Have we got the final answer on pregnancy induction in PCOS?
A recent controlled trial(Legro et al) compared pregnancy rates over 6 months in women with PCOS treated with metformin alone, clomiphene alone and the combination of the two drugs. The rates of live birth were greater with clomiphene alone (22.5%), compared to metformin alone (7.2%). The combination of the two drugs resulted in live birth pregnancy rate of 26.8% although this figure was not statistically different form the rate on clomiphene alone. Clomiphene was associated with greater rates of multiple pregnancies.Background
The results of the Legro et al’s study show a similar trend to the meta-analytical study of Lord et al, except that the latter study showed a greater effect with the drug combination than either alone
“The results are inconsistent with data from several (smaller) studies reporting benefits of metformin, especially in combination with clomiphene, in stimulating ovulation in women with polycystic ovarian disease” quoting directly from Legro et al. The authors have demonstrated that ovulation induction by a drug does not equate to pregnancy
Legro et al’s results differ strikingly from those of Palomba et al who, in a similarly designed study, showed a live birth rate of 52% with metformin, compared to 18% for clomiphene alone
Moll et al found that adding metformin to clomiphene made no difference to the rates of pregnancy and suggested that the two drugs may use common pathways to induce ovulation and therefore an additive effect of the two would not be expected
Commentary
Most women with PCOS are not interested in becoming pregnant when they seek medical advice. The program for managing these women would be regular aerobic exercise, low GI eating and, in most cases, treatment with insulin sensitizers. The first line insulin sensitizer is metformin. This program improves symptoms and reduces percentage body fat and the waist to hip ratio. Periods become more predictable and ovulatory
For women who wish to become pregnant we suggest three months on this program and if pregnancy not occur, clomiphene would be introduced
A crucial element missing in the recent studies comparing the efficacy of different drugs in enhancing ovulation and pregnancy rates in women with PCOS is diet. Our own extensive experience convinces us that low GI eating is very important in enhancing pregnancy rates. Palomba et al studied Italian women who habitually eat a low GI diet. By contrast the average American diet is far from low GI (Legro et al), nor indeed is the average Dutch diet (Moll et al). Moreover, the patients studied by Legro et al were heavier than those recruited in the Italian study
The importance of diet (and, possibly, other environmental factors) in determining the outcome of studies in women with PCOS is, of course, an inference on our part. There is, however, substance in the potential role of diet to warrant the inclusion of a low GI diet as a variable in controlled studies of ovulation and pregnancy in women with PCOS
References
1 Legro RS et al, New England Journal of Medicine 356:551-566,2007
2 Lord et al, British Medical Journal 327:951-953,2003
3 Palomba et al, Journal of Clinical Endocrinology and Metabolism 90: 4068-4074, 2005
4 Moll et al, British Medical Journal, 332:1485, 2006