Hum. Reprod. Advance Access originally published online on December 23, 2007
Human Reproduction 2008 23(3):642-650; doi:10.1093/humrep/dem391
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Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24-week pilot study
1 Unit of Reproductive Medicine and Surgery, Chair of Obstetrics and Gynecology, University ‘Magna Græcia’ of Catanzaro, Via Pio X, 88100 Catanzaro, Italy 2 Department of Clinical Medicine, Cardiovascular and Immunological Sciences, University ‘Federico II’ of Naples, 80131 Naples, Italy 3 Department of Obstetrics and Gynecology, University ‘Federico II’ of Naples, 80131 Naples, Italy 4 Department of Molecular and Clinical Endocrinology and Oncology, University ‘Federico II’ of Naples, 80131 Naples, Italy 5 Department of Endocrinology, University ‘Parthenope’ of Naples, 80131 Naples, Italy
6 Correspondence address. Tel: +39-3475880503; Fax: +39-0961961820; E-mail: stefanopalomba{at}tin.it
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Abstract |
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BACKGROUND: Lifestyle modifications are successfully employed to treat obese and overweight women with polycystic ovary syndrome (PCOS). The aims of the current pilot study were (i) to compare the efficacy on reproductive functions of a structured exercise training (SET) programme with a diet programme in obese PCOS patients and (ii) to study their clinical, hormonal and metabolic effects to elucidate potentially different mechanisms of action.
METHODS: Forty obese PCOS patients with anovulatory infertility underwent a SET programme (SET group, n = 20) and a hypocaloric hyperproteic diet (diet group, n = 20). Clinical, hormonal and metabolic data were assessed at baseline, and at 12- and 24-week follow-ups. Primary endpoint was cumulative pregnancy rate.
RESULTS: The two groups had similar demographic, anthropometric and biochemical parameters. After intervention, a significant improvement in menstrual cycles and fertility was noted in both groups, with no differences between groups. The frequency of menses and the ovulation rate were significantly (P < 0.05) higher in the SET group than in diet group but the increased cumulative pregnancy rate was not significant. Body weight, body mass index, waist circumference, insulin resistance indexes and serum levels of sex hormone-binding globulin, androstenedione and dehydroepiandrosterone sulphate changed significantly (P < 0.05) from baseline and were significantly different (P < 0.05) between the two groups.
CONCLUSIONS: Both SET and diet interventions improve fertility in obese PCOS patients with anovulatory infertility. We hypothesize that in both interventions an improvement in insulin sensitivity is the pivotal factor involved in the restoration of ovarian function but potentially acting through different mechanisms.
Key words: diet/exercise/infertility/obesity/polycystic ovary syndrome
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of authors' rolesReferences |
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Polycystic ovary syndrome (PCOS) is a common endocrinopathy, affecting about 5–10% of women of reproductive age (Knochenhauer et al., 1998
; Asuncion et al., 2000; Azziz et al., 2004). The main clinical features of this syndrome are hirsutism, menstrual dysfunctions and anovulatory infertility (Ehrmann, 2005). In addition, PCOS subjects are predisposed to have a body mass index (BMI) outside the normal range and a central distribution of adiposity (Rebuffe-Scrive et al., 1989; Balen et al., 1995; Norman et al., 1995).
During the last decades, different therapies have been proposed for the treatment of anovulation in PCOS patients (Palomba and Zullo, 2006). Moreover, almost all of the medical therapies for infertility seem to be less effective in obese subjects (Imani et al., 1999; Mulders et al., 2003; Amer et al., 2004; Maciel et al., 2004).
To date, several studies evaluating the efficacy of lifestyle modifications in PCOS women are available in literature (Norman et al., 2004; Pasquali et al., 2006). Lifestyle modification programmes were shown to improve reproductive function in obese and overweight PCOS patients, and diet-related weight loss, as little as 5% of the initial body weight (BW) value, exerted beneficial effects on the reproductive function (Norman et al., 2004; Pasquali et al., 2006). For these reasons, lifestyle changes and weight loss are considered to be a valid alternative to the first-line drug therapy in obese women by the majority of endocrinologists and gynecologists (Cussons et al., 2005).
Unfortunately, these programmes are often not followed by weight loss maintenance, probably because of the low retention rate frequently related to changes in lifestyle (Anderson et al., 2001). Moreover, a high drop-out rate often characterizes these interventions, even if they are performed for short periods (Stamets et al., 2004). This suggests that the cause of the poor compliance to the lifestyle modification programme is unlikely to be the length but the type of intervention.
During lifestyle modification interventions, fixed or personalized hypocaloric diet programmes are always used in combination with an encouragement to increase daily physical activity but are not formally assessed. There is little information available on the PCOS population regarding the efficacy of exercise programmes or diet intervention not integrated into a more complex strategy for lifestyle modification.
Recently, the benefits of a 3-month structured exercise training (SET) programme on cardiopulmonary functional capacity in young overweight women affected by PCOS were demonstrated (Vigorito et al., 2007). In addition, a significant improvement in insulin sensitivity and menstrual cyclicity with a concomitant excellent adhesion to the protocol was detected (Vigorito et al., 2007). Since insulin resistance is considered to be one of the main factors involved in the pathogenesis of the PCOS-related ovarian dysfunction, and considering the favourable effect on menstrual cycles following the SET programme (Vigorito et al., 2007), we were induced to investigate whether the same programme could have any clinical and/or biochemical benefit.
On the basis of these considerations, the aims of the present pilot study were: (i) to compare the efficacy of a SET programme with that of a hypocaloric diet on the reproductive function in obese PCOS patients with anovulatory infertility and (ii) to study their clinical, hormonal and metabolic effects to elucidate potentially different mechanisms of action.
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Materials and Methods |
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The procedures used during the study were in accordance with the guidelines of the Declaration of Helsinki on human experimentation and of Good Clinical Practice. The study-protocol was approved by the Ethical Committee of the Department of Gynecology & Obstetrics (University ‘Magna Graecia' of Catanzaro), and submitted on the website for clinical trial (www.clinicaltrials.gov, identifier number: nCT00473538 [ClinicalTrials.gov] ).
The purpose of the protocol was carefully explained and written informed consent was obtained from each patient.
Subjects
Between January 2004 and February 2006, a cohort of 40 obese anovulatory infertile patients with PCOS was enrolled in the current study-protocol. All patients were referred to our Unit of Reproductive Medicine and Surgery because they wished to conceive.
Diagnosis of anovulatory infertility was made in presence of regular intercourse for at least 1 year and of a history of irregular periods (cycle length > 35 days) plus normal serum FSH and estradiol (E2) levels, as recommended by the European Society for Human Reproduction (ESHRE) (The ESHRE Capri Workshop Group, 1995). In all subjects, the diagnosis of PCOS was based on the presence of chronic anovulation and of clinical and/or biochemical hyperandrogenism [The Rotterdam ESHRE/American Society of Reproductive Medicine (ASRM)-Sponsored PCOS consensus workshop group, 2004]. Chronic anovulation was diagnosed by serum luteal progesterone assay (value below 2 ng/ml for at least two previous consecutive cycles). Clinical hyperandrogenism was defined as a Ferriman–Gallwey score greater than or equal to eight (Ferriman and Gallwey, 1961). Biochemical hyperandrogenism was defined by supranormal serum androstenedione, dehydroepiandrosterone sulphate (DHEA-S) and total testosterone concentrations according to normal reference values. In particular, using the analyzer of our laboratory (Immulite 2000, Los Angeles, CA, USA) the normal range values were 0.3–3.3 ng/ml, 35–430 µg/dl and not detectable-81 ng/dl for androstenedione, DHEA-S and testosterone, respectively, with a coefficient of variation ranging between 5 and 10%. Finally, a BMI value higher than 30 kg/m2 was considered as the criterion for obesity (National Heart, Lung, and Blood Institute/National Institutes of Diabetes and Digestive and Kidney diseases, 1998).
The exclusion criteria for all subjects included age younger than 18 or older than 35 years, BMI higher than 35 kg/m2, neoplastic, metabolic [including diabetes as excluded by fasting glucose level >126 mg/dl (SI: >6.99 mmol/l) or a 2-h oral glucose tolerance test (OGTT) value >200 mg/dl (SI: >11.10 mmol/l) (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003)], endocrine (including hypothyroidism, hyperprolactinemia, Cushing's syndrome and non-classical congenital adrenal hyperplasia as excluded by appropriate tests), hepatic, renal and cardiovascular disorders or other concurrent medical illnesses, current or previous (a wash-out period of at least 3 months was considered appropriate before enrolment) use of oral contraceptives, glucocorticoids, antiandrogens, ovulation induction agents, antidiabetic and antiobesity drugs or other drugs affecting hormone levels, carbohydrate metabolism or appetite.
Other exclusion criteria were organic pelvic diseases, previous pelvic surgery, suspected peritoneal factor infertility/subfertility (i.e. previous diagnosis of endometriosis, sactosalpinx or pelvic inflammatory disease and clinical history of chronic pelvic pain, dyspareunia or other symptom/sign suggestive for these diseases) and tubal or male factor infertility/sub-fertility, as excluded by hysterosalpingogram and semen analysis, respectively.
None of the patients who participated to the study were cigarette smokers or alcoholic beverage abusers.
Protocol and intervention
At enrolment, all patients received detailed information about the role of weight loss in reproductive disorders and the benefits due to lifestyle modification with particular regard to physical activity and diet. Thus, after a careful explanation of the current study-protocol, patients were asked to undertake the SET programme (SET group) or diet intervention (diet group), according to their preference.
The SET group underwent a 24-week SET programme on a hospital ambulatory-based regimen, whereas the diet group followed a 24-week hypocaloric hyperproteic diet intervention. The SET programme consisted of three training sessions per week. During each session, the patient performed exercises for 30 min on a bicycle ergometer with the target of 60–70% of the maximal oxygen consumption (VO2max). The target for each patient was previously established according to the initial cardiopulmonary exercise test, monitored by a wearable device. Exercise workload was gradually increased until the achievement of the predefined target. Each session was preceded by a 5-min warm-up and followed by a 5-min cool-down. The training sessions were performed under continuous electrocardiographic monitoring and supervised by a cardiologist, a physiotherapist and a graduate nurse.
The diet programme was characterized by a high protein composition (35% protein, 45% carbohydrate and 20% fat), and a 800 kcal deficit per day. The Harris–Benedict equation using an adjusted BW for obesity and an activity factor of 1.5 (Harris and Benedict, 1919) was used to calculate the patient's energy need, which was successively adjusted to create an 800 kcal deficit per day. Multivitamin/mineral supplement (Multicentrum 41.2 mg tablets, Whitehall Italia, Milan, Italy) was added to the diet programme (1 tab daily). Weekly interactive group education meetings were offered to each subject who received the diet programme, and the attendance to these sessions was carefully recorded for each patient.
At study entry, glucose levels were detected both at fasting and after 2 h-OGTT in order to exclude patients with diabetes and to identify those with glucose intolerance. In particular, glucose concentrations were measured 30 min after insertion of the i.v. catheter to detect the fasting levels (time 0) before OGTT. Then, each subject received orally 75-g glucose load, and further blood samples (10 ml each) were obtained at 30-min intervals for the following 2 h during the infusion period, and glucose concentrations were determined. In both groups, glucose response to OGTT was analysed by calculating the area under curve (AUCglucose) that was determined according to the mathematical method described by Tai (1994) for the metabolic curves.
At baseline and at each follow-up visit (after 12 and 24 weeks from study start), all subjects underwent clinical evaluation and venous blood drawing to evaluate complete hormonal assays and serum fasting glucose and insulin levels.
Clinical evaluation consisted of Ferriman–Gallwey score assessment, anthropometric measurements [including height, BW, BMI, waist circumference (WC) and waist-to-hip ratio (WHR)] and transvaginal ultrasonography. The Ferriman–Gallwey score was calculated by the standard method (Ferriman and Gallwey, 1961). BMI was calculated as the ratio between the weight and the square of the height, whereas, WHR was calculated as the ratio between the waist (considered to be the smallest circumference of torso between the 12th rib and the iliac crest) and the circumference of the hip (considered as the maximal extension of the buttocks). All measurements were performed when the patients were in a standing position with relaxed abdomen, arms at their sides and joined feet (Yanovski, 1993).
Blood samples were obtained in the morning between 8:00 and 9:00 a.m. after a 12-h overnight fast, resting in bed, during the early proliferative phase (second–third day) of a spontaneous or progesterone-induced (100 mg natural progesterone i.m.) withdrawal uterine bleed. The hormone assays included the evaluation of FSH, LH, thyroid-stimulating hormone (TSH), prolactin, E2, progesterone, 17-OH-progesterone, testosterone, androstenedione, DHEAS and sex hormone-binding globulin (SHBG) levels. The homeostasis model of assessment-insulin resistance (HOMA-IR) [fasting glucose (mmol/l) x fasting insulin (µU/ml)/22.5] (Matthews et al., 1985), the fasting glucose-to-insulin ratio (GIR) (mg/10-4 U) (Legro et al., 1998), and the free androgen index (FAI) [testosterone (nmol/l)/SHBG x 100]) (Morley et al., 2002) were also calculated for each subject. All plasma hormone concentrations were measured by specific radioimmunoassay, whereas SHBG levels were measured using an immunoradiometric assay. Serum insulin was assayed by a solid-phase chemiluminescent enzyme immunoassay using commercially available kits, and serum glucose levels were determined by the glucose oxidase method.
In order to eliminate bias due to arbitrary changes in diet and physical activity, the daily diet and physical activity were monitored in all patients during the study.
Daily diet charts were compiled by each patient and faxed to the investigators weekly during the study. Specifically, the food consumption was assessed using a self-administered semi-quantitative validated food-frequency questionnaire (Willett, 1998), which was used as a cross-check of the dietary history. Daily diet was evaluated by an experienced clinical dietician using software which is specific for the analysis of food habits and for the estimation of nutrient and caloric intake (WinFood, release 1.5; Medimatica, Martinsicuro, Te, Italy). Lack of adherence to the diet programme was defined as inability to tolerate the caloric restriction or composition of the diet, and was calculated according to changes in caloric intake and diet composition. Adherence was defined as ‘high' with a mean caloric deficit lower than 4900 kcal per week and/or with a diet composition of 30–35% protein and 50–45% carbohydrate, ‘moderate' with a mean caloric deficit ranging from 4900 to 3500 kcal per week and/or with a diet composition of 25–30% protein and 55–50% carbohydrate and ‘low' with a mean caloric deficit higher than 3500 kcal per week or with a diet composition of less than 25% protein and higher than 55% carbohydrate.
Daily physical activity was initially monitored with the use of a leisure-time physical activity (LTPA) questionnaire (Roeykens et al., 1998). The self reported LTPA, including all recreational activities, and house- and yard-work was recorded in each patient. Using a standardized classification of the energy expenditure associated with physical activities (Ainsworth et al., 2000), we calculated a weekly energy expenditure score (total LTPA level) in metabolic equivalents per hour/week. LTPA level was graded into four categories of increasing order using the following scheme: (i) no weekly LTPA; (ii) only light LTPA most of the week; (iii) strenuous LTPA (large increase in heart rate, breathing and perspiration) for at least 20 min once or twice a week; (iv) strenuous LTPA for at least 20 min three times a week or more.
To evaluate the adherence with the SET intervention, the number of SET sessions lost per month was recorded. In particular, up to two sessions lost per month were considered as ‘high adherence', a number between five and three sessions lost per month was considered as ‘moderate adherence', and more than six sessions lost per month was defined as ‘low adherence'.
All subjects, in the absence of spontaneous withdrawal bleeding after 35 days from last progesterone-induced uterine bleeding and after exclusion of a pregnancy by a serum HCG assay, received a further dose of 100 mg natural progesterone i.m.
In no case ovulation monitoring was performed, even if each patient was motivated and requested by the study to have sexual intercourse regularly (intercourse at least once every three days, on four occasions) starting 9 days after the progesterone-induced uterine bleeding.
All subjects were also instructed to report on a personal daily diary the number and the timing of their intercourses, the characteristics (number and frequency) of their menstrual cycles and the onset of any adverse experiences (AEs). The frequency of menstrual bleedings was calculated as percentage of spontaneous menses per number of expected menses, whereas the quantity of the bleedings was evaluated subjectively by each patient using a rank analog scale. Specifically, a value of 0 was given arbitrarily in the absence of menses, a value of 5 was given for uterine bleedings defined as normal, and a value of 10 for uterine bleeding defined as severe. For each AE reported, severity, duration and any possible cause-effect relationship with interventions was noted.
During the study, the ovulation, pregnancy and abortion rates were evaluated in each patient. The ovulation was defined by plasma progesterone assay [>10 ng/ml (SI: 32 nmol/l)] performed 21 days after the spontaneous or P-induced bleedings (7 days before the expected menses).
The ovulation rate was calculated as the percentage of ovulatory cycles/total observed cycles. The ovulation frequency was defined as number of ovulatory patients with 1, 2, 3, 4 and 5 ovulation(s) throughout the study. The pregnancy rate was defined as number of pregnancies/total observed cycles. A rising hCG and the sonographic evidence of intrauterine gestational sac and fetal cardiac activity at 7 weeks of pregnancy were considered criteria to define a clinical pregnancy. The abortion rate was defined as the number of miscarriages during the first 12 weeks of gestation/total pregnancies. The cumulative ovulation rate was defined as the number of patients who ovulated under intervention/total patients. The cumulative pregnancy rate was defined as number of pregnant patients/total patients.
Patients in both SET and diet groups who achieved a pregnancy stopped the experimental intervention, and the clinical, endocrine and reproductive data obtained at the last follow-up visit were analysed.
Statistical analysis
The primary endpoint of our pilot study was the cumulative pregnancy rate. To date, no data on patients with similar characteristics are available for the pre-study sample size calculation. Therefore, our population sample was determined according to the expected rate of obese patients with primary anovulatory infertility who are referred to our Unit over 2 years and we estimated that about two patients every month with similar characteristics could be enrolled.
At the end of the study, the post-study power calculation was performed using SamplePower release 2.0.
Data were analysed using the intention-to-treat method (ITT) on the basis of treatment assignment and not on treatment receipt. Specifically, the data recorded at the last follow-up visit were used in the final analysis.
To study the different mechanisms of action, if any, of the interventions on ovarian function restoration, the percentage changes from baseline of the main clinical, hormonal and metabolic data after 12 and 24 weeks were analysed in both groups, dividing our patients into subpopulations according to the presence/absence of ovulation.
The distribution of continuous variables was evaluated with the use of Kolmogrov–Smirnov test, and the results showed normal distributions. Continuous variables were expressed as mean ± SD, and analysed with the unpaired t Student test and general linear model for repeated measures analysis with Bonferroni test for the post hoc analysis as required. For categorical variables, the Pearson chi-square test was performed, whereas conversely, the Fisher's exact test was required for frequency tables when more than 20% of the expected values were less than 5. A P-value of 0.05 or less was considered significant.
The Statistical Package for the Social Science (SPSS 13.0 Sep 2004; SPSS Inc., Chicago, IL, USA) was used for statistical analyses.
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Results |
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During the 2-year enrolment period, 52 patients were screened. Twelve patients refused to participate for personal reasons, preferring an integrated strategy of lifestyle modification programme. Thus, 20 subjects for each group entered our protocol-study.
In all cases, PCOS diagnosis satisfied both the Rotterdam ESHRE/ASRM (2004) and the National Institutes of Health (Zawadzki and Dunaif, 1992) criteria. At enrolment, all patients had polycystic ovaries at transvaginal ultrasonography (Balen et al., 2003).
At study-entry, two groups were similar in anthropometric, hormonal and metabolic data (Table I). Four and three patients for SET and diet group, respectively, had glucose intolerance [4/20 (20%) versus 3/20 (15%), P = 0.677].
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Clinical findings
The cumulative drop-out rates for SET and diet group were 3/20 (15%) and 7/20 (35%), respectively (P = 0.144).
The proportion of patients who ended the study showed a similar adherence to both interventions (P = 0.668). Specifically, no difference between groups was detected in patients showing ‘high adherence' [12/17 (70.6%) and 10/13 (76.9%), respectively; P = 0.697], ‘moderate adherence' [4/17 (23.5%) and 3/13 (23.1%), respectively; P = 0.977] and ‘low adherence' [1/17 (5.9%) and 0/13 (0.0%), respectively; P = 0.374] to the programmes.
At 12-week follow-up, LTPA level was significantly (P < 0.05) improved versus baseline in SET group, whereas it remained unchanged in diet group (Table II), and no further improvement occurred by week 24. No significant variation in daily diet was observed in SET group (data not shown).
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At the end of the study, the attendance in diet group to the education meetings was 87.5% (21/24), 79.2% (19/24) and 70.8% (17/24) for two, ten and one patients, respectively.
No relevant AE was observed throughout the study in both groups.
All subjects had regular sexual intercourse, and no difference was observed in number and frequency of intercourse between groups (data not shown).
At the end of the study, a significant improvement of menstrual cyclicity was noted in both groups. No significant difference between groups was detected in quantity (4.2 ± 1.0 versus 4.6 ± 1.3, for SET and diet group, respectively; P = 0.520) and length (5.0 ± 1.0 versus 4.7 ± 1.2, for SET and diet group, respectively; P = 0.567) of menstrual bleeding. The menses frequency was significantly (P = 0.043) higher in SET group in comparison with diet group (Table III).
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After 24 weeks, the ovulation rate was significantly (P = 0.032) higher in SET group than in diet group. The cumulative ovulation rate was also significantly (P = 0.011) higher in SET group than in diet group. A trend towards higher pregnancy (P = 0.075) and cumulative pregnancy (P = 0.058) rates in the SET group versus the diet group was observed at 24 weeks, whereas no significant (P = 1.0) difference between groups was observed in abortion rate (Table III). At the end of the study, no difference in ovulation frequency was observed between groups (Table III).
After 24-week follow-up, considering a difference in cumulative pregnancy rate of 25% between groups, we would need to enrol at least 43 patients per arm to obtain a study power >80%.
Subanalysis
Table IV shows the percentage change from baseline of the clinical, hormonal and metabolic data after 12 and 24 weeks of intervention categorizing data according to patients who ovulated or did not ovulate under SET or diet.
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At 12-week follow-up, BW, BMI, WC and WHR significantly (P < 0.05) changed from baseline in patients who ovulated under both interventions. At same time, significant (P < 0.05) differences in BW, BMI and WC were observed between patients who ovulated under SET and those who ovulated under diet, whereas no difference was detected in WHR. At 12 and 24 weeks serum testosterone and SHBG levels, and FAI were significantly (P < 0.05) reduced in comparison with baseline in patients who ovulated under both interventions. Serum testosterone levels were similar between patients who ovulated under SET programme and those who ovulated under diet, whereas SHBG concentrations and FAI were significantly (P < 0.05) lower in subjects who ovulated under diet. No significant changes from baseline were observed in both ovulatory groups in Ferriman–Gallwey score. Serum androstenedione and DHEA-S levels were significantly (P < 0.05) reduced versus baseline in patients who ovulated under diet, whereas they were unchanged in patients who ovulated under SET programme, resulting in significantly (P < 0.05) higher values in the SET than the diet group. Fasting insulin, GIR, and HOMA-IR significantly (P < 0.05) changed from baseline in patients who ovulated under both interventions, and were significantly (P < 0.05) different between two groups.
During the study, no significant change was detected in other hormonal and metabolic parameters assessed.
During the study, no significant change from baseline in any clinical, hormonal and metabolic parameter was observed after SET and diet programmes in anovulatory patients (Table IV).
At 12-week follow-up, BW, BMI, WC, serum testosterone and SHBG levels, fasting insulin, GIR, FAI and HOMA-IR were significantly different between ovulatory and anovulatory patients in SET and diet groups. In the diet group at 12 weeks, WHR, androstenedione and DHEA-S were significantly different in ovulatory versus anovulatory patients.
At 24-week follow-up, no further changes were observed in any parameter in comparison with those recorded at 12-week follow-up in any group.
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Discussion |
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The main aim of the present clinical prospective non-randomized controlled study was to compare in a clinical setting the effects on reproductive functions of two different lifestyle interventions in obese infertile PCOS patients who chose to undergo SET or a hypocaloric hyperproteic diet programme, having the cumulative pregnancy rate as a primary end-point.
Previous studies demonstrated that weight loss induced by diet and/or physical activity causes endocrine, metabolic and reproductive improvements in obese PCOS patients who wish to conceive (Norman et al., 2004; Pasquali et al., 2006). Each 1-kg increase in BW is associated with a 2.84 (95% confidence interval (CI): 1.33–4.35) day increase in time to pregnancy and each 1-kg decrement is associated with a 5.50 (95% CI: 1.35–9.65) days decrease in time to pregnancy (Ramlau-Hansen et al., 2007). In particular, modest BW losses reduced central fat, improved insulin sensitivity and restored ovulation in overweight/obese women with PCOS (Clark et al., 1995; 1998; Huber-Buchholz et al., 1999).
UK guidelines for managing obese women with PCOS recommend weight loss, preferably to a BMI of less than 30, before starting drugs for ovarian stimulation (National Institute for Clinical Excellence, 2004). Some authors (Nelson and Fleming, 2007) consider the weight loss essential for obese women who wish to conceive not only prior to receiving infertility treatments, but prior to exposing them to the risks of pregnancy given the high incidence of fetal risks associated with maternal obesity, such as isolated fetal anomalies, fetal deaths, preterm delivery and early neonatal death.
On the basis of these observations an aggressive approach to reduce weight, including pharmacological strategies and the use of contraception and high-dose folic acid (National Institute for Clinical Excellence, 2004), was proposed for obese women before planning a pregnancy.
Our study confirms the beneficial effects of both 24-week SET and diet programmes. At the end of the study, significant improvements in menstrual cyclicity and fertility were observed in both groups, and a trend towards higher pregnancy and cumulative pregnancy rates was detected in the SET group. Furthermore, our study was underpowered to detect a difference in our primary end-point, the cumulative pregnancy rate. However, if we consider the cumulative ovulation rate, we observed a difference of 40% between groups. In this case, our study reached a power of 75%.
Since the data analysis was performed using the ITT principle, our findings might reflect the trend observed in the compliance rate between two interventions, with a drop-out of 15 and 35% for the SET and diet group, respectively. Drop-out is one of the main concerns in studies on lifestyle modifications. In fact, programmes that involved lifestyle modifications and, in particular diet programmes, are related to a very low compliance, even if they were followed for a short-term period (Moran et al., 2003; Stamets et al., 2004). Keeping in mind that cumulative fertility depends on the number of ovulatory cycles, it is clear that lifestyle modifications cannot be proposed in a poorly compliant infertile PCOS patient who desires to conceive as soon as possible.
On the other hand, in some studies (Clark et al., 1995, 1998), the clinical efficacy of lifestyle modification programmes was compared with drop-out or non-compliant patients. These studies (Clark et al., 1995, 1998) demonstrate the ideal effectiveness of a lifestyle intervention but not its usefulness in clinical practice. In addition, these findings can be biased because the dropped-out or non-compliant patients could be less responsive to the intervention. On the contrary, in the current study we used the ITT principle for the data analysis. Even if the ITT method is used in randomized controlled trials to maintain the homogeneity of the groups due to randomization, in the present non-randomized study it was applied to obtain findings closely adherent to the real clinical practice.
Considering the duration of the present study, a good compliance rate was observed in both intervention groups. This result was due to a sample composed of infertile women who wished to conceive, and to the study design. In fact, our study-protocol was also designed to optimize the compliance to interventions. First, the patients' assignment to a specific intervention was established on the basis of their personal choice. Secondly, we chose not to use integrated strategies but single interventions to evaluate the specific adherence to diet or SET. Thirdly, weekly interactive group education meetings were offered to each subject of the diet group. Finally, a well monitored and low aggressive hypocaloric hyperproteic diet was offered to patients in the diet group. In particular, the diet programme was characterized by a high protein composition (35%) and an 800-kcal deficit per day. This diet regimen is characterized by a high compliance (Stamets et al., 2004), low potential for high protein kidney dysfunction (Skov et al., 1999), and low fat intake (20%).
The patients' assignment to a specific intervention was organized according to a personal choice to improve the treatments' compliance and effectiveness. However, this same design could influence our data because it was obtained in a non-randomized fashion. In spite of this limitation, the purpose of our study was not the pure evaluation of the effectiveness of two interventions but to compare SET and diet programmes in a more realistic scenario.
Although no cost-analysis was performed in the current study, both two approaches were cheaper than pharmacological treatments for infertility. Furthermore, SET intervention is a clinically feasible treatment option for PCOS patients only at sites where this approach is already applied for patients with heart disease. Conversely, diet programmes have the lowest economic impact and can be performed without any specific equipment and/or support.
The current study was also designed to elucidate the potentially different mechanisms involved in the restoration of ovarian function in PCOS patients who ovulated under different lifestyle modification interventions. In fact, the lifestyle modification programmes are always proposed as integrated strategies, consisting of the combination of hypocaloric diets, increased daily physical activity and reduction of voluptuary habits. Furthermore, no formal specific assessment of each single intervention is performed at all times.
To our knowledge, this is the first study evaluating both the efficacy and the metabolic/endocrine effects of a single lifestyle intervention in responding patients. To exclude any confounding factors, we carefully assessed the daily physical activity and diet in both groups. In fact, in clinical practice it is possible to observe an arbitrary change in daily physical activity, as well as in daily caloric intake, in patients who receive lifestyle modification programmes.
Our findings demonstrated that both interventions induce clinical, hormonal and metabolic improvements within 12 weeks, without further changes at 24 weeks. In particular, significant improvements in BW, BMI, WHR, WC, insulin resistance indexes, FAI, and serum testosterone and SHBG levels were observed in both groups.
It is noteworthy to mention that significant differences between the groups were observed in BW, BMI, WC, insulin resistance indexes and in serum SHBG, androstenedione and DHEA-S levels. These two last parameters changed from baseline only in the diet group.
Despite the different changes observed in insulin sensitivity indexes after SET and diet interventions, we hypothesize that in both cases insulin sensitivity improvement itself is the pivotal factor involved in the restoration of ovarian function. However, different mechanisms can be involved to explain their beneficial effects on glucose/insulin homeostasis. In particular, a change in BW seems to be the main mechanism by which diet ameliorates insulin sensitivity, and, thus, reproductive function. In fact, several reports (National Institute for Clinical Excellence, 2004; Hamilton-Fairley et al., 1993) have demonstrated that loss of BW is related to insulin sensitivity improvement. In this regard, BW and BMI were reduced significantly more in the diet group than in the SET group.
On the other hand, the SET programme ameliorates insulin sensitivity acting in two main potential ways. First of all, SET results in a large reduction of WC and, thus, of visceral adipose tissue, even if related to a modest BW loss and BMI change. The visceral adipose tissue is more metabolically active than subcutaneous fat, and the central fat distribution (android obesity) is closely related to insulin resistance (Despres et al., 2001; Lord et al., 2006). In this regard, unlike BW and BMI, WC was significantly reduced in patients who ovulated under SET programmes compared to those who ovulated under diet. Instead, no difference in WHR was observed between patients who ovulated under diet and SET programmes. Indeed, WC has been shown to correlate better with visceral fat than WHR (Lord et al., 2006).
SET could also improve insulin sensitivity not only by BW reduction but also by cellular muscle metabolism enhancement. In fact, skeletal muscle is the main site of glucose deposition implicated in insulin resistance, and it is well known that physical exercise influences the expression and/or activity of proteins involved in insulin signal transduction in skeletal muscle (Hawley, 2004).
As a result of WC reduction and muscular insulin sensitivity improvement, women who ovulated under the SET programme showed better insulin resistance indexes than those who ovulated under the diet programme, even if they showed a smaller reduction in BW.
Of note, a significant improvement in hyperandrogenism was observed after SET and diet programmes. Furthermore, at the end of the study serum adrenal androgen levels were higher in ovulatory women undergoing the SET programme than in those undergoing the diet programme, whereas no difference was detected in testosterone levels. One possible explanation of this figure could be the adrenal stimulation induced by SET, which may be considered as a stress factor.
In conclusion, the present work strengthens the recommendation of making a tailored decision by choosing between two effective non-pharmacological first-step interventions, such as diet or exercise, for obese anovulatory PCOS patients who wish to conceive. In compliant patients, both SET and diet similarly improve fertility in obese PCOS patients with anovulatory infertility, acting through potentially different mechanisms. However, further evidence from a larger series is needed to confirm our results.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of authors' rolesReferences |
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S. Palomba designed the trial and wrote the manuscript, F. Giallauria and C. Vigorito elaborated the hypocaloric hyperproteic diet and the structured exercise training programme, A. Falbo performed the statistic analysis and wrote the manuscript, T. Russo enrolled the patients and performed the clinical and instrumental assessment, R. Oppedisano performed the revision of personal diaries, A. Tolino enrolled the patients, A. Colao enrolled the patients, F. Zullo wrote the manuscript and F. Orio designed the trial. Registration ID number from clinicaltrials.gov: nCT00473538 [ClinicalTrials.gov] .
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Submitted on July 24, 2007; resubmitted on October 31, 2007; accepted on November 14, 2007.
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