Thirty studies were included in the review: 12 RCTs, 2 cohort studies and 16 uncontrolled observational studies. The numbers of patients were not provided for all studies, so a total cannot be calculated.
Twelve studies evaluated the effectiveness of metformin alone in restoring regular menstruation in unselected PCOS. Three studies were RCTs, of which 2 reported a significant improvement in menstrual cycle frequency in the metformin group.
Nine studies evaluated the effectiveness of metformin alone in restoring ovulation in unselected PCOS. Four studies were RCTs, of which 2 found that significantly more women ovulated with metformin than with placebo: 34% after 1 month and 82% after 4 months, compared with 4 and 64%, respectively. However, these studies contained totals of only 61 and 94 women respectively. The other 2 studies (n=25 and n=31) showed non significantly higher ovulation in the metformin group. When data from all 4 trials were added together, 56% of the patients ovulated with metformin compared with 35% of those on placebo; the relative risk (RR) was 1.5 (95% confidence interval, CI: 1.2, 2.0, P=0.002).
One study, an RCT, evaluated the effectiveness of metformin alone in restoring ovulation and subsequent pregnancy rate in unselected PCOS. It found that significantly more women ovulated on metformin (37 out of 45, i.e. 82%) than on placebo (30 out of 47, i.e. 64%), while of the women who wished to conceive, 4 (17%) of the 23 became pregnant on metformin compared with 1 (5%) of the 19 on placebo.
Five studies evaluated the effectiveness of metformin combined with CC in restoring ovulation and/or achieving pregnancy in unselected PCOS. The 2 RCTs (n=61 and n=90), which both contained only obese patients, found that significantly more women ovulated with meformin in combination with CC (90 and 80%) than with placebo and CC (8 and 65%). One study also showed a significantly higher pregnancy rate in the metformin and CC group (29%) than the CC and placebo group (8%).
Four studies evaluated the effectiveness of metformin combined with CC in restoring ovulation and/or achieving pregnancy in CC-resistant patients. Three studies were RCTs, of which one (n=20) showed no significant difference between the groups. Two studies (n=56 and n=27) found significantly more women ovulated and became pregnant in the metformin combined with CC group than in the CC and placebo group. When data from the 3 studies were added, more women ovulated on metformin combined with CC than on placebo and CC (RR 4.0, 95% CI: 1.6, 4.1, P<0.001), while more women became pregnant on metformin combined with CC than on CC alone (RR 2.2, 95% CI: 1.5, 3.0, P=0.04).
Two studies evaluated the effect of pretreatment with metformin on FSH treatment in women with CC-resistant PCOS. Both studies were RCTs comparing FSH alone with FSH combined with metformin. One crossover study (n=20) found no difference in ovulation or pregnancy rates between the treatments. One parallel-group RCT (n=32) reported that metformin combined with FSH produced fewer dominant follicles (2.4 versus 4.5, P<0.01) and a lower treatment cycle cancellation rate (0 versus 32%, P<0.03) because of excessive follicular development.
One study, a retrospective cohort study, evaluated the use of metformin during the IVF treatment of CC-resistant patients. It reported a higher fertilisation rate (64 versus 43%, P<0.05) and a higher clinical pregnancy rate (70 versus 30%, P<0.05) in patients given metformin.