Infertility Unit of the First Department Obstetrics and Gynecology, University of Milan, Via della Commenda 12, 20122 Milan, Italy
1 To whom correspondence should be addressed. e-mail: piergiorgio.crosignani{at}unimi.it
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Abstract |
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Key words: diet/fertility/ovarian morphology/PCOS
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Introduction |
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Weight loss in obese PCOS patients reduces circulating androgens and raises SHBG (Kiddy et al., 1990; Hollmann et al., 1996
), enhances insulin sensitivity (Guzick et al., 1994
; Andersen et al., 1995
; Holte et al., 1995
; Huber-Buchholz et al., 1999
) and regularly improves menstrual cyclicity and fertility rates (Bates and Whitworth, 1982
; Franks et al., 1991
; Pasquali et al., 1997
). On clinical grounds, weight loss can re-establish ovulation in obese anovulatory patients or improve their response to ovulation induction (Clark et al., 1995
, 1998; Crosignani et al., 1999
, 2002). No data are available on ovarian morphology systematically checked during weight loss.
The aim of this study was to correlate weight reduction and anthropometric indices, ovarian morphology, menstrual cyclicity and spontaneous fertility in overweight PCOS patients following a diet combined with a programme of physical exercise.
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Materials and methods |
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Characteristics of the patients are reported in Table I. The study design is presented in Figure 1. Patients were prescribed a 1200 kcal/day diet (20% protein, 25% lipids, 55% carbohydrates plus 30 g of fibre/week); we did not directly ascertain if the prescribed diet was followed: compliance with diet treatment was ascertained indirectly by evidence of weight reduction. Aerobic exercise was recommended. No particular exercises were specified, with no specific duration or frequency. Patients were simply advised to do some swimming or aerobics at least once or twice a week. They were prescribed regular controls and weight assessment every 68 weeks. The maximum time to 5% body weight reduction response was 6 months: non-responders after 6 months dropped out and underwent ovulation induction. Similarly, patients who achieved a 5 or 10% reduction in body weight and subsequently did not respond in terms of resumption of ovulatory cycles within 6 months also dropped out to undergo ovulation induction.
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Ovarian volume and the number of microfollicles were evaluated by transvaginal ultrasonography (Ansaldo 580 system and a transvaginal 6.5 MHz probe). Ovarian volume was calculated as 4/3 (1/2 diameter)3, where the diameter was taken as the mean of the height, width and depth of the ovary, in the absence of a dominant follicle (Conway et al., 1989
). Microfollicles were counted by progressive ultrasound scan of the entire ovary. All ultrasonographic examinations were done on days 35 of a spontaneous or progestin-stimulated cycle by the same operator (M.C.) who was blinded to the study design. Intra-observer variation assessed in a preliminary series of 10 overweight patients with polycystic ovaries was <5%.
Body height and weight were measured, respectively, without shoes and without clothes. Waist circumference was recorded as the smallest measurement between the iliac crest and the lateral costal margin; hip circumference was the largest measurement over the buttocks, using a 1 cm wide metal measuring tape (World Health Organization, 1997). Subscapularis, tricipital, bicipital and suprailiac folds were measured using a HoltainTanner/Whitehouse plicometer (Holtain Ltd, UK). Body composition was analysed by whole body bioelectrical impedance analysis (BIA). Bioelectric impedance is a relatively new method to assess body fat composition by calculating total body fluid (Goodpaster et al., 2002
; Jinno et al., 2000
). The BIA was performed using a Multifrequency Human-Im Scan (Dietosystem, Milan, Italy) which analyses bioelectric behaviour over a range of 256 frequency values from 300 Hz to 100 KHz. The test was completely non-invasive and used electrodes in an adhesive gel which were applied in pairs (source electrodes and sensor electrodes) to the right hand (third metacarpal joint) and to the right foot (second metatarsal joint, on the dorsal side) of patients lying down on an examination table in a supine position with the legs slightly apart. The surface area of the electrodes was at least 5 cm2. The standard supplied software includes, out of many available parameters, weight and percentage lean and fat mass. The fat mass ratio (fat mass/total body mass) was calculated directly by the software (Trovato et al., 1996
).
All anthropometric measurements were made by the same operator (A.G.) who was blinded to the study design. Intra-observer variation, assessed in a preliminary series in 10 overweight patients with polycystic ovaries, was <5%.
Data were analysed using the Statistics Package for Social Sciences (SPSS, Chicago, IL, USA). Baseline characteristics of patients who did and did not lose weight were compared using categorical, unpaired non-parametric rank tests and analysis of variance (ANOVA) using post hoc tests. Paired analyses were performed to evaluate anthropometric and ultrasonographic modifications in patients who achieved weight loss. Specifically, paired non-parametric rank test or paired Student t-test adjusting for multiple comparisons were employed, as appropriate. P-values of <0.05 were considered significant.
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Results |
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Anthropometric modifications are shown in Table II. A parallel reduction in ovarian volume and in the number of follicles was observed in patients who lost weight (Figure 2). Ovarian volume was reduced by 18% [95% confidence interval (CI) 729] in women who lost 5%, and by 27% (95% CI 1041) in those who reached 10% weight loss. Similarly, the number of microfollicles per ovary decreased from 23.5 ± 11.5 to 19.9 ± 9.9 with 5% weight loss and to 18.3 ± 7.5 with 10% weight loss.
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Resumption of regular menstrual cycles was reported by 18 patients (72% of the compliant subjects). In addition, 15 had ovulatory cycles during the study period (Figure 3). Ten (30%) of the 33 women enrolled became pregnant spontaneously within 12 months (Figure 3) and eight delivered singleton healthy newborns at term. Two patients were lost to follow-up after echographic assessment of a viable pregnancy at 7 and 8 weeks gestation. The pregnancy rate and percentage of women with ovulatory cycles increased to 40 and 60% respectively, when only patients who reached at least a 5% reduction in body weight were analysed. The eight patients who did not lose weight had no improvement in menstrual cyclicity or in their ovulatory values of progesterone, and no pregnancies occurred.
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Discussion |
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According to Zaadstra et al. (1991), the central distribution of fat is more important than body weight in reducing fecundity. In addition, obesity is associated with an increased rate of miscarriage in women with PCOS or normal ovarian morphology (Pettigrew and Hamilton-Fairley, 1997
). Obesity lowers the success rate of assisted reproduction technique (ART) cycles (Homburg et al., 1989
; Hamilton-Fairley et al., 1992
; Crosignani et al., 1994
; Imani et al., 1998
; Fedorcsak et al., 2000
). Overweight and obesity have a positive relationship with the risk of spontaneous abortion in women who become pregnant after assisted reproductive technology treatment (Wang et al., 2002
).
Insulin stimulates androgen secretion and, together with androgens, influences the pattern of body fat distribution in overweight women (Pasquali et al., 1991; Sharp et al., 1991
; Ditkoff et al., 1995
). In obese women, weight loss after gastroplasty quickly restores normal insulin secretion, clearance and action on glucose metabolism (Letiexhe et al., 1995
).
In other studies, weight loss resulted in a significant reduction in blood glucose, insulin and androgen concentrations in obese, non-PCOS women (Hollmann et al., 1996), and more consistently in obese PCOS patients (Lefebvre et al., 1997
; Pasquali et al., 1997
, 2000). In these patients, the raised production of SHBG induced by weight loss further reduces circulating free androgen (Kiddy et al., 1990
) and, in addition, in PCOS patients, weight reduction enhances insulin sensitivity (Guzick et al., 1994
; Andersen et al., 1995
; Holte et al., 1995
; Huber-Buchholz et al., 1999
).
This study found a prompt improvement in the indices of body fat and its distribution, and rapid reduction of ovarian volume and microfollicle number. A possible controversy in our study may be related to the study design since our trial was not randomized. In particular, the lack of controls does not allow us to rule out that the observed effects could not be period or observer related. However, in light of current available literature on this topic that clearly demonstrates the benefits of diet (Bates and Whitworth, 1982; Franks et al., 1991
; Clark et al., 1995
, 1998; Pasquali et al., 1997
), we believe that a randomized trial is no more ethically tenable and practically feasible than our study. Overall, although we are unable to assess the importance of this aspect, it seems highly unlikely that our study design could play an important role in explaining the relevant modifications detected in our study population.
The mechanism through which body weight reduction modifies ovarian morphology can only be guessed: it might involve a more favourable endocrine environment after a rise in SHBG and a reduction in free androgens, and improved insulin sensitivity. The decrease in volume might be due to the reductions in microfollicles and ovarian stroma. The amount of ovarian stroma is correlated with overproduction of theca-derived steroids, particularly androstenedione (Kyei-Mensah et al., 1998), in PCOS patients: a reduction in ovarian volume and in the number of microfollicles could therefore be involved in lowering circulating androstenedione and improving the clinical picture of these patients during diet treatment.
Interestingly, Falsetti et al. (2000) recently reported a comparable improvement in ovarian morphology with long-term pharmacological inhibition of ovarian function in 140 PCOS patients under oral contraceptive treatment. Our data show comparable and quicker changes in this easy-to-check parameter after only moderate body weight reduction; to the best of our knowledge, this is an important and original observation.
At the same time, weight loss improves menstrual cyclicity, ovulation and fertility. Clark et al. (1998) found that weight loss re-established ovulation in obese anovulatory patients or improved their response to ovulation induction: in a series of 67 anovulatory women, 90% resumed ovulation after weight loss and 78% conceived (Clark et al., 1998
). The same group confirmed these findings in a larger series (Clark et al., 2000
), and similar results were obtained in preliminary observations by our group (Crosignani et al., 1999
, 2002). In our series, among the 27 out of 33 patients with irregular menstrual cycles who lost weight, 18 re-established regular cycles. A total of 60% had ovulatory levels of plasma progesterone after weight loss. In a year of observation, 10 spontaneous pregnancies occurred in the 25 patients who lost weight (40% pregnancy rate). Neither menstrual cycle improvement, ovulatory values of progesterone nor pregnancies occurred in the eight patients who did not lose weight. In contrast, it should be noted that we obtained resumption of ovulatory cycles and pregnancy even after a slight (5%) reduction of baseline body weight.
In conclusion, weight loss is an effective treatment and should be considered the first-line approach for infertile overweight PCOS patients.
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References |
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Submitted on January 24, 2003; resubmitted on April 3, 2003; accepted on May 23, 2003.