I was excited when I read of the discovery of H. pylori (an infectious cause of gastric ulcers?), because it was known that bacteria could not survive in the high-acid environment of the stomach. I was excited when I was first presented with a lecture showing human papillomavirus as an infectious cause of cervical cancer, because cancer and infection were known to be two completely separate causes of pathology. So much for how much we know. These events turned my ideas upside down. Similarly, I was happily surprised when I read the results of this trial by Vivian Lee et al. It is often the surprises that can lead to real advances in medicine (did that area of mold on the agar plate really eliminate those bacterial colonies?). Lee et al. report the effect of letrozole, an aromatase inhibitor that inhibits the peripheral conversion of androgens to estrogens, on the Doppler blood flow indices of the uterine artery in early pregnancy, comparing these to placebo through the mechanism of a randomized trial. They demonstrated that pregnancies exposed to letrozole had a significant decrease in uterine artery resistance (RI) and pulsatility (PI) indices, concluding that blood flow in the uterine artery is increased in response to letrozole. This is a moderately surprising finding, given an inherent bias in most physicians towards the belief that estrogen in mammals is responsible for the marked increase in uterine blood flow in early pregnancy. The results are important mostly in terms of our disease knowledge or knowledge about the hormonal support of early pregnancies. This article reports findings that I believe are important to help eliminate biases in our understanding of how pregnancy-related hormones affect the early developing pregnancy and specifically the uterine vasculature. Our bias is that, in humans, estradiol increases blood flow and thus helps to support a pregnancy, and that a decrease in estradiol would lead to a marked reduction in blood flow, but the available data are few. There are two conclusions to be drawn from the data of Lee et al. presented in the current issue of the Journal. One is that there are other placentally derived growth factors that sustain uterine blood flow when an insult to uterine blood flow (such as letrozole) emerges1. However, it is, of course, the transformation of the uterine and spiral arteries by destruction of the smooth muscle in early pregnancy that allows the decreased resistance and increased blood flow throughout pregnancy, so the second conclusion is that estrogen plays a completely different role; indeed, there is some evidence available to suggest that estrogen actually limits the extent to which the uterine arteries are transformed by regulating expression of vascular endothelial growth factor and integrins2. If estrogen limits this process, then decreasing estrogen by the use of letrozole in early pregnancy should give us precisely the results seen in the current study. The limitations of this study are related to the narrow aims, which follow from the study design. Broad or general statements or conclusions about the clinical use of letrozole are not possible or are not wise at this stage in our knowledge. The strength of this study lies in the randomized design. Having a properly randomized and blinded placebo study demonstrates clearly that there are differences between normal ongoing first-trimester pregnancies (receiving placebo) and those exposed to letrozole. In addition, the surprising findings open doors for future investigations. The results of the trial by Lee et al., although perhaps not as dramatic a change in the world of medicine as the other examples I have mentioned above, confirm that reconsideration of the mechanisms of early pregnancy support through the action of estrogens is warranted. Let's get to work on these new studies! D. Skupski*, * Department of Obstetrics and Gynecology, New York Hospital Queens, 56-45 Main Street, Room M-372, Flushing, NY 11355, USA
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Aug 8, 2023
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