European Mast Cell and
Basophil Research Network

Mast cells, hormones and pregnancy

In mammals, the successful implantation of the blastocyst into the endometrium and the subsequent development of a decidual cell response involve many interactions between the mother and the conceptus [1]. Uterine-derived histamine has long been suspected as a key regulator in implantation due to its ability of altering uterine vascular permeability and inducing stromal decidualization [2]. Histamine is produced mainly by MCs that are present in both the uterus and placenta [3]. Moreover, human preimplantated embryos induce MCs to release histamine by secreting histamine releasing factor [4]. The invasion of trophoblast cells into the maternal endometrial tissue is not the result of passive growth pressure but of an active biochemical process [5–7]. It necessarily involves the destruction and/or displacement of the basement membrane, extracellular matrix (ECM) and possibly cellular components of the maternal decidua. This process is regulated by a fine balance between the production of proteolytic pro-enzymes (in particular matrix metalloproteinases, MMPs), their physiological activators (e.g. plasmin) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs). The proteolytic enzymes, capable of digesting the different constituents (several collagen types, laminin, fibronectin) of the endometrial basement membrane/ECM, are considered the rate-limiting steps of the trophoblastic invasion [8–10]. The potential role of the MCs on mediating ECM degradation trough the activation and production of metalloproteinases MMPs has been highlighted [11]. Moreover, MC tryptases and chymases have been shown to activate the precursors of MMP2 [12], MMP9 [13], collagenase and stromelysin [14].
The presence of MCs in the uterus has been already described in many species including human [15], mouse [16], rat [17], hamster [18] as well as goat [19]. Besides, the number of MCs in the uterus was shown to fluctuate during estrous cycle suggesting an influence of female sex hormones on MC recruitment to the uterus [17]. Thereby, these hormones might act directly as MCs express  estradiol and progesterone receptors (ER and PR) [20-26]. Zaitsu et al. demonstrated that estradiol rapidly stimulated MC degranulation which could be blocked by tamoxifen, a tissue specific ER antagonist, clearly indicating that estradiol-induced MC degranulation throughout one of its receptors. Bone marrow-derived MCs (BMMCs) isolated from ERα knockout animals did not degranulate in response to E2 treatment confirming that the E2 effect on MCs is more likely mediated by the ERα [25]. Ovariectomized mice, in which estradiol and progesterone are almost absent, have less number of uterine MCs compared to control, non-ovariectomized animals [20]. Hormonal replacement, estradiol alone or in combination with progesterone, restored the number of uterine MCs after ovariectomization, which was comparable to the levels observed in control mice [20]. Hormonal replacement additionally induced an augmentation in the levels of MC-related proteases expression in the uterus as well as boosted MC degranulation [20].


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19. Karaca T, Arikan S, Kalender H, Yoruk M (2008) Distribution and heterogeneity of mast cells in female reproductive tract and ovary on different days of the oestrus cycle in Angora goats. Reprod Domest Anim 43:451–456.
20. Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S, Malfertheiner SF, Zenclussen AC (2010) Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One 5:e14409.
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