, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 1996; 65:940–949. 38. Huber-Buchholz M, Carey D, Norman R. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab 1999;84:1470– 1474. 39. Despre´s JP, Lemieux I, Prud’homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 2001;322:716–720. 40. Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951–953. 41. Norman R, Homan G, Moran L, Noakes M. Lifestyle choices, diet, and insulin sensitizers in polycystic ovary syndrome. Endocrine 2006;30:35–43. 42. Norman R, Davies M, Lord J, Moran L. The role of lifestyle modification in polycystic ovary syndrome. Trends Endocrinol Metab 2002;13:251–257. 43. Salley K, Wickham E, Cheang K, Essah P, Karjane N, Nestler J. Position statement: glucose intolerance in polycystic ovary syndrome – a position statement of the androgen excess society. J Clin Endocrinol Metab 2007;92: 4546–4556. 44. Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome: a randomized, placebo-controlled, double-blind multicenter study. Hum Reprod 2006;21:80–89. 45. Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Collita D, et al. Effects of long term treatment with metformin added to hypocaloric diet on body composition, fat distribution and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab 2000;85:139–146.
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PCOS
Clinical, metabolic, and endocrine parameters in response to metformin and lifestyle intervention in women with polycystic ovary syndrome: A randomized, double-blind, and placebo control trial
CAROLINA FUX OTTA1, MYRIAM WIOR1, GABRIEL S. IRACI2, RAQUEL KAPLAN3, DIANA TORRES3, MARI´A ISABEL GAIDO4, & EDUARDO P. WYSE1
1Departamento de Endocrinolog´ıa, Centro Me´dico de Co´rdoba, Hospital Privado, Co´rdoba Capital, Argentina, 2Facultad de Ciencias Me´dicas, Ca´ tedra de Farmacolog´ıa, Hospital Nacional de Cl´ınicas, Universidad Nacional de Co´rdoba, Co´rdoba Capital, Argentina, 3Fundacio´n para el Progreso de la Medicina, Co´rdoba Capital, Argentina, and 4Laboratorio de Bioqu´ımica Cl´ınica, Centro Me´dico de Co´rdoba, Hospital Privado, Co´rdoba Capital, Argentina
(Received 19 July 2009; accepted 20 July 2009)
Abstract The aim of this study was to evaluate the effects of metformin in addition to diet and exercise on endocrine and metabolic disturbances in women with polycystic ovary syndrome (PCOS) in a prospective, double-blind, randomized, placebo (PBO) control trial. Thirty women with insulin resistance and PCOS received lifestyle modification and 1500 mg of metformin or placebo for 4 months. Before and after treatment, body mass index, waist/hip ratio, blood pressure, hirsutism, and menstrual patterns were evaluated. Serum concentrations of gonadotropins, androgens, progesterone, glucose, insulin, and lipids were measured. Lifestyle interventions resulted in similar weight and menstrual cycle’s improvements in both groups. A significant reduction in serum fasting insulin, HOMA index, waist and testosterone levels was only observed with metformin. There were no significant changes in androstenedione, dehydroepiandrosterone sulfate, gonadotropins, and lipids levels. No other changes were observed in hirsutism or blood pressure. These findings suggest that metformin has an additive effect to diet and exercise to improve parameters of hyperandrogenism and insulin resistance. Although, a small decrease in body weight trough lifestyle changes could be enough to improve menstrual cycles in insulin-resistant women with PCOS.
Keywords: Polycystic ovary syndrome, insulin resistance, lifestyle intervention, metformin
Introduction
Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder in women of reproductive age. Hyperandrogenism and chronic anovulation characterize it. Several studies in diverse populations estimate its prevalence at 5–10% [1–3]. Women present, in a high percentage of cases, with obesity, hirsutism, acne, menstrual irregularities and infertility [4]. Although the exact physiopathology of PCOS remains unknown, several studies tend to point to insulin resistance (IR) as the cause of the syndrome [5]. IR is present in 60–70% of the patients independent of obesity [6]. Compensatory hyperinsulinism has a pivotal role in the physiopathogenesis of PCOS. In vitro, insulin stimulates androgen synthesis
in thecal cells and decreases sex hormone-binding globulin (SHBG) synthesis in the liver, therefore increasing free androgen availability [7,8]. Because of the high prevalence of IR, PCOS shares components of metabolic syndrome like abdominal obesity, impaired glucose tolerance, gestational and type 2 diabetes, abnormalities in lipid profile, blood hypertension, endothelial dysfunction, and probably cardiovascular disease [9–18].
In the past, PCOS treatment was focused on ovulation induction for infertility, oral contraceptives for irregular bleeding or androgen antagonists for hirsutism and acne. In later years, insulin sensitizing agents have been used to reduce hyperinsulinemia, improve ovary function and associated metabolic abnormalities [19]. Metformin, a biguanide, usually
Correspondence: Carolina Fux Otta, Departamento de Endocrinolog´ıa, Hospital Privado, Centro Me´dico de Co´ rdoba, Co´ rdoba Capital, Argentina. E-mail: [email protected]
ISSN 0951-3590 print/ISSN 1473-0766 online ª 2010 Informa UK Ltd. DOI: 10.3109/09513590903215581
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174 C. F. Otta et al.
prescribed in obese patients with type 2 diabetes, inhibits glucose hepatic production, reduces fatty acids oxidation, and increases glucose uptake in peripheral tissues therefore reducing insulin secretion [20,21]. Some studies using metformin have reported an improvement in insulin sensitivity associated with reduction of hyperandrogenism and improvements in reproductive abnormalities. On the other hand, other authors failed to observe those changes. Prescribing metformin to treat PCOS has grown dramatically in later years. Despite metformin is ‘off label’ by the FDA for the treatment of this disorder and there is lack of large controlled trials to support its use [22,23].
In obese women with PCOS, weight loss ameliorates hyperandrogenism and metabolic disorders by improving IR. The present randomized double-blind and placebo-controlled study, was designed to test the effects of metformin in addition to lifestyle modifications on menstrual cycles, endocrine, and metabolic disturbances in women with PCOS.
Methods
Ethical approval
Every subject gave written informed consent before entering the study, which was conducted in accordance with the Declaration of Helsinki and approved by the institutional ethical committee.
Subjects
We enrolled 30 women who were 20–34 years old. They were outpatients attending the Department of Endocrinology of Hospital Privado Centro Me´dico de Co´ rdoba (Argentina). All women had PCOS, as defined by hyperandrogenemia (elevated serum testosterone concentrations) and oligomenorrhea (cycles of 35 days or longer) or amenorrhea (no menses in the last 6 months) after negative screening pregnancy test. Estimation of IR was derived from the HOMA index (basal glucose mmol/l 6 basal insulin mIU/ml/22.5) to 2. Other causes of hyperandrogenism (Cushing’s syndrome, late-onset congenital adrenal hyperplasia, and androgen-secreting tumors) were excluded with appropriate diagnostic tests. None of them had concomitant thyroid dysfunction, hyperprolactinemia, diabetes, severe infections, cardiovascular, renal, or hepatic abnormalities. And they have not taken any medications for atleast 3 months before enrollment in the study.
Study protocol
Gynecological history and pregnancy willing were addressed. Familial history of PCOS, type 2 diabetes,
hypertension, hyperlipidemias, obesity, cardiovascular diseases, and early coronal male androgenetic alopecia were also evaluated. Menstrual cycles were assessed by recording the last 6-month period before entering the study and during it. Body mass index, (weight in kilograms divided by the square of height in meters), waist circumference, waist/hip ratio, blood pressure, acanthosis nigricans, and clinical signs of androgen excess (hirsutism measured by a modification of the Ferriman-Gallwey method, acne, seborrheic skin, and androgenetic alopecia) were recorded by a single trained observer using standardized techniques [24]. During the follicular phase of the menstrual cycle or during amenorrhea, after a 12-h overnight fast, blood samples were drawn at 8:00 a.m. for measurement of androgens (total testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S)), gonadotropins, insulin, glucose, total cholesterol, HDL and LDL cholesterol and triglycerides. A standardized 75 g oral glucose tolerance test (OGTT) was performed with measurement of fasting insulin and glucose at 0 and 120 min. Every determination was done at baseline and at the end of the study. Serum progesterone was measured on Days 22–24 and ovulation was presumed to have occurred if the concentration exceeded 4 ng/ml (12.7 nmol/l). The women were randomly assigned through a computerized allocation software in a double-blind way to receive oral metformin or placebo for 4 months. Fifteen women received metformin and 15 placebo. To reduce gastrointestinal side effects of metformin, doses were tapered from 500 mg with lunch during the first week, then 500 mg with lunch and dinner during the second week, and finally 750 mg twice in day. Patients were also given a nutritional plan of 1500 calories daily, composed of 50% from carbohydrates, 20% from proteins, and 30% from fat. The women were advice to exercise (a minimum of 40 min of brisk walking per day, 4 times a week) and to use barrier contraceptives during the whole study. Monthly visits were arranged to evaluate clinical, anthropometrical parameters, treatment compliance and adverse events.
Assays
Androstenedione was measured with radioimmunoassay kit (Active Androstenedione RIA DSL3800. Diagnostic Systems Laboratories, Texas, Berthold LB 2111) with coefficient of variation of 5.6% intra-assay and 9.8% inter-assay. Testosterone, LH, FSH, DHEA-S, progesterone, and insulin were determined with electrochemiluminescent (Elecsys 2010 Roche, Germany). Glucose, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were measured with an analyzer (Hitachi 917 Roche, Germany).
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Statistical analysis
Normal distribution was tested with skewness and kurtosis. Symmetric variables were expressed with arithmetic mean and +1 standard deviation and asymmetric variables were expressed with median and interquartilic range (IqR). Percentiles 25 and 75 were estimated with Tukey’s Hinges method. Qualitative variables in treatment arms were contrasted with Chi square test and adjusted for continuity with Yates. Analysis of quantitative variables was performed with Student’s t-test in case of symmetric distribution and Mann–Whitney test for asymmetric distribution. Wilcoxon or Student t-test was used, when corresponding for contrasting variables before and after treatment in each arm. In normal distribution, the variables were calculated at a confidence interval of 95% (CI 95%) and the variables were considered statistically significant at a p value 50.05. Analysis was performed using SPSS Statistics 17.0 software.
Results
One woman in metformin group was withdrawn for lack of adherence to treatment, so 14 patients received metformin and 15 placebo to the end of the study. There were neither serious nor mild adverse events in both groups.
Baseline characteristics
The clinical, anthropometric, metabolic, and hormonal characteristics of the patients are depicted in Tables I–III. Overall, there were no significant differences in baseline features between treatment groups.
Table I. The baseline clinical parameters.
Variable
Metformin
Placebo
p
Age (years)* Systolic blood
pressure (mmHg) Diastolic blood
pressure (mmHg) F-G score Acne Androgenetic alopecia{ Seborrheic skin Acanthosis Nigricans Pregnancy willing Familiar history
Hypertension Obesity Diabetes Hyperlipidemias
25.47 [4.82] 119.3 [11.4]
77.1 [9.4]
11.73 [5.31] 8 (57.1) 4 (28.6)
11 (78.6) 7 (50) 3 (21.4)
11 (78.6) 9 (64.3)
10 (71.4) 8 (57.1)
24.7 [3.46] 120.7 [8.0]
79.7 [7.7]
13.5 [5.97] 10 (66.7)
5 (35.7) 10 (66.7)
9 (60) 2 (13.3)
11 (84.6) 9 (69.2) 8 (61.5) 7 (53.8)
0.510 0.707
0.426
0.4 0.885 1.00 0.763 0.867 0.932
1.000 1.000 0.892 1.000
*X [SD]: Student’s t-test. Data are arithmetic mean and standard
deviation between brackets. {n (%): Number of cases and percentage between parenthesis.
Metformin & lifestyle in PCOS 175
Effect on menstrual abnormalities
An improvement in menstrual cycling in both groups was observed. Baseline means of menstrual cycling were 120.33 + 81.05 days and 121.42 + 75.30 days in metformin and placebo groups, respectively. After treatment means significantly decreased to 66.35 + 47.09 days (p ¼ 0.003) with metformin and to 77.86 + 56.48 days (p ¼ 0.009) with placebo.
Eight patients experienced normalization of menstrual cycling (four metformin group and four in placebo) and the other 16 patients (nine in metformin group and seven in placebo) reported amelioration of menstrual cycle abnormalities. Forty-five percent of patients ovulated, 7 in metformin group and 6 in placebo group.
Effects on anthropometric variables
Both groups showed a non-significant small reduction in body mass index. Metformin group obtained a significant reduction in waist circumference compared pre to post treatment: 98.6 cm (IqR: 84.1–113.1 cm) to 93.7 cm (IqR: 77.6–109.8 cm) (p ¼ 0.007). However, metformin only showed a statistical positive trend in waist to hip ratio 0.88 (IqR: 0.82–0.94) to 0.85 (IqR: 0.78–0.92) (p ¼ 0.062). Women in placebo group did not show a statistical significant difference after treatment on those parameters (Table II).
Effects on serum insulin and glucose profiles
In metformin group, mean serum insulin concentration decreased from 14.2 + 4.03 to 9.42 + 5.13 mU per ml (p ¼ 0.003) and HOMA-IR decreased from 3.25 + 1.11 to 2.06 + 1.36 (p ¼ 0.01). None of these values significantly changed with placebo (Table II). The serum glucose concentration in fasting and 2 h after OGTT and insulin after 2-h OGTT did not change significantly in both groups. Nevertheless, five patients had pre-diabetes diagnosed (17%), (one in metformin group and four in placebo group) that became normal at the end of the study.
Effect on lipid profile
Both groups showed a favorable profile in total and LDL cholesterol at the end of the study, but none reached statistical significance (Table II).
Effect on clinical and biochemical androgen excess
The administration of metformin was associated with a statistically significant 18.06% reduction in serum total testosterone concentrations (93.2 + 22.02 to 76.36 + 13.59 ng/dl) (p ¼ 0.02); however, no significant changes were seen in the rest of the androgen
176 C. F. Otta et al.
Table II. Anthropometric and metabolic parameters at baseline and after 4 months of treatment.
Metformin
Placebo
Pre
Post
p
Pre
Post
p
BMI (kg/m2)*
32.4 + 6.7{
31.53 + 4.98
0.73
35.6 + 4.98
34.16 + 4.95
0.4
Waist (cm){
98.6 (84.1–113.1){ 93.7 (77.6–109.8) 0.007 106 (92.5–119.5) 103 (93.4–112.6) 0.59
Waist /hip ratio
0.88 (0.82–0.94){
0.85 (0.78–0.92) 0.062 0.91 (0.83–0.99)
0.92 (0.84–1)
0.59
Cholesterol (mg/dl)
159 + 33.17{
158.5 + 29.42
0.54
190 + 31.2
185 + 28.71
0.24
LDL-C (mg/dl)
93.2 + 27.1{
76.35 + 22.35
0.68
94.47 + 29.85
88.2 + 27.112 0.25
HDL-C (mg/dl)
48.27 + 9.38{
43.29 + 8.25
0.75
44.47 + 10.22
43.29 + 8.25
0.47
Triglycerides (mg/dl)
107.93 + 42.77{
115.28 + 70.5
0.73
124.8 + 64.53
124.25 + 61.92
0.98
Fasting glucose (mg/dl)
86.87 + 9.01{
85.14 + 11.12
0.65
89.33 + 13.96
89 + 10.82
0.94
2 h-OGTT glucose (mg/dl)
94.13 + 24.47{
86.57 + 20.73
0.27
100 + 23.08
94.93 + 16.9
0.49
Fasting insulin (mU/ml)
14.2 + 4.03{
9.42 + 5.13
0.003
17.18 + 6.73
15.31 + 5.36
0.4
2 h-OGGT insulin (mU/ml)
36.66 + 15.2{
30.6 + 18
0.13
58.39 + 41.1
50.8 + 34.6
0.32
HOMA-IR
3.25 + 1.11{
2.05 + 1.36
0.01
3.91 + 2.22
3.31 + 1.08
0.35
*X + SD: Student’s t-test. Data are arithmetic mean and standard deviation. {p ¼ NS vs. Placebo. {M (RI): Mann–Whitney. Median and percentiles 25–75% of interquartile range.
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Table III. Hormone results baseline and after 4 months of treatment.
Testosterone (ng/dl)* DHEA-S (mg/dl){ Androstenedione (ng/ml) LH (mUI/ml) LH/FSH ratio
Metformin
Pre
Post
93.2 + 22.01{ 342.5 [295–390]{
2.87 + 1.01{ 5.6 [4.1–6.1]{ 1.03 + 0.74{
76.36 + 13.59 344.5 [300–400]
2.58 + 1.21 5.1 [3.9–8.4] 1.11 + 0.57
p
0.02 0.61 0.466 0.470 0.76
Placebo
Pre
Post
94.47 + 18.22 376 [290.5–408.5]
2.98 + 1.27 6.2 [4.6–7.4] 1.06 + 0.48
88.2 + 24.83 350 [267–392] 2.96 + 1.44 4.8 [3.2–6.0] 1.07 + 0.48
*X [SD]: Student’s t-test. Data are arithmetic mean and standard deviation between brackets. {p ¼ NS vs. Placebo. {M [RI]: Mann–Whitney. Median and percentiles 25–75% of interquartile range.
p
0.43 0.955 0.927 0.112 0.97
profiles. No changes were observed in placebo group (Table III).
Hirsutism scores did not improve during the 4 months of treatment: 11.73 + 5.31 to 11.6 + 5.29 (p ¼ 0.47) with metformin vs. 13.5 + 5.97 to 13 + 5.95 (p ¼ 0.46) with placebo before and after treatment, respectively. We did not find changes in the rest of the signs of hyperandrogenism as acne, seborrheic skin, and androgenetic alopecia.
Effect on gonadotropin levels
LH levels and LH/FSH ratio did not substantially change in either group (Table III). However not an objective of the trial, we emphasize that the patients who were seeking pregnancy before enrollment (n ¼ 5), got pregnant after the study without medical intervention (two in placebo group and three in metformin).
Discussion
PCOS is an endocrine and metabolic dysfunction closely associated with IR. Many trials suggested that
weight loss could improve metabolic parameters and hyperandrogenism in obese patients with PCOS [25– 30]. These changes could be explained by the improvement in hyperinsulinism and insulin sensitivity. Our randomized, placebo-controlled study was designed to evaluate the clinical efficacy and metabolic effects of metformin in addition to lifestyle interventions in insulin-resistant women with PCOS.
In 1994, Velazquez et al. reported, in a noncontrolled study of 26 women with PCOS, a reduction in free testosterone plasma levels after 8 weeks of treatment with metformin. That study was designed to evaluate the endocrine and metabolic characteristics of PCOS after reduction of IR and hyperinsulinemia. Most patients in that study were obese and at the end of it, five patients got pregnant spontaneously and eight normalized their menstrual cycles. However, those benefits could also been explained due to weight loss [31]. In 1996, a study, in which women with PCOS received thiazolidinediones, demonstrated that these treatments decrease androgen levels in parallel with decrease in insulin levels and improvement in insulin sensitivity without changes in body weight [32]. Nestler and Jakubowicz
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studied 24 obese women with PCOS treated with metformin during 4–8 weeks and reported a significant reduction in serum levels of insulin, androgens and LH with increases in SHBG. Those changes were independent of weight reduction [33]. Similar findings were published in non-obese women with PCOS [34]. Those findings were promising and proposed the use of insulin sensitizing drugs (like metformin and thiazolidinediones) for PCOS treatment; but other trials evaluated the effects of metformin over androgens profile and could not confirm those results [35–37]. Possible reasons for those differences remained unclear. Changing definition of PCOS for lack of consensus about it over time, could be one possible reason. Anyway, the use of metformin in PCOS is accepted and widespread; but clinical practice is ahead of the evidence [22].
In our trial, independently of treatment allocation to metformin or placebo, diet and exercise helped patients to improve her menstrual cycles and the ones who were seeking pregnancy, got pregnant at the end of the study. However non-statistically significant, weight reduction could have effectively helped women to restore menstrual cycles and fertility. Similarly, other trials have demonstrated that a modest weight reduction of 5–10% was enough to get these favorable effects [26,38,39]. Metformin showed effectiveness to induce ovulation in women with PCOS [19], but in our study we found a high percentage of ovulation in both groups at the end of the study. Similar findings, with high rates of ovulation, were reported on patients treated with placebo [36,40].
We did not find important changes in serum androgen levels, except for a statistically significant reduction (18.06%) in total testosterone in metformin group. Other investigators reported greater reductions of 25–35% in androgen levels, in response to metformin [19]. Consistent with testosterone decrease, some trials have registered an improvement in hirsutism, although in our experience we did not find changes due to the insufficient duration of the study to detect a difference in hair growth cycle [22].
Our patients were moderately obese, hirsute and presented irregular menses. In obese women with PCOS, weight loss improves IR and leads to an effective amelioration of hyperandrogenism and metabolic disorders [41]. Physical activity and lifestyle modifications are thought to be the most effective interventions to reduce visceral fat, which is associated with metabolic syndrome and cardiovascular disease [42]. As metformin demonstrated benefits in patients with impaired glucose tolerance, it resulted in the increase in prescribing metformin for women with PCOS [43]. In our studied population, a reduction in waist circumference after 4 months of metformin treatment was observed. Our results were consistent
Metformin & lifestyle in PCOS 177
with findings in others trials. There is also evidence that metformin may enhance the degree of visceral fat loss when taken concomitant with an hypocaloric diet and also an associated improvement in cardiovascular risk factors [44,45].
Five patients had pre-diabetes at baseline and it was normalized at the end of the study irrespective of allocation. We observed in this subset of patients that they had more first grade family members with type 2 diabetes than the normal ones (80% in pre-diabetes subgroup and 50% in normal ones).
In summary, our findings suggest that lifestyle changes help to improve menstrual cycling in obese, insulin-resistant women with PCOS. And metformin offers an additive benefit to lifestyle, leading to modest improvements in hyperandrogenism and abdominal fat, independently of weight reduction. Besides, other trials with similar design are being needed to increase the evidence on the efficacy of adding metformin to lifestyle modifications in women with PCOS.
Acknowledgment
This trial was done with a grant from National Institutes of Health (NCT00679679).
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