High Levels of Intrauterine Corticotrophin-Releasing Hormone, Urocortin, Tryptase, and Interleukin-8 in Spontaneous Abortions

P. Florio, P. Ciarmela, F. Arcuri and F. Petraglia

Chair of Obstetrics and Gynecology (P.F., P.C., F.P.), Department of Pediatrics, Obstetrics and Reproductive Medicine; and Institute of Pathological Anatomy and Histology (F.A.), University of Siena, Siena 53100, Italy

Address correspondence to: Pasquale Florio, M.D., Ph.D., University of Siena, Department of Pediatrics, Obstetrics, and Reproductive Medicine, Policlinico "Le Scotte", Viale Braci, Siena 53100, Italy.

To the editor:

We read with great interest the recently published article by Madhappan et al. (1). The authors have carefully reported that under stress in habitual spontaneous abortions, there are high levels of CRH and urocortin (UCN) in products of conception that, consequently, activate uterine mast cells to secrete abortogenic tryptase and IL-8. Furthermore, the authors suggested that systemic CRH or UCN is the source of elevated CRH and UCN in product of conception and that the placenta and intrauterine pregnant tissues, local nerve endings, immune and mast cells serve as local sources.

However, when the authors refer to the source of UCN, they affirm (on pages 2285 and 2286) that this peptide is not expressed in the uterus outside of pregnancy whereas, on the contrary, we clearly showed (2) that UCN mRNA is expressed by isolated endometrial epithelial and stromal cells of nonpregnant human uterus. We already reported that UCN peptide is present in endometrial luminal and glandular epithelial cells, is moderately expressed in stromal cells of both proliferative and secretory phase endometrial specimens, and in myometrial cells. Thus, UCN is expressed and synthesized by human endometrium outside of pregnancy (2), and by human decidua of the first (3) and third (3, 4) trimesters of pregnancy.

Another point of discussion is related to the putative role of CRH on implantation and, mainly, on the link between stress and CRH activation. Indeed, Madhappan et al. (1) reported higher levels of CRH in products of conception from women with spontaneous abortion than controls, suggesting that the hypersecretion of CRH and of UCN, through mast cells activation, is the cause of the abortion. However, locally produced CRH has been reported to promote implantation and maintenance of early pregnancy, primarily by inducing apoptosis and, consequently, killing activated T cells at the maternal-fetal interface, allowing trophoblast invasion and implantation into maternal decidua (5). Taken together, these findings would suggest that hypersecretion of CRH and UCN in spontaneous abortion may be viewed as a reactive response of the product of conception to escape from a hostile environment and not as the causative link between stress and abortion. We also have concern about the role of stress on CRH output in pregnancy. Data provided by us (6, 7, 8) and others (9, 10) have indicated that the effect of the stress on the CRH secretion may be dependent on gestational age and stimuli. On the contrary, Madhappan et al. (1) did not define or quantify the stress stimuli in the actual and previous gestation of their study group, nor did they discuss the effect of different stress stimuli on CRH secretion.

Received July 21, 2003.

References

  1. Madhappan B, Kempuraj D, Christodoulou S, Tsapikidis S, Boucher W, Karagiannis V, Athanassiou A, Theoharides TC 2003 High levels of intrauterine corticotropin-releasing hormone, urocortin, tryptase, and interleukin-8 in spontaneous abortions. Endocrinology 144:2285–2290[Abstract/Free Full Text]
  2. Florio P, Arcuri F, Ciarmela P, Runci Y, Romagnoli R, Cintorino M, Di Blasio AM, Petraglia F 2002 Identification of urocortin mRNA and peptide in the human endometrium. J Endocrinol 173:R9–R14
  3. Petraglia F, Florio P, Gallo R, Simoncini T, Saviozzi M, Di Blasio AM, Vaughan J, Vale W 1996 Human placenta and fetal membranes express human urocortin mRNA and peptide. J Clin Endocrinol Metab 81:3807–3810[Abstract]
  4. Clifton VL, Gu Q, Murphy VE, Schwartz J, Madsen G, Smith R, Qing G 2000 Localization and characterization of urocortin during human pregnancy. Placenta 21:782–788[CrossRef][Medline]
  5. Makrigiannakis A, Zoumakis E, Kalantaridou S, Coutifaris C, Margioris AN, Coukos G, Rice KC, Gravanis A, Chrousos GP 2001 Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance. Nat Immunol 2:1018–1024[CrossRef][Medline]
  6. Florio P, Severi FM, Ciarmela P, Fiore G, Calonaci G, Merola A, De Felice C, Palumbo M, Petraglia F 2002 Placental stress factors and maternal-fetal adaptive response: the corticotropin-releasing factor family. Endocrine 19:91–102[Medline]
  7. Florio P, Petraglia F 2001 Human placental corticotropin-releasing factor (CRF) in the adaptive response to pregnancy. Stress 4:247–261
  8. Petraglia F, Hatch MC, Lapinski R, Stomati M, Reis FM, Cobellis L, Berkowitz GS 2001 Lack of effect of psychosocial stress on maternal corticotropin-releasing factor and catecholamine levels at 28 weeks’ gestation. J Soc Gynecol Investig 8:83–88[Medline]
  9. Hobel CJ, Dunkel-Schetter C, Roesch SC, Castro LC, Arora CP 1999 Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks’ gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol 180:S257–S263
  10. Erickson K, Thorsen P, Chrousos G, Grigoriadis DE, Khongsaly O, McGregor J, Schulkin J 2001 Preterm birth: associated neuroendocrine, medical, and behavioral risk factors. J Clin Endocrinol Metab 86:2544–2552[Abstract/Free Full Text]




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