Polycystic ovary syndrome (PCOS) is the commonest endocrine disturbance in females (Balen and Michelmore, 2002), affecting at least 1 in 15 women during their reproductive life (Rad, 2004; Trivax and Azziz, 2007). The polycystic ovary syndrome (PCOS) is one of the most common causes of infertility due to anovulation. The syndrome is a heterogeneous condition whose pathophysiology appears to be multifactorial and polygenic. It can be suggested that the main factors responsible for the increasing prevalence of the PCOS are related to the influence of the environment, including dietary habits, behaviour and other still undefined factors. Key features include menstrual irregularity, hyperandrogenism and obesity (Carmina et al., 2005).
It has been found that 50%-80% of PCOS women are obese (Schachter et al., 2003). A gain in weight is associated with a worsening of both the symtomatology and the endocrine profile. Obesity is one of the principal causes of insulin resistance. Elevated serum concentrations of insulin are more common in obese women with PCOS, 50% to 70% of PCOS population (Ovalle and Azziz, 2002). Indeed it is hyperinsulinaemia that appears to be the key to the pathogenesis of the syndrome as insulin stimulates androgen secretion by the ovarian stroma and appears to affect the normal development of ovarian follicles by the adverse effects of androgen on follicular growth. In addition to that the frequent history of weight gain usually precedes the clinical features of the syndrome indicates the possible impact of obesity on the pathophysiology of disease (Pasquali et al., 2003). Weight loss has so far been the most physiological way to improve insulin sensitivity, and improve metabolic abnormalities associated with the syndrome. It has also been demonstrated that even with relatively modest weight loss improves the hormonal profile and improvement of reproductive outcome for all forms of fertility treatment (Ayyad and Andersen, 2000). Since the association between BMI and insulin resistance is strong in obese women with PCOS the benefits of weight loss should be even greater in these women (Norman et al., 2004; Pasquali et al., 2003).
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More recently metformin, an oral biguanide used for type 2 diabetes mellitus, has been shown to induce ovulatory cycles in anovulatory patients with PCOS (Lord et al., 2003; Kashyapet et al., 2004). Metformin lowers blood glucose levels mainly by inhibiting hepatic glucose production and increases in the peripheral glucose uptake (DeFronzo et al., 1991). Several other actions may contribute, such as increased intestinal use of glucose and decreased fatty acid oxidation. Therefore, metformin can reduce peripheral insulin concentrations and improve glucose tolerance and metabolism (Attia et al., 2001; lord et al., 2003). It has been shown that metformin ameliorates hyperandrogenism and abnormalities of gonadotrophin secretion in women with PCOS and can restore menstrual cyclicity and fertility. Treating PCOS women with metformin causes significant decrease in body mass index BMI (Nieuwenhuis-Ruifrok, 2009).
Much has been written about treatment of PCOS. However, treatment of infertility due to PCOS is still surrounded by many controversies. Additionally, to date no specific recommendation can be given as first-step drug in treatment of infertility due to PCOS (Palomba et al., 2009). As far as the researchers known only one study has asked the same question. The trail was a prospective comparative study carried out by Qublan et al., (2008) to demonstrate the difference between dietary interventions versus metformin in improving the reproductive outcome in obese women with polycystic ovary syndrome. The pregnancy rate was a secondary outcome in that study and the pregnancy rates were similar in both groups after treatment (Qublan et al., 2008 [abstract only]). In terms of critical review, the sample size in that study was very small; only forty-six (46) women were enrolled in the study. Moreover, by using the sample size and the study result (using Minitab version 15 [power and sample size calculation]) the power of the study was only 50% rather than 90 or 80%. Therefore, and for more power, if larger sample size was used the result would have been more significant (i.e demonstrate the effectiveness of one mode of intervention over the other).
Most importantly, the world is facing a serious public health emergency due to the increasing epidemic of obesity and its related disorders. Obesity can be defied in terms of body mass index BMI as grade two, with a BMI of 30 kg/m2 or more (WHO, 2000). The price of obesity is represented by a long list of co-morbidities and social, psychological and demographic problems. Obese women are characterised, in common with males, by number of different morbidities, particularly type 2 diabetes mellitus and cardiovascular diseases (Ford, 2004). They also have some specific problems, including fertility-related disorders and some hormone-dependent forms of cancer (Pasquali et al., 2003; Linne, 2004). There is consistent evidence that weight loss represents a simple and cost-effective safe way to improve spontaneous ovulatory cycles and pregnancy rates in affected women. Obese women should, therefore, encouraged losing weight. From this concept we thought that life style modification should be the first line treatment in management of obese infertile polycystic ovary syndrome women. Weight reduction in the management of PCOS will be of dull benefit, on the one hand, improving the reproductive outcome, hopefully, over all forms of fertility treatment. On the other hand, prevent the long term complications of obesity associated with PCOS.
Aims and Research questions
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From the previous evidences it can be concluded that lifestyle interventions and insulin sensitizers play a fundamental role in the treatment of PCOS, particularly in the presence of obesity. The rationale is represented by the reasoning that the decrease in insulin concentration, as a result of improved insulin resistance, may lead to metabolic alterations and have important effects on hyperandrogenism, and, in particular, on fertility. Referring to these evidences we formulate our question.
Is life style modification superior to metformin in management of infertile obese PCOS patient?
to evaluate the effectiveness of life style modification verses metformin in treatment of infertile obese PCOS women, by comparing the clinical results and reproductive outcome in obese women with polycystic ovary syndrome (PCOS) following dietary intervention or treatment with metformin.
Hopefully, weight reduction in the management of PCOS will be superior to metformin in treatment of obese infertile PCOS women, although this does not represent a common rule worldwide.
life style modification is superior to metformin in management of obese infertile women with polycystic ovary syndrome.
Plan, methods, expertise available, statistical power:
Plan and methodology:
Method: A one centre Randomized non-blind control trial
Study Type: a comparative interventional prospective study
Study Period: six months.
Setting: the study will be conducted in Mosrata infertility treatment centre, Mosrata, Libya. The city located 200 kilometres from Tripoli, the capital city of Libya. The centre is one of the biggest infertility treatment centres in Libya receiving patients from all areas in the country.
Primary Outcome: Pregnancy success rate
Secondary Outcomes: Changes in - Endocrine parameters: LH, FSH, serum testosterone and Insulin sensitivity
- Anthropometric measurements: body mass index (BMI) and waist hip ratio
- Menstrual frequency.
Study Design and Participants:
The proposed unblinded prospective, randomized, control trial will be a 6 months study, conducted in Mosrata infertility treatment centre, Mosrata, Libya. The median age of women will be 28, ranging from 18 to 38, femaleswith PCOS will be studied prospectively. The participants will be recruited following attendance at outpatient department.All patients referred to Mosrata infertility treatment centre, will be screened for PCOS. The patients who are diagnosed with PCOS and seeking for pregnancy will be included in the study. The diagnosis of PCOS will be based on ESHRE/ASRM criteria (The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004), which included at least two of three criteria of the following:  chronic anovulation;  clinical or biochemical signs of hyperandrogenism; and  polycystic ovary (PCO) morphology, shown on ultrasound scan, defined as the presence of 12 or more follicles (with one ovary being sufficient for diagnosis) measuring 2-9 mm in diameter or increase in ovarian volume of more than 10 mL. The pelvic ultrasound examinations will be done by same investigators using a vaginal endoprobe.
Application for ethical approval will be made via the main clinical research ethics committee as well as at Mosrata infertility treatment centre ethics committee. When the ethical approval has been achieved, recruitment of the subjects will begin. Study progress reports will be provided through out research period to the main Research Ethical Committee. Any considerable amendments within the study will be notified to them and safety reports for any acute or serious adverse effects will be also supplied periodically. In addition, the main Research Ethical Committee will be informed of the study end using study end declaration form within 90 days of the last visit of the last participants. Then, a final research report including weather the study's aim has been achieved or not, the main findings, and the arrangement for dissemination and publication of the research result will also be provided.
Information Sheet and Consent Form:
Informed consent will involve giving as much information as possible about the potential research so that the participants can make an informed decision about their possible involvement. This information will be supplied in written form (information sheet) and will be signed off (consent form) by the research participant(s). It will be written in terms that an ordinary person rather than a specialist in the field can understand by avoiding technical jargon. The information provided will be accurate and concise, specific to the proposed research and appropriate for the social and cultural context in which it is being given. The information sheet will include the following: the name of the researchers, an explanation of what the researcher is hoping to achieve by the research, an explanation of the risks, (e.g. side effect of metformin, that the participant may experience) a clear explanation of what the participant is expected to do during the study, a statement that the participant is not obliged to take part, and may withdraw at any time duration of the study, location of the study, and consent statement. Signed consent forms will be stored separately from the data to maintain confidentiality. The participants will be reassured that information they provide will not be disclosed to others other than within the context of the research, or at a minimum will be made anonymous.
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18-38 years old - Anovulatory patients with a diagnosis of PCOS based on clinical, biochemical and/or ultrasound scan and in good general health seeking pregnancy - body mass index BMI 29-40 -Previously untreated - fertile partner with no other endocrine disorder.
The exclusion criteria for all subjects will include neoplastic, metabolic, hepatic, and cardiovascular disorders or other concurrent medical illnesses; hypothyroidism, hyperprolactinemia, Cushing's syndrome, and non-classical congenital adrenal hyperplasia will be excluded by appropriate tests; or current or previous use (within the last 6 months) of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, antidiabetic and antiobesity drugs or other hormonal drugs. Other exclusion criteria are organic pelvic diseases, previous pelvic surgery, suspected peritoneal factor infertility. Tubal or male factor infertility or subfertility will be excluded by hysterosalpingogram and semen analysis, respectively. Women, who started a diet or a specific program of physical activity, or have vitamin B12 deficiency, will be also excluded.
all women who meet the inclusion criteria and after obtaining the written consent, will be subjected to:
1. Anthropometric measurements:
Clinical evaluation consisted of anthropometric measurements [including height, weight, BMI, and waist to hip ratio (WHR). Height will be measured using a stadiometer and weight will be measured using electronic digital scales. Specifically, BMI will be calculated as the ratio between the weight and the square of the height, and WHR as the ratio between the waist (considered to be the smallest circumference of torso between the 12th rib and the iliac crest using an anthropometric tape) and the circumference of the hip (considered as the maximal extension of the buttocks) (Yanovski, 1993). All measurements will be performed when the patients are in a standing position with relaxed abdomen, arms at their sides, and joined feet.
2. Metabolic Examinations:
A complete clinical and laboratory evaluation including renal profile, liver function test, will be performed at the initial visit. The Blood samples will be also obtained according to standard practice, in the morning between 0800 and 0900 h after 12-h overnight fasting and resting in bed during the early proliferative phase (second to third day) of the Progestin (P)-induced withdrawal uterine bleeding (100 mg natural P, im). Complete hormonal assays consisting of FSH, LH, TSH, prolactin (PRL), total testosterone (T), will be evaluated.
All plasma hormone concentrations will be measured by specific Raidioimmuno Assay (RIA). Serum insulin will be assayed by a solid-phase chemiluminescent enzyme immunoassay using commercially available kits, and serum glucose levels will be determined by the glucose oxidase method. Fasting blood sampling and 75mg oral glucose tolerance test (OGTT) will also be investigated. Insulin sensitivity index, SI, will be calculated by application of the minimal model of glucose kinetics to plasma glucose and insulin. All of these parameters will be measured in the main laboratory, in Mosrata infertility treatment centre, Libya. The laboratory is well equipped and operated by specialized persons.
Quality control measure:
All steps of recruitment and data collection in the study will be monitored by data safety and monitoring team. Their role will be mainly focused on collection of any important missing data, ensuring that the collected data are consistent with adherence to the trial protocol with strict security measures to maintain confidentiality.
All subjects, in the absence of spontaneous withdrawal bleeding after 35 day from last period induce uterine bleeding and after exclusion of a pregnancy with a serum _-hCG assay, will receive a further dose of 100 mg natural Progestin (P), intramuscular (im). After progestin withdrawal, subjects will be randomly divided into two groups. Randomizations will be done by picking an envelope labelled A, or B, assigned to metformin, or life style modification. Equal number of envelopes will be labelled. The randomization will be done centrally by an assigned nurse who is naive to the treatment and who then will communicate with the investigator. The envelope that will be picked will not return for further randomization. The investigators and patients will not be blind to the types of intervention.
(A) Metformin group:
Patients in this group will receive 850 mg metformin twice a day. To avoid occurrence of gastrointestinal side effects we will gradually introduce Metformin. Metformin will be taken before lunch during the first week and thereafter before lunch and dinner. Patients of metformin arm will be given the tablets at the initial dose of 500 mg and increased in a stepwise fashion during the first 3 weeks to accommodate the side effects until patients take a total dose of 850 mg/day (Diamanti-Kandarakis et al., 2009). Compliance will be assessed by the return of empty drug containers.
Metformin expected adverse events:
The most common adverse effects of metformin relate to the gastrointestinal tract, including watery diarrhea, nausea, abdominal pain, abdominal bloating, flatulence, dyspepsia metallic taste and anorexia, occur in 10-50% of patients, but resolve within a few days to weeks after the initiation of therapy. Metformin can cause malabsorption of vitamin B12 in the distal ileum in 10% to 30% of patients, and rarely Lactic acidosis, a potentially fatal metabolic condition (Diamanti-Kandarakis et al., 2009).
(B) Life style modification group:
Dietary advice to follow hypo-caloric diet:
Women will be prescribed with 1200-1400 kcal/day diet (25% proteins, 25% fat, and 50% carbohydrates plus 25-30 gm of fibre per week). It will be taken in to consideration that dilatory advice is practical, sustainable and compatible with lifestyle. To facilitate compliance, the diet included specific daily quantities of foods in a checklist that subjects completed daily. Participants will meet with a dietician in small groups or individually fortnightly throughout the study to discuss dietary issues, nutrition guidelines, and the importance of compliance with the diet to promote weight loss.
An increase physical activity is essential, preferably as a part of daily routine. Women in this group will also be encouraged to increase daily exercise (such as walking, using stairs) by 15 min, although this will not be formally assessed. The participants will receive further encouragement to adhere to the regime at the monthly review visits.
All subjects will be instructed to report the characteristics of their menstrual cycles and the onset of any adverse events (AEs) in a personal daily diary. For each adverse effects reported (especially in metformin group), severity, duration, and possible cause effect relationship with drug administrations will be noted. Moreover, each patient will be motivated and instructed to have sexual intercourses regularly (at least one intercourse every 3 days) starting 9 days after the P-induced uterine bleedings.
Reassessment and Measurement of outcomes:
Each participant will be reassessed monthly with a re-evaluation of anthropometric measurements, endocrine and biochemical parameters together with an ultrasound scan and record of the patient's menstrual cycle. Blood samples will be taken for LH, fasting insulin (FI) and glucose, testosterone and FSH. Hormones will be measured as described previously. The pregnancy rate will be defined as the percentage of pregnancies per total observed cycles. The rate of pregnancies for each ovulatory cycle will be also calculated. A regular rising human chorionic gonadotrophin (hCG) and the sonographic evidence of intrauterine gestational sac will be considered criteria to define a pregnancy. Menstrual cyclicity will be assessed using completed menses calendars. Improvements in menstrual cyclicity is defined as a change from nonovulatory to ovulatory cycles or from irregular to regular cycles or an improvement in consecutive Inter cycle variation. The assessment will be performed by the same person. The mode of intervention will be discontinued when there is a positive pregnancy test. Side-effects of the treatment and reason for any withdrawals from the study will be recorded. After the end of the study period, clinical and biochemical data, before and after both treatments along with the reproductive outcome, will be compared between the two groups.
The primary end point of the study will be the pregnancy rate.One goal of the proposed study is to test the null hypothesis. The criterion for significance (alpha) will set at 0.05 and the data will be checked for normality. Statistical analysis will be performed using Statistical Package, Minitab version 15, and P value <.05 will be considered statistically significant. All results will be expressed as the mean ± SD. Homogeneity tests for variance will be performed when necessary. For numerical data, analysis of variance (ANOVA) will be used to compare the homogeneity of the subject between and within the groups. A Pearson Chi square (x2) test will be used for testing differences among the two study groups for categorical variables. Linear regression will be used to assess relationship between variables. The differences between treatments [with 95% confidence intervals (95% CI)] for changes from baseline to the end of will be presented for each outcome. . Insulin sensitivity index, SI will be compared with various steady state glucose, insulin, endocrine and metabolic parameters with Pearson's correlation coefficient. Stepwise regression will be performed with SI as the dependent variable and waist circumference (WC) and as the independent variables.
With a power of at least 80% using a two-sided x2 test with a 5% significance level. Taking a possibility of a dropout rate of about 20%, at least... women will be needed in this study (which should have be calculated from the previous study (Qublan et al., 2008 [abstract only]), otherwise the pilot study is essential). The data on the dropouts will not be included in the analysis.
the limitations of this study would be the development of side effect in metformin group. This study could include patients, who are slightly obese or have longer duration of infertility. An important point is shorter duration of exposure to study treatments (6 months), and another limitation of the study is that the trail is not blinded and hence may be subjected to bias.
Recruitment of patients will continue until reaching the required sample size. Each mode of intervention will continue up to 6 months. The participants will be asked for a monthly visit for clinical and biochemical reassessment. The total period of the trail including patient's recruitment, data collection, data analysis (clinical and statistical), report preparation, and dissemination of the end results will be.......years, [depending on the sample size].
The final research result will be disseminated locally, nationally and internationally. The research outcomes will be initially presented locally to all research members as well as patients who will participate in the trail. The research result will also be presented to different clinical specialism meetings and reliable newsletters, local research conferences and social groups. National and international dissemination will be the main target to gain the pleasing impacts on health care. The original research result will be presented to international seminars, conferences and submitted to high quality peer-reviewed journals. The researchers will use websites and media including popular press for wider dissemination to the public.
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