VCU news

By Lorraine Cichowski and John Nestler

RICHMOND, Va. - Concentrations of two proteins believed to play a key role in the first trimester of pregnancy are significantly lower in women with polycystic ovary syndrome (PCOS) than healthy women, according to an international study led by the Virginia Commonwealth University Medical Center.

The findings, reported in the February issue of the Journal of Clinical Endocrinology & Metabolism, implicate a dysfunction in the uterine lining for early miscarriages in women with PCOS, a disorder of the endocrine system that causes hormone imbalances and  infertility, affecting as many as 10 percent, or five million, women. Women with PCOS suffer miscarriages at a rate three times higher than that reported for healthy women.

The team of researchers studied 134 pregnant women during the first trimester of pregnancy - 72 with PCOS and 62 without it. The women, who were similar in age and body mass index, were recruited from hospitals in Caracas, Venezuela.

The researchers measured concentrations of glycodelin and IGF binding protein-1 (IGFBP-1), which are proteins secreted during pregnancy by the endometrium, or the membrane that lines a women's uterus, and are believed to play an important part in implantation of the embryo and maintenance of the pregnancy.

The data showed that both proteins were markedly lower in pregnant women with PCOS than the other women. Glycodelin levels were 56 percent lower in women with PCOS in weeks 3-5 and 23 percent lower in weeks 6-8. The level of glycodelin was similar between the two groups by weeks 9-11.  Levels of IGFBP-1 were as much as 70 percent lower in women with PCOS during weeks 3-8 and 39 percent lower during weeks 9-11.

Of the 134 women studied, 12 women had miscarriages in the first trimester. Of those women, 10 were women with PCOS. The rate of miscarriage was 14 percent for women with PCOS vs. 3 percent for normal women.  Among the PCOS women who miscarried, levels of glycodelin were decreased by 48 percent in weeks 3-5 and 78 percent in weeks 6-8.  Levels of IGFBP-1 were 60 percent lower in women with PCOS during weeks 9-11.

"These findings are significant because they may provide a mechanism for first-trimester miscarriage in PCOS and help us identify pregnant women with PCOS who are at increased risk for miscarriage," says Dr. John E. Nestler, M.D., professor and chair of VCU's Division of Endocrinology and Metabolism and vice chair of the Department of Internal Medicine.

"Because glycodelin inhibits certain responses of the immune system and natural killer cell activity, impaired production of glycodelin could allow a maternal immune response against the embryo," said Nestler, who is recognized internationally for his work on infertility and use of insulin-sensitizing drugs to induce ovulation in women with PCOS. "Low concentrations of serum glycodelin suggest a deficient endometrial environment for early development of pregnancy."

Nestler explained that IGFBP-1 helps the adhesion process, so low concentrations would adversely affect embryo implantation.  

The results are consistent with previous studies by Nestler and colleagues that showed that the insulin-sensitizing drug, metformin, increased levels of glycodelin and IGFBP-1 in nonpregnant women with PCOS and reduced early miscarriages in women with PCOS who conceived while taking metformin and remained on the drug throughout the first trimester.

In addition to VCU, other medical centers involved in the study were the Hospital de Clinicas Caracas and Central University of Venezuela; Helsinki (Finland) University Central Hospital, and Universite de Sherbrooke (Canada).  

The research was supported by grants from the National Institutes of Health, the Finnish Cancer Center Foundation, the University of Helsinki and the Helsinki University Central Hospital Research Fund.