Insulin Sensitizers and Pregnancy Outcomes

Although ovulatory dysfunction is an important etiological feature of the infertility of PCOS, ovulation is only one aspect of fertility. In addition to ovulatory problems, women with PCOS suffer a high rate of early pregnancy loss (EPL) during the first trimester (30-50% in PCOS vs 10-15% in normal women) (38-42). It is possible that insulin resistance may contribute to EPL by adversely affecting the endometrial environment and/or endometrial function.

The effect of metformin on endometrial function has been studied using surrogate markers, such as circulating levels of glycodelin and insulin-like growth factor binding protein-1(IGFBP-1) (43). Glycodelin is secreted by endometrial glands (44,45) to lessen the endometrial immune response against the developing embryo (46,47). Decreased endometrial secretion of glycodelin has been associated with EPL (48,49). IGFBP-1 modulates adhesion processes at the feto/maternal interface (50,51) and hence may be important in the peri-implantation period. Besides being synthesized by the endometrium, IGFBP-1 is primarily synthesized in the liver, and insulin is known to inhibit hepatic IGFBP-1 production. Importantly, serum levels of glycodelin and IGFBP-1 during the first trimester are decreased in women with PCOS compared with normal women (52).

Hyperinsulinemia in PCOS may contribute to EPL by decreasing glycodelin and IGFBP-1 expression. The insulin sensitizer metformin has been shown to have a beneficial effect to increase glycodelin and IGFBP-1 levels in women with PCOS (15). In one study, luteal phase glycodelin and IGFBP-1 levels were measured in PCOS women whose ovulations were induced by clomiphene at baseline. These women were then randomized to metformin 500 mg three times daily or placebo for 4 weeks. After the treatment period, luteal phase glycodelin and IGFBP-1 levels were again determined after a clomiphene-induced ovulation. The metformin group had a significant threefold increase in luteal-phase glycodelin (from 3434 ± 1299 to 10624 ± 1803 pmol/L; p < 0.001) and IGFBP-1 levels (from 1220 ± 136 to 4916 ± 596 pmol/L; p < 0.001). Glycodelin and IGFBP-1 levels did not change in the placebo group. In addition, uterine vascular penetration and blood flow of uterine spiral arteries increased in the metformin group (demonstrated by a decrease of the resistance index), whereas these parameters did not change in the placebo group. These data suggest that hyperinsulinemia in PCOS decreases production of glycodelin and IGFBP-1 and modulates undesirable uterine vascular changes, all of which contribute to an adverse endometrial environment for the establishment and continuation of pregnancy. Metformin reduces serum insulin and its unfavorable effects on luteal-phase endometrial function and therefore may improve the peri-implantation endometrial milieu in PCOS.

A recent retrospective study compared the pregnancy outcomes of women with PCOS who became pregnant but were not exposed to metformin with those who became pregnant while taking metformin and remained on metformin throughout pregnancy (53). These were nondiabetic women with PCOS who were seen at an academic endocrinology clinic in Caracas within a 4.5-year period. Among these women, 65 became pregnant using metformin, while 31 women never exposed to metformin became pregnant. The EPL rate in the metformin group was 8.8% (6 of 68 pregnancies), while the EPL rate in women never exposed to metformin was 41.9% (13 of 31 pregnancies; p < 0.001). In women with a prior history of miscarriage, the EPL rate in the metformin group was 11.1% (4 of 36 pregnancies) vs 58.3% (7 of 12 pregnancies) in women not taking metformin (p = 0.002). Metformin was not associated with adverse fetal outcomes except for a single infant born with achondrodysplasia.

The observations from this retrospective study suggest that improving insulin sensitivity is associated with a reduction in EPL rates in PCOS. However, because the women in this study took metformin throughout pregnancy, the optimal duration of metformin administration to achieve desirable pregnancy outcomes remains unknown. For example, metformin may need to be administered throughout the pregnancy, only during the first trimester, or only during conception to confer maximal protection, as suggested by two recent studies by Palomba et al. (24,27). Importantly, the beneficial effect of metformin on EPL seen in this retrospective study needs to be confirmed by a randomized and controlled prospective trial.

Metformin is classified by the U.S. Food and Drug Administration (FDA) as a Category B drug for use in pregnancy, which means that either animal studies have not shown a teratogenic risk or that adverse effects shown in animal data were not confirmed in controlled studies in women in the first trimester. Current evidence of metformin's use in pregnancy does not suggest that it is teratogenic. Women with PCOS who conceived while taking metformin and continued taking metformin throughout pregnancy have been described in several studies. Glueck et al. described several cohort studies examining metformin's maternal and fetal effects in women with PCOS who conceived on metformin and continued metformin therapy throughout their pregnancies (54). In these reports, metformin use during pregnancy was not associated with maternal lactic acidosis or with neonatal or maternal hypoglycemia. In 126 infants who were studied up to 18 months of life, metformin did not appear to affect birth length and weight, motor-social development, or growth (55). In addition, metformin use throughout pregnancy may reduce the incidence of gestational diabetes (54-56). However, it is important to note that these reports utilized historical controls that may limit interpretation of the data.

Despite several reports suggesting that metformin may lead to favorable pregnancy outcomes, there is still uncertainty regarding metformin use during pregnancy. Metformin has been shown to cross the placenta in women with PCOS, and fetal serum levels are comparable to maternal serum concentrations (57). In addition, data in one retrospective study in diabetic women suggested an increased rate of pre-eclampsia in women treated with metformin compared to those treated with sulphonylureas or insulin during their pregnancies. However, the groups in this study were not matched due to the retrospective nature of the study (58), and the women who took metformin were more obese and had more poorly controlled diabetes, both of which are known risk factors for pre-eclampsia. Moreover, the excess perinatal mortality in the metformin group in this study occurred in two subjects who had poorly controlled diabetes and were noncompliant, and therefore cannot be attributed to metformin treatment alone (58).

The only prospective, randomized study assessing metformin's effects on maternal and fetal outcomes was conducted by Vanky et al. (59). In this study 40 pregnant women with PCOS were randomized to metformin 850 mg twice daily or placebo. Randomization occurred at gestational age between 5 and 12 weeks. At conception, 11 of 22 women in the placebo group and 8 of 18 women in the metformin group were taking metformin. All women who were on metformin at conception stopped their metformin therapy for at least 2 days before inclusion in the study. Seven of the 22 women (32%) in the placebo group experienced severe pregnancy complications (such as preterm deliveries and severe pre-eclampsia) or postpartum complications (sepsis, acute respiratory distress syndrome, deep vein and pulmonary embolism). None in the metformin group had any severe pregnancy or postpartum complications.

In summary, preliminary data suggest that metformin may decrease spontaneous abortion, gesta-tional diabetes, and pregnancy-related complications in women with PCOS. Importantly, current data do not suggest that metformin is teratogenic. However, questions remain regarding the optimal time to discontinue metformin (or whether metformin should be continued throughout the entire pregnancy) once pregnancy has been achieved.

The commercially available thiazolidinediones rosiglitazone and pioglitazone are both FDA Pregnancy Category C medications, which means that teratogenicity has been demonstrated in animal models, and thus they are unsuitable drugs for women desiring pregnancy.

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