Ovarian steroids, stem cells and uterine leiomyoma: therapeutic implications

Abstract

Background: Uterine leiomyoma is the most common benign tumor in women and is thought to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a cellular insult. Leiomyomas cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are the most common indication for hysterectomy in the USA. A slow rate of cell proliferation, combined with the production of copious amounts of extracellular matrix, accounts for tumor expansion. A common salient feature of leiomyomas is their responsiveness to steroid hormones, thus providing an opportunity for intervention.

Methods: A comprehensive search of PUBMED was conducted to identify peer-reviewed literature published since 1980 pertinent to the roles of steroid hormones and somatic stem cells in leiomyoma, including literature on therapeutics that target steroid hormone action in leiomyoma. Reviewed articles were restricted to English language only. Studies in both animals and humans were reviewed for the manuscript.

Results: Estrogen stimulates the growth of leiomyomas, which are exposed to this hormone not only through ovarian steroidogenesis, but also through local conversion of androgens by aromatase within the tumors themselves. The primary action of estrogen, together with its receptor estrogen receptor α (ERα), is likely mediated via induction of progesterone receptor (PR) expression, thereby allowing leiomyoma responsiveness to progesterone. Progesterone has been shown to stimulate the growth of leiomyoma through a set of key genes that regulate both apoptosis and proliferation. Given these findings, aromatase inhibitors and antiprogestins have been developed for the treatment of leiomyoma, but neither treatment results in complete regression of leiomyoma, and tumors recur after treatment is stopped. Recently, distinct cell populations were discovered in leiomyomas; a small population showed stem-progenitor cell properties, and was found to be essential for ovarian steroid-dependent growth of leiomyomas. Interestingly, these stem-progenitor cells were deficient in ERα and PR and instead relied on the strikingly higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone action via paracrine signaling.

Conclusions: It has been well established that estrogen and progesterone are involved in the proliferation and maintenance of uterine leiomyoma, and the majority of medical treatments currently available for leiomyoma work by inhibiting steroid hormone production or action. A pitfall of these therapeutics is that they decrease leiomyoma size, but do not completely eradicate them, and tumors tend to regrow once treatment is stopped. The recent discovery of stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma has the potential to provide the missing link between developing therapeutics that temper leiomyoma growth and those that eradicate them.

Keywords: aromatase; estrogen; leiomyoma; progesterone; stem cells.

Figure 1

Typical histology of human leiomyoma. Representative slides demonstrating the typical hematoxylin/eosin (H/E) slide and immunohistochemistry stains for estrogen receptor-α (ER-α) and PR in myometrium and leiomyoma; *denotes extracellular matrix (ECM) in the H/E-stained leiomyoma section. Note the expanded ECM leiomyoma tissue and increased nuclear size in leiomyoma smooth muscle cells. Immunoreactive ER and PR (brown stain) are localized to the nuclei of myometrial or leiomyoma smooth muscle cells. Images courtesy of Dr Jian-Jun Wei, Department of Pathology, Northwestern Memorial Hospital, Chicago, IL, USA. Scale bar represents 50 μm.

Figure 2

Role of estrogen in leiomyoma pathogenesis. Although leiomyomas are exposed to circulating estrogens from the ovary, it appears that substantial amounts of estrogen are also produced in situ via aromatization of androgens from the adrenal gland and ovary. The biologically active estrogen, estradiol, acts primarily through ERα to induce transcription of genes involved in proliferation and ECM formation, but its principal function is up-regulation of PR expression, thereby increasing leiomyoma responsiveness to progesterone. Aromatase inhibitors effectively block the in situ production of estradiol, thus decreasing leiomyoma responsiveness to both estrogen and progesterone signaling.

Figure 3

Role of progesterone in leiomyoma pathogenesis. Ovarian progesterone acts via PR to regulate transcription of key genes for apoptosis, proliferation and ECM formation. Effective SPRMs act as progesterone antagonists at PR and block transcription of these genes.

Figure 4

Proposed role of stem-progenitor cells in leiomyoma pathogenesis. It has been proposed that a single myometrial stem-progenitor cell goes through tumorigenic transformation following a cellular insult and gives rise to daughter leiomyoma stem-progenitor cells, which proliferate, undergo self-renewal and clonally expand in response to steroid hormones via paracrine signaling from surrounding differentiated myometrial and leiomyoma cells. Pathways involved in the paracrine signaling have not been fully elucidated, but there is recent evidence for a critical role of the WNT/β-catenin pathway. Treatments targeting these paracrine interactions, or the stem-progenitor cells themselves, could not only treat existing leiomyoma, but also possibly prevent the development and growth of new tumors.