Novel regulation of pregnant human myometrial smooth muscle cell gap junctions by human chorionic gonadotropin.

Abstract

Human myometrium contains hCG/LH receptors. There are fewer of these receptors during labor compared to no labor at preterm or term deliveries. Exogenous hCG can directly inhibit oxytocin-stimulated human myometrial contractions. These findings suggest that hCG may directly maintain myometrial quiescence during pregnancy. As maintenance of uterine quiescence may involve down-regulation of myometrial gap junctions, we investigated the effect of hCG on connexin-43 (CX-43) gene expression from RNA to protein and morphological gap junctions. The addition of 5 or 10 nM highly purified hCG to subconfluent cultures of pregnant myometrial smooth muscle cells resulted in a significant decrease in CX-43 protein levels. Higher hCG concentrations (100 and 1000 nM), however, had no effect. The maximal effect of hCG was seen at 4-8 h of culture, followed by recovery after a longer duration of culture. hCG treatment also concomitantly decreased CX-43 messenger RNA and morphological gap junctions. The hCG effect on CX-43 protein levels is hormone specific and mediated by protein kinase-A signaling. Estradiol and oxytocin increased, whereas progesterone decreased, CX-43 protein levels and morphological gap junctions. The oxytocin-induced increase was reversed by cotreatment with hCG. Although RU 486 alone had no effect on CX-43 protein levels, it prevented the down-regulating action of hCG and progesterone. In summary, our results demonstrate that hCG can directly decrease CX-43 messenger RNA, protein, and morphological gap junctions in cultured pregnant human myometrial smooth muscle cells. The hCG action is concentration and time dependent, hormone specific, and mediated by protein kinase-A signaling and appears to involve progesterone receptors. These data lend support to the concept that hCG could be one of the hormones responsible for maintaining uterine quiescence by down-regulating myometrial gap junctions during pregnancy.

In vitro activity of human chorionic gonadotropin (hCG) on myometrium contractility

“…Different hypotheses have been suggested, such as a decrease in intracellular free calcium concentrations, down-regulation of myometrial gap junctions, activation of BKCa channels, as well as inhibition of uterotonic agents [8,24,26,28].…”

“…In the last years, since the discovery of LH/hCG receptors in pig uterus by Ziecik et al, it is well known that gonadotropins receptors are present not only in male and female gonads, but also in extragonadal reproductive tissues both in humans and domestic animals [7][8][9][10][11]. LH/hCG receptors are expressed in the myometrium of the woman, pig, rabbit and cow, and their expression is dependent on the stage of the estrous cycle, and can be modulated by steroid hormones [7,9,[12][13][14][15][16].…”

It is Time to Evaluate Human Chorionic Gonadotropin for the Treatment of Preterm Births

“…In contrast, hCG is an inhibitor of myometrial contractions, antagonizes the oxytocin actions and the mechanisms of action are rather fairly well defined. [2][3][4]16 It has minor side effects that do not generally require medical attention. In addition, it is cheap and can be made even cheaper by scaling up the production of recombinant hormone.…”

Immunohistochemical Expressions of Receptors for Luteinizing Hormone/Human Chorionic Gonadotropic Hormone and for Sex Steroid Hormones in Pregnant Fallopian Tubes

“…In vitro and in vivo human studies have demonstrated that the activation of LHR in uterine and Fallopian tube results in numerous changes that are required for pregnancy initiation (21,22), maintenance (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) and for parturition to occur in a timely manner (37).…”

“…The results of other studies suggested that estradiol promotes LHR synthesis in the epithelium and smooth muscle and, along with LH, causes the relaxation of the porcine oviduct, especially during the periovulatory stage of the oestrous cycle (10,(30)(31)(32)(33)(34)(35)(36)(37)(38). The results of an animal study indicated that LHR can control oviductal contractions directly and may be partially responsible for the relaxation of the isthmus during fertilization in pigs (10).…”