To the Editor:
Our group thanks Dr. Maruyama (1) for his positive comments on our paper “Decreases in adrenomedullin expression and ciliary beat frequency in the nasal epithelium in tubal pregnancy.” In this study, we were inspired by our collaborators. We found that the nasal cilia beat frequency reported by Ho et al. (2) was similar to that observed by us in the oviduct. If the cilia at the two different sites behave similarly, the nasal cilia sampling can perhaps provide an easier alternative when we have great difficulties in getting oviductal tissues.
We would like to elaborate on Dr. Maruyama’s comments that it remains uncertain whether or not the plasma ADM level independently determines tubal ciliary activity. We wish to stress that it is the oviductal tissue adrenomedullin (ADM) level that is important. Plasma ADM level only serves as an indirect indicator of ciliary activity on the assumption that the decrease in oviductal ADM level is reflected in the plasma. The oviductal ADM level is dependent on the hormone environment but the effect of ADM is probably direct and not via the steroid hormones, which will take a much longer time to act than ADM. Another way whereby estrogen and progesterone may mediate the ADM effect is via the ADM receptors. Progesterone has been reported to increase calcitonin gene-related peptide (CGRP) and ADM receptors in the rat uterus (3). However, if ADM is deficient, any up-regulation of the receptors is perhaps not important.
As suggested by Dr. Maruyama, it is true that “serum [human chorionic gonadotropin] hCG may be lower in tubal ectopic pregnancy (tEP) than normal pregnancy.” However, the effects of hCG on ADM and ciliary beat frequency (CBF) have not been studied. If hCG is stimulatory, this may contribute to the lower ADM level; on the other hand, if hCG is inhibitory, the lower hCG may not be able to increase ADM in tEP if the deficiency is innate. If samples are available, we will try to study the effect of hCG and progesterone in the oviduct. Our work in the testis (4) and the ovary (5) of the rat suggests that the effect of hCG may be inhibitory.
On the issue of whether the reduction in ADM expression is the “causal factor or the result of tEP,” our replacement study with ADM in CBF suggests that it is a cause rather than a result. This can be best resolved by a time-course study designed to show whether the decrease in ADM precedes or follows the manifestation of tEP, but unfortunately this can only be done in an animal model, which is not yet available. Regarding Dr. Maruyama’s suggestion to see whether fertility treatment that leads to successful pregnancy will increase plasma and nasal ADM levels and nasal CBF, we would like to point out that while ADM deficiency may lead to infertility without tEP, the majority of cases of infertility are not due to ADM deficiency.
Wai Sum O, Ph.D.
Faculty of Medicine, University of Hong Kong
Hong Kong, China
1. Maruyama T. The nose knows tubal function? Fertil Steril, 2013 (In Press)
2. Ho JC, Chan KN, Hu WH, Lam WK, Zheng L, Tipoe G, et al. The effect of aging on nasal mucociliary clearance, beat frequency, and ultrastructure of respiratory cilia. Am J Respir Crit Care Med 2001;163:983-8.
3. Thota C, Gangula PR, Dong YL, Yallampalli C. Changes in the expression of calcitonin receptor-like receptor, receptor activity-modifying protein (RAMP) 1, RAMP2, and RAMP3 in rat uterus during pregnancy, labor, and by steroid hormone treatments. Biol Reprod 2003;69(4):1432-7.
4. Chan YF, O WS, and Tang F. Adrenomedullin in the rat testis I: its production, actions on testosterone secretion, regulation by human chorionic hormone and its interaction with endothelin 1 in the Leydig cell. Biol Reprod 2008;78,773-9.
5. Li YY, Li L, Hwang ISS., Tang F, O WS. Coexpression of adrenomedullin and its receptors in the reproductive system of the rat: effects on steroid secretion in the ovary. Biol Reprod 2008;79:200-8.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2013.05.006