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

T. C. Theoharides, B. Madhappan, D. Kempuraj and N. Papadopoulou

Departments of Pharmacology and Experimental Therapeutics (T.C.T., B.M., D.K., N.P.), Internal Medicine (T.C.T.), and Biochemistry (T.C.T.), Tufts University School of Medicine, and Tufts-New England Medical Center, Boston, Massachusetts 02111

Address correspondence to: T. C. Theoharides, Ph.D., M.D., Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111. E-mail: Theoharis.Theoharides{at}tufts.edu.

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.

Alternatively, mast cells may not be stimulated during implantation but may become susceptible to stimulation later when their numbers increase or they could express more CRH receptors. In fact, mast cell accumulation may also contribute to the abnormally high CRH/Ucn during habitual spontaneous abortions (4) (also see Ref. 50 in our article). Moreover, we recently showed that CRH is not present in 2-wk-old human umbilical cord-derived cultured mast cells but was particularly high and could be secreted from 8-wk-old cells (5). This finding could also mean that intrauterine mast cells do not express CRH receptors and/or that they are not responsive in the first week during implantation but express sufficient receptors or become responsive by the time miscarriage was studied at 7–9 wk gestation.

Details of the mechanisms involved are not known, but complex interactions with other peptides have been reported. The differential expression pattern of CRH receptors during pregnancy suggests that CRH/Ucn acting via different subtypes, some of which were identified on resident macrophages, may be able to exert distinct actions in the human uterus (6). In the myometrium, CRH receptors are present but nonfunctional in the nonpregnant state, whereas they become active as pregnancy progresses. Moreover, the range of CRH receptors, agonist peptides, and second messengers involved in these processes could have different effects at different times.

We had hypothesized that stressors in the subjects studied may have been involved in the high intrauterine CRH/Ucn we reported (1). However, that study did not attempt to investigate the extent and type of stressors that are the subject matter of a large ongoing study. A case in point is interstitial cystitis, a sterile bladder condition with frequency, nocturia, and pelvic pain (7) characterized by bladder mastocytosis (8), the symptoms of which worsen during stress (9). In an animal model of this condition, acute restraint stress induced bladder mast cell activation (10). It is, therefore, of interest that in a survey of 100 interstitial cystitis patients, the incidence of first time and habitual abortions was extremely high (11).

Received August 5, 2003.

References

  1. Madhappan B, Kempuraj D, Christodoulou S, Boucher W, Tsapikidis S, 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. Hillhouse EW, Grammatopoulos DK 2002 Role of stress peptides during human pregnancy and labour. Reproduction 124:323–329[Abstract/Free Full Text]
  3. Makrigiannakis A, Zoumakis E, Kalantaridou S, Mitsiades N, Margioris A, Chrousos GP, Gravanis A 2003 Corticotropin-releasing hormone (CRH) and immunotolerance of the fetus. Biochem Pharmacol 65:917–921[CrossRef][Medline]
  4. Kempuraj D, Lytinas M, Madhappan B, Christodoulou S, Athanassiou A, Theoharides TC, Human mast cells synthesize and secrete corticotropin-releasing hormone (CRH) and urocortin (Ucn). Experimental Biology 2003 (Abstract 9216)
  5. Kempuraj D, Papadopoulou N, Lytinas M, Kandere-Grzybpwska K, Huang M, Madhappan B, Boucher W, Christodoulou S, Athanassiou A, Theoharides TC, Corticotropin-releasing hormone (CRH) and its structurally related urocortin (Ucn) are synthesized and secreted by human mast cells. Endocrinology, in press
  6. Wetzka B, Sehringer B, Schafer WR, Biller S, Hor C, Benedek E, Deppert WR, Zahradnik HP 2003 Expression patterns of CRH, CRH receptors and CRH binding protein in human gestational tissue at term. Exp Clin Endocrinol Diabetes 111:154–161[CrossRef][Medline]
  7. Theoharides TC, Pang X, Letourneau R, Sant GR 1998 Interstitial cystitis: a neuroimmunoendocrine disorder. Ann NY Acad Sci 840:619–634[Abstract/Free Full Text]
  8. Theoharides TC, Kempuraj D, Sant GR 2001 Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57(Suppl 6A):47–55
  9. Rothrock NE, Lutgendorf SK, Kreder KJ, Ratliff T, Zimmerman B 2001 Stress and symptoms in patients with interstitial cystitis: a life stress model. Urology 57:422–427[CrossRef][Medline]
  10. Spanos C, Pang X, Ligris K, Letourneau R, Alferes L, Alexacos N, Sant GR, Theoharides TC 1997 Stress-induced bladder mast cell activation: implications for interstitial cystitis. J Urol 157:669–672[Medline]
  11. Osborne J, Sant GR, Theoharides TC, Increased incidence of spontaneous abortions in interstitial cystitis patients. Proc Research Insights into Interstitial Cystitis Symposium, Washington, DC, 2003




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