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Abstract:In vitro fertilization, popularly referred to as IVF, has captured the attention of the public since its sensational introduction in 1978. Today assisted reproductive technology is available throughout most of the civilized world, and the practice is largely different from that used during the early days. Refinements in laboratory technology and clinical practice have allowed IVF to evolve into a medical procedure that is efficient, safe, readily accessible, and relatively affordable. More than 2 million IVF children have been born to date, and it is likely that continued enhancements will widen its appeal and applicability.

The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR-2) pathway regulates proliferation, survival, and permeability of vasculature. This pathway is active during the formation of a corpus luteum, a highly vascularized, endocrine organ with a short life span during the nonpregnant state. In the pregnant state, the life span of corpora lutea is much longer because they play a critical role in supporting pregnancy development. We hypothesized that the VEGF/VEGFR-2 pathway plays a critical role in regulating angiogenic events in the corpora lutea of pregnancy. Injection of the neutralizing anti-VEGFR-2 antibody DC101 (ImClone Systems, Inc., New York, NY) on embryonic d 3.5 (preimplantation) or 6.5 (postimplantation) disrupts function of the corpora lutea of pregnancy in CD1 mice, as evidenced by a decrease in organ size, regression of luteal vessels, and a fall in progesterone secretion within 24 h postinjection. Inhibition of the VEGFR-2 caused removal of endothelial cells, mostly through endothelial cell detachment from the vascular basement membrane. Luteal steroid-producing epithelial cells were eliminated through apoptosis secondary to vasculature becoming dysfunctional. Disruption of luteal function caused arrest of embryonic development. The effect of antibody is specific to the ovary, because pregnancy progresses normally in ovariectomized, progesterone-replaced animals treated with anti-VEGFR-2 antibody. Embryonic blood vessels were not affected directly by the antibody, because it did not reach the embryo. Administration of an antibody against VE-cadherin (E4G10), which specifically blocks endothelial proliferation, did not disrupt luteal function and pregnancy development. Thus, VEGFR-2-mediated endothelial cell signals are critical to maintain functionality of luteal blood vessels during pregnancy. Potential clinical applications of inhibitors of the VEGF/VEGFR-2 pathway include emergency contraception and medical treatment of ectopic and abnormal intrauterine pregnancies.

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The conflicting results from studies on the predictive capabilities of serum anti-Müllerian hormone (AMH) for IVF pregnancy outcomes may be attributed to small sample sizes and disparities in the age of the study populations. The relationship between AMH and IVF pregnancy outcomes was clarified with retrospective cross-tabulation analyses (n=1558) stratified by age to control for its confounding effects. Serum AMH concentrations were divided into tertiles (≤ 0.29, 0.30-1.20, ≥ 1.21 ng/ml) and ages into four groups (<34, 34-37, 38-41, ≥ 42 years). For women <34, having serum AMH in the lowest tertile did not reduce the chance of IVF pregnancy/live birth compared with those with higher AMH concentrations. For women 34-41, a significant positive relationship existed between serum AMH and pregnancy rates. For women ≥ 42, serum AMH concentrations ≤ 0.29 ng/ml were associated with a 3% chance of pregnancy, and women with AMH ≥ 1.21 ng/ml had the same pregnancy rate as women with concentrations 0.30-1.20 ng/ml. In conclusion, AMH has limited predictive value for IVF outcomes in the two extremes of female reproductive age; however, for women between 34 and 41, higher serum AMH concentrations are associated with significantly greater chances of pregnancy (P<0.01).