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T. C. Theoharides, B. Madhappan, D. Kempuraj, N. Papadopoulou, Authors’ Response: High Levels of Intrauterine Corticotrophin-Releasing Hormone, Urocortin, Tryptase, and Interleukin-8 in Spontaneous Abortions, The Journal of Clinical Endocrinology & Metabolism, Volume 88, Issue 11, 1 November 2003, Pages 5580–5581, https://doi.org/10.1210/jc.2003-031382
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To the editor:
We appreciated the letter by Florio et al. concerning our recent article reporting increased levels of CRH, urocortin (Ucn), IL-8, and tryptase in the decidua of spontaneous recurrent abortions (1). We were aware of the findings they discuss in their letter; in fact, we did refer to the two key publications (Refs. 8 and 10 in our article) that the authors discuss at length in their letter. However, space limitations did not permit an exhaustive discussion of the subject matter because we focused on abortion and not human pregnancy and labor, which had been adequately reviewed (2). Moreover, unlike what the authors assert in their first paragraph, we never suggested that the source of elevated CRH/Ucn is systemic. On the contrary, we speculated that the source of these peptides is local from intrauterine tissues.
We agree that, at first glance, it appears confusing that CRH/Ucn could participate in miscarriages in humans, whereas on the other hand studies in rodents suggest that CRH is required for successful egg implantation. It is also clear that CRH can induce immune tolerance during early gestation (3). However, there is sufficient evidence to indicate that either one or both hormones may have dual actions. During gestation, locally produced CRH acts on myometrium via specific receptors (CRHR-1) to generate cAMP and subsequently maintains myometrial relaxation; yet, apparently, as term approaches, serum CRH increases, whereas the ability of the CRH receptor-complex to activate adenylate cyclase is reduced. Instead, CRH/Ucn through different receptor subtypes and second messengers could stimulate prostanoid secretion and augment the effects of oxytocin (2). These combined effects are associated with delivery (1). Moreover, high serum CRH levels have been well documented to correlate with premature/abnormal pregnancies and preterm deliveries. It therefore appears that the amount of CRH/Ucn may be important in that some CRH is necessary for implantation, but more during the early weeks of gestation is detrimental.
