Metformin Weight Loss and PCOS

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The initial use of metformin in the treatment of PCOS has now been widely accepted to be a valuable and inexpensive therapeutic modality. Recent systematic reviews have indicated that metformin is highly effective in inducing ovulation and increasing pregnancy rates (8,9). The numbers needed to treat for ovulation are around four patients, and there is an improvement in serum insulin levels and a reduction in free testosterone in response to metformin. The drug appears to be safe in early pregnancy with respect to congenital abnormalities, although it is controversial whether miscarriage rates are reduced. The predictors of success of metformin have not been established, although there is some evidence that patients who are substantially overweight do not respond as well. Side effects of metformin include nausea, vomiting, diarrhea, and other forms of gastrointestinal intolerance, and patients need to be warned about the interaction between metformin and alcohol. The ovulatory response to clomiphene can be increased in obese women with PCOS by decreasing insulin secretion with metformin (10). The role of metformin in weight loss is controversial with a number of studies showing some weight loss and others showing no change at all. The National Institute of Child Health and Human Development's Reproductive Medicine Network has begun a randomized, double-blind trial of clomiphene vs metformin vs clomiphene plus metformin for the induction of ovulation in patients with PCOS seeking pregnancy, with live-birth rate as the primary outcome (11). This trial should definitively answer the question of the relative efficacy of metformin, clomiphene, and combination therapy in the treatment of infertile women with PCOS.

One of the best studies relating to metformin use in androgen excess was that by Pasquali et al. (12). They randomized patients with PCOS or obesity alone who were weight index-matched to a lifestyle-modification program including diet plus metformin or placebo. After 6 months the frequency of menstrual cycles was better with metformin, and metformin was superior to placebo alone in the loss of weight, reduction in waist circumference and visceral fat, and reduction in testosterone. There was no differential benefit of metformin on fasting serum glucose, insulin, or SHBG. Patients with androgen excess responded better than matched patients with obesity to metformin with respect to reduction of visceral fat and testosterone, but not in terms of weight loss, weight circumference, fasting serum glucose, or insulin.

This suggests that the addition of metformin to lifestyle modification may be of some benefit to all obese subjects in terms of weight loss and reduction of central fat, particularly so for PCOS patients with regard to central fat. Whether this is a direct effect of metformin alone or indirect through the contribution of gastrointestinal side effects remains to be verified. Weight loss (3.9 kg after 8 months) is a feature of protracted metformin therapy (1.5 g/day) in obese women with PCOS, with greater weight reduction potentially achievable with higher doses (1.50 or 2.55 g/day) (13). No dose-response effect in weight loss was noted in the morbidly obese with PCOS, and there was no dose-response effect with reductions in androstenedione, which was significant with both doses. Systematic reviews of metformin's effect on weight loss do not suggest that this trend can be generalized beyond PCOS. Given the relatively fewer side effects of metformin, there would appear to be no harm in using metformin as part of a weight loss program in patients with PCOS. At present, however, metformin should probably be stopped as soon as pregnancy is established. Alcohol should be avoided, and the very rare occurrence of lactic acidosis should be borne in mind.

It is likely that weight reduction plays the most significant role in restoration of ovulation in obese women with PCOS and that this may be the primary mechanism for the effects noted with metformin, independent of its insulin-sensitizing effects (14). More recently, drugs that target weight loss have been compared with metformin therapy in women with PCOS. Treatment with orlistat for 3 months led to a 4.7% reduction in body weight, a more significant loss than was observed in metformin-treated women (1.0%). Serum testosterone levels declined significantly in both groups with no change in levels of SHBG. This agent has potential as an adjunct to the treatment of PCOS (15).

The effects of metformin (1700 mg/day) vs acarbose (300 mg/day) on insulin resistance, hormone profiles, and ovulation rates in patients with clomiphene citrate-resistant PCOS have recently been assessed (16). The ratio of LH to follicle-stimulating hormone (FSH) and total testosterone concentrations decreased and ovulation rates increased in both groups. Reduction in weight and body mass index (BMI) was only significant in the acarbose group.

In a placebo-controlled, double-blind study, Tang et al. (17) randomized 143 oligo-/amenorrheic obese women with PCOS to metformin (850 mg) or placebo twice daily for 6 months. All received diet and lifestyle advice from a dietitian. Both groups showed significant improvements in menstrual frequency and weight loss, with no significant differences between the groups. Logistic regression analysis showed that only percentage weight loss correlated with an improvement in menses. Women who received metformin achieved a significant reduction in waist circumference and free androgen index (FAI). Because this is one of the largest such studies conducted, it suggests that metformin does not improve weight loss or menstrual frequency in obese patients with PCOS receiving weight-management advice and that weight loss alone through lifestyle changes, if this can be achieved, can significantly improve menstrual frequency.

The benefits of weight reduction in women with androgen excess and PCOS are well documented. In overweight women with hyperandrogenism and PCOS, weight loss decreases abdominal fat, hyperandrogenism, and insulin resistance and improves lipid profiles, menstrual cyclicity, and fertility and risk factors for diabetes and cardiovascular disease (18-21). An important point is that a minimal amount of weight loss is sufficient to improve the presentation of PCOS. A moderate weight loss of 5% initial body weight on an energy-restricted diet results in reduction in insulin concentrations, reciprocal changes in SHBG, and improved menstrual cyclicity and fertility in the majority of patients (21). In this study a reduction in hirsutism was also noted in 40% of women.

Moran et al. have (20) also confirmed that a 7.5% weight loss in overweight women with PCOS increases SHBG, decreases the FAI and testosterone, and improves menstrual cyclicity, and that this can occur as soon as within the first 4 weeks of energy restriction and be sustained through weight loss. Energy restriction and weight loss is thus a desirable outcome in overweight women with PCOS for short- and long-term improvements in reproductive and metabolic health.

Replacing protein for carbohydrate within the context of an energy-restricted diet was not associated with significant differences in reproductive outcomes, although postprandial glucose response was 3.5-fold lower on the higher protein dietary pattern. No changes in hirsutism were noted (20).

High concentrations of serum LH in the follicular phase are associated with PCOS and with decreased reproductive function (22). Tonic hypersecretion of LH appears to induce premature oocyte maturation, causing problems with fertilization and miscarriage. Van Dam et al. (23) noted that 7 days of calorie restriction on a very-low-calorie diet (VLCD) (471 kcal/day) paradoxically increased basal and pulsatile LH secretion, despite reductions in plasma glucose, insulin, leptin, and testosterone concentrations, which decreased by 18, 75, 50, and 23%, respectively. Serum estrone, estradiol, SHBG, and androstenedione concentrations remained unchanged.

Van Dam et al. (24) examined predictors of improvements in ovarian function in response to a 6-month weight loss, noting that responders exhibited a significant decline of circulating estradiol concentrations and a concurrent increase in LH secretion in response to 7 days of acute energy restriction using a VLCD, whereas neither parameter changed significantly in nonresponders. The authors suggest that this hormonal response to energy restriction may be a marker or precedent for follicle maturation and ovulation in these patients. It is concluded that in PCOS women receiving long-term downregulation and stimulation with recombinant FSH, insulin resistance is related to neither hormone levels nor the outcome of in vitro fertilization. Obesity, independent of insulin resistance, is associated with relative gonadotropin resistance (25).

2.4. Dietary Composition and Weight Management

Although low-fat, high-carbohydrate diets have been the mainstream approach for weight management, they appear to be no more effective than other dietary patterns that restrict kilojoules (26). Furthermore, high-carbohydrate dietary patterns may worsen the metabolic profile if weight loss is not achieved. Modifying the type of dietary carbohydrate or glycemic index (GI) has been highly controversial (27,28). GI is proposed to both improve the cardiovascular risk profile and aid in weight loss (29,30), although education on GI has not shown an improvement in weight loss at 10 weeks (31) or 1 year (32). Surprisingly, there appear to be no studies on the utility of using GI as a strategy for weight management in women PCOS. Increasing the amount of dietary protein at the expense of carbohydrate has been shown to reduce abdominal fat in insulin-resistant subjects (33,34) and has been shown to be more effective in improving weight loss after 6 months and 1 year (35,36). However, in two small studies in PCOS subjects, no differential effect of protein was observed (20,37), although these dietary studies were not ad libitum. Improvements in postprandial glucose response were noted on the higher protein pattern. A proposed mechanism whereby protein is thought to exert effects on weight management is through increased satiety (38). This could be advantageous, as it has been shown that satiety appears impaired in women with PCOS (39).

PCOS is frequently associated with morbid obesity, in which conventional lifestyle modification may present a challenge. Sustained and marked weight loss has been achieved by bariatric surgery (40). A weight loss of 41 kg after 12 months was paralleled by a decrease in the hirsutism score and free testosterone, androstendione, and DHEAS and the restoration of regular menstrual cycles and/or ovulation in all patients. There is some indication that weight loss studies in women with PCOS have increased drop-out rates: 26-38% over 1-4 months (20,37) and 8-9% over 4 months in non-PCOS subjects (33,38). This may be a result of the increased difficulty of energy restriction consequent to lower satiety (41).

The use of alternative dietary compositions provides patients with an increased range of dietary options and may be more successful for optimally improving the metabolic profile and achieving and sustaining a reduced weight. However, continued follow-up is required to sustain weight loss, as this is likely to outweigh the effects of dietary composition (42).

Meal replacements have been shown to be an effective weight loss strategy in overweight women with PCOS. Moran et al. (43) placed 34 overweight women with PCOS on a weight-loss intervention (two meal replacements, low-fat snacks, and evening meal daily) for 8 weeks and reviewed them every 2 weeks (Fig. 2). The intervention resulted in a 5.6-kg (6%) reduction in weight and a 6-cm reduction in waist circumference. There was no change in SHBG, but a significant reduction in serum testosterone (0.3 ± 0.7 nmol/L) and FAI (3.1 ±4. 6nmol/L, 16.8%). This change in FAI occurred from weeks 0 to 2 and corresponded with a weight loss of 2.4 ± 1.0 kg (2.5%), with no further changes in FAI occurring from weeks 2 to 8. These data suggest that reproductive function can be restored very quickly by acute energy restriction. The implication is that only short-term energy restriction may be required to improve reproductive function and that weight loss is needed to sustain it, but this requires further investigation.

2.5. Physical Activity, Insulin Sensitivity, and Hormonal Control

Despite the considerable evidence that physical activity provides an effective medium for improving insulin sensitivity in a wide range of insulin-resistant states, the potential benefits of exercise for

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