We found that the addition of metformin to lifestyle had no significant benefit on ovulation and circulating androgen levels,. However due to high dropout, our study had limited power to detect differences between the treatment arms. Nevertheless we noted beneficial effects of the addition of metformin to lifestyle including improved insulin sensitivity and increased bone mineral density. There was no benefit to either treatment on QOL or skin parameters, i.e. acne or hirsutism, though our trial may have been too short. With the exception of increased diarrhea and fewer bladder infections in MET, the therapies were equally well tolerated and safe.
The strengths of our study include the relatively large numbers of subjects recruited into a combination lifestyle study, their racial and socioeconomic diversity, and the detailed study of reproductive and metabolic effects of treatment, including QOL measures. (29
) We found no improvement in our primary outcome of ovulation rates by adding metformin to lifestyle., similar to the larger study of Tang et al,(8
) which reported change in self reported menstrual frequency and did not quantify ovulation. Similarly a smaller study in PCOS adolescents showed no change in ovulation, based on urinary PdG levels, following lifestyle/metformin therapy.(10
) These studies also did not detect any additional benefit of lifestyle/metformin.
Our study demonstrated a significant benefit in weight loss with metformin, at least compared to baseline(~3 kg). This is consistent with the largest trial of metformin alone(with no lifestyle modification) in PCOS, where the six month weight loss was ~2 kg,(30
) and with the Diabetes Prevention Program where metformin was compared to placebo(~2 kg at 6 mos). Other studies have shown similar modest decreases in weight with combination or lifestyle therapy.(8
) However there are studies of lifestyle therapy alone in women with PCOS, which have shown significantly more weight loss over a comparable period(as much as 8–10 kg).(31
Metformin may have multiple metabolic benefits in women with PCOS. (32
) Metformin significantly decreased body fat and also raised circulating HDL cholesterol. Fasting or glucose challenged glucose levels and the insulinogenic index were unaltered.(33
) Improvements in the insulinogenic index lower diabetes risk, so the relative benefit of lifestyle alone on this parameter is probably small. The relative small impact of combination therapy on glycemic parameters is supported by other studies in women with PCOS with metformin added to oral contraceptives(34
) or to lifestyle(9
). Given the absence of glycemic improvement, weight loss may be the primary metabolic benefit of metformin in our study.(33
Increased BMD in the metformin group, after such a short period. has been seen after prolonged metformin treatment in girls with premature pubarche,(35
) perhaps due to favorable effects on circulating sex steroids. The impact of this finding in our older group is probably minor. We noted no effect of treatment on the hip, and women with PCOS have generally been noted to have normal or increased bone mineral density, without increased risk for Osteoporosis and hip fractures. (36
) Though pregnancy was considered an adverse event, we note that all pregnancies occurred in the placebo arm, further questioning the reproductive benefits of metformin,(30
) and supporting lifestyle alone as a treatment for infertility in these women.
Our study has limitations. Recruitment was slow and dropout was high. It is possible that with more subjects and a higher retention, we would have demonstrated more benefit with metformin. However other lifestyle trials in PCOS have had high dropout, in adolescents,(10
) and in an Australian trial of adults.(31
) Our project included an urban minority medical center that focused on recruiting Blacks. The difficulty in recruiting and retaining minority women into clinical trials is well known (37
),. Our study completion rate of 47% in Whites was comparable to that in the Australian trial (50%) that lasted 20 weeks versus our longer 24 week trial. We further examined factors at baseline and could not identify factors that predicted dropout. We conclude that it is difficult to individualize lifestyle therapy to those likely to complete all or part of it.
Our trial also enrolled many subjects who were severely or morbidly obese, subjects with the most difficulty complying and responding to lifestyle changes. Because of these drawbacks, some lifestyle studies in PCOS exclude subjects in this BMI range.(38
) Our subject’s predicted VO2
max did not change during the trial, indicating that even the subjects who stayed in the protocol did not increase their aerobic capacity. Similar aerobic capacity and muscle strength has been noted in PCOS as weight matched controls, such that PCOS per se
in unlikely to limit physical activity.(39
Overall although the effects of lifestyle/metformin, alone or in combination, are generally beneficial, the absolute changes are quite modest. Many women with PCOS are unwilling to participate in such interventions or lose motivation and dropout early in the process. Thus the external validity of such studies, given the low rate of study completion, is questionable. These results bring into doubt routine recommendations that lifestyle is effective therapy for severely obese women with PCOS.(6
) More meaningful reproductive and metabolic changes in women with PCOS may be achieved in this weight group with massive weight loss, such as from bariatric surgery.(40