Human Chorionic Gonadotrophin as a Possible Mediator of Leiomyoma Growth during Pregnancy: Molecular Mechanisms

Abstract

Uterine fibroids are the most common gynecologic benign tumors. Studies supporting a strong pregnancy-related growth of leiomyomas generally claimed a crucial role of sex steroid hormones. However, sex steroids are unlikely the unique actors involved as estrogen and progesterone achieve a pick serum concentration in the last trimester while leiomyomas show a typical increase during the first trimester. Given the rapid exponential raise in serum human Chorionic Gonadotrophin (hCG) at the beginning of gestation, we conducted a review to assess the potential role of hCG in the striking growth of leiomyomas during initial pregnancy. Fibroid growth during initial pregnancy seems to correlate to the similar increase of serum hCG levels until 12 weeks of gestation. The presence of functional Luteinizing Hormone/human Chorionic Gonadotropin (LH/hCG) receptors was demonstrated on leiomyomas. In vitro treatment of leiomyoma cells with hCG determines an up to 500% increase in cell number after three days. Expression of cyclin E and cyclin-dependent kinase 1 was significantly increased in leiomyoma cells by hCG treatment. Moreover, upon binding to the receptor, hCG stimulates prolactin secretion in leiomyoma cells, promoting cell proliferation via the mitogen-activated protein kinase cascade. Fibroid enlargement during initial pregnancy may be regulated by serum hCG.

Keywords: estrogen; fibroid; human chorionic gonadotropin; leiomyoma; progesterone.

Figure 1

Histological patterns of leiomyoma in the pregnant uterus: (a) photomicrograph of non-pregnant normal myometrium; (b) photomicrograph of a leiomyoma with extensive mixo-edematous changes in a pregnant woman; and (c) photomicrograph of a leiomyoma in a pregnant woman with a cellular area constituted by smooth muscle cells with cytoplasmic vacuoles. Stained with hematoxylin and eosin. Magnification: (a,b) 125×; and (c) 250×.

Figure 2

hCG signaling and effects on leiomyomal cells. In human myometrial smooth muscle and leiomyomas cells, hCG: (I) activates the cAMP/PKA signaling pathway causing changes in the expression of several target genes mediated by related transcription factors such as CREB; (II) promotes cell cycle, increasing expressions of key proteins like PCNA, cyclin E and cdc2; and (III) promotes production of prolactin that, directly and through autocrine/paracrine effect, increases cell proliferation. The signaling pathways regulating cell cycle progression genes in leiomyomal cells have not been clarified yet. hCG: human Chorionic Gonadotropin; LH: luteinizing hormone; LH/hCG rec: LH/hCG receptor; AC: Adenylate cyclase; PKA: protein kinase A; CREB: cAMP Responsive Element Binding Protein; CRE: cAMP Responsive Element; PCNA: Proliferating cell nuclear antigen; CDK1: cyclin-dependent kinase 1; PRL: Prolactin; PRL-R: Prolactin Receptor; the red arrows represent increased expression.

Figure 3

Potential mechanisms of hCG action on leiomyomal cells. hCG: (I) may activate the TGF-β/Smad pathway; (II) may interact with the Vitamin D signaling; and (III) may affect the IGF-I-induced cell proliferation. hCG: human chorionic gonadotropin; Vit D: vitamin D; TGF-β: transforming growth factor-β; IGF-I: insulin growth factor I.