Hormonal regulation of sex steroid receptors and growth related genes in human myometrium and leiomyomas

Abstract

Uterine fibroids, or leiomyomas, are the most common benign tumors in the female genital tract.They represent a major cause of gynaecologic morbidity. The etiology of these tumors is largely unknown but the levels of estrogen (E) and progesterone (P) are considered to be the major determinants for fibroid growth. The aim of the present study was to clarify some aspects regarding the selective growth advantage of fibroids when compared with normal myometrium. Fibroids and/or myometrium were obtained at surgery. One group of women were preoperatively treated with a gonadotropin releasing hormone agonist (GnRHa). The women were carefully characterized concerning hormonal status. The ER and PR were determined with enzyme immunoassay (EIA), the mRNA expression was measured by solution hybridization and the IGF-I concentration in tissue by radioimmunoassay.

The ER and PR protein content was higher in fibroids than in myometrium in all groups, except postmenopausal and pregnant women. The ER content was high in all tissues when the P level was low, whereas low levels of ER were present in tissues obtained in P dominated conditions. The PR content was low in both tissues when serum E was low and a high level of PR was found in the E dominated proliferatory phase.The lowest levels were found in the pregnant group. There is a marked variation in the content of ER and PR, both between fibroids and myometrium and between tissues in different endocrine conditions. E seems to up-regulate PR and to down-regulate its own receptor, while P seems to down-regulate both ER and its own receptor. The exceptionally low levels observed during pregnancy are probably due to down-regulation caused by high hormone levels.

A lower level of c-fos and c-jun was observed in fibroids than in myometrium and the only sign of an influence by hormones was a significant increase in c-jun expression in myometrium from pregnant women. The low expression in fibroids may be part of the benign phenotype of the fibroids, although overexpresssion of protooncogenes in general are considered to be associated with tumorigenesis.

Both IGF-I and its mRNA were higher in fibroids than in myometrium in premenopausal, non treated patients but no differences were seen between the phases. Low levels of mRNA was found in the GnRHa treated and postmenopausal women and the highest levels of both IGF-I mRNA and IGF-I were seen in the pregnant group. IGF-I seems to be involved in sex steroid mediated growth regulation of uterine tissues and contribute to the growth advantage of fibroids. However, the bioavailability of the peptide is strongly regulated by the different binding proteins of which our knowledge is limited. The EG17R mRNA was lower in fibroids than in myometrium in the premenopausal groups but not in postmenopausal and pregnant women. The highest tissue levels were found in pregnant women and the lowest in the postmenopausal group. Despite the hormonal regulation of the EGFR the role of EG17 and its receptor in fibroid growth is presently unclear.

The selective gro wth advantage of fibroids is regulated in a complex way. These tumors maintain a high degree of differentiation and in most conditions they respond to hormonal stimulation in a simailar way as the myometrium. Altered signal transduction pathway(s) in fibroids might alter the cells normal response to hormones, such as E and P.