Estrogens in polycystic liver disease: A target for future therapies?

Abstract

Background and aims: Patients suffering from polycystic liver disease (PLD) can develop large liver volumes, leading to physical and psychological complaints, reducing quality of life. There is an unmet need for new therapies in these patients. Estrogen seems to be a promising target for new therapies. In this review, we summarize the available experimental and epidemiological evidence to unravel the role of estrogens and other female hormones in PLD, to answer clinical questions and identify new targets for therapy.

Methods: We identified all experimental and epidemiologial studies concerning estrogens or other female hormones and PLD, to answer pre-defined clinial questions.

Results: Female sex is the most important risk factor for the presence and severity of disease; estrogen supplementation enhances liver growth and after menopause, liver growth decreases. Experimental studies show the presence of the estrogen receptors alfa and beta on cystic cholangiocytes, and increased in vitro growth after administration of estrogen.

Conclusions: Based on the available evidence, female PLD patients should be discouraged from taking estrogen-containing contraceptives or hormone replacement therapy. Since liver growth rates decline after menopause, treatment decisions should be based on measured liver growth in postmenopausal women. Finally, blockage of estrogen receptors or estrogen production is a promising target for new therapies.

Keywords: ADPKD; GnRH analogues; estrogen; polycystic liver disease; progesterone; tamoxifen.

FIGURE 1

An example of localized polycystic liver disease with several large, dominant cysts (left panel) and diffuse polycystic liver disease with numerous smaller cysts (right panel), both resulting in hepatomegaly

FIGURE 2

Summary of estrogen, progesterone, FSH and GnRH associated growth pathways in polycystic liver disease. A, Pathways that are found in bile duct‐ligated rats and confirmed in human hepatic cyst cells. B, Receptors and associated pathways studied in human hepatic cyst cells only. C, Receptors and pathways studied in bile duct‐ligated rats only. The growth receptors IGF‐1, VEGF and EGFR are present on the cell membrane and induce proliferation. IGF‐1 receptor induces proliferation directly, but is also indirectly involved in estrogen‐induced proliferation. The ER‐α and ER‐β are thought to be a nuclear receptors that have genomic effects, but are also found as epithelial receptor in ADPKD hepatic cysts cells, and induce proliferation via non‐genomic pathways such as the Src‐Shc‐MAPKK‐ERK1/2 pathway and via Ca⁺⁺. Next to the ER‐α and ER‐β receptor, a third estrogen receptor, the G‐coupled Protein Estrogen Receptor 1 (GPER‐1) is present on the cell membrane (work in progress from our own group). The EGFR is possibly activated by activation of the ER‐α and ER‐β as well as by the GPER‐1. The FSH receptor stimulates cell proliferation via cAMP related pathways. In bile duct‐ligated rats, GnRH receptors are found en GnRH induces proliferation. However, it is unclear whether this is a direct effect or most effects are related to enhanced production of other female hormones. Progesterone membrane receptors are present on the cell membrane (PGRMC1 and PGRMC2) and the nucleus (PRA and PRB)

FIGURE 3

Immunohistochemistry images for CK19, ER‐α, ER‐β and GPER in normal liver and ADPLD hepatic cysts from separate patients. CK19 (cytokeratin 19) is a marker for cholangiocytes. In this tissue, we recognize lesions with cuboidal cholangiocytes such as Von Meyenburg complexes (*) and one cyst with flat epithelium (**). In this ADPLD‐patient, all cholangiocytes stained positive for ER‐α, ER‐β and GPER

FIGURE 4

Liver volumes increase before, and decrease after menopause in female patients with large liver volumes suffering from polycystic liver disease. Change in height‐adjusted liver volume in the 32 female ADPKD patients with baseline height‐adjusted liver volume >1700 ml/m, showing that liver volume in most cases increases before, and decreases after menopause. Age of menopause in 95% of polycystic liver disease patients is between 45 and 55 years (the grey shaded area). This figure is adapted by the authors of this review from the figures in Chebib et al (2016) to show more clearly what the effect of menopause may be

FIGURE 5

Schematic overview of different approaches to inhibit estrogen and other female hormones in polycystic liver disease. A, Using a SERD (selective estrogen receptor degrader) the ER‐α and ER‐β are blocked. However, oestrogen could still have effect via the GPER‐1 receptor and other female hormones could also influence cholangiocyte proliferation. B, It is unclear whether a SERM (selective estrogen receptor modulator) would have antagonistic of agonistic effects on ER‐α and ER‐β on human cholangiocytes. A SERM would have no effect on the GPER‐1 receptor or receptors for other female hormones. C, A GnRH analogue blocks the production of the female hormones estrogen, progesterone, LH and FHS. Therefore, the receptors for female hormones will not be activated

FIGURE 6

Schematic overview of the effect of GnRH analogues on the production of female hormones. On the left, the normal situation in premenopausal women is shown. The hypothalamus produces GnRH, which stimulates the pituitary to produce LH and FSH. These hormones stimulate the ovaries to produce estrogen and progesterone. A GnRH analogue stimulates the pituitary so heavily, that desensitization occurs, a no more LH and FSH is produced. Therefore, the ovaries will not produce estrogen and progesterone anymore