ASRM2010: Targeting steroidogenesis in endometriosis

Denver, 25 October 2010

Professor Serdar Bulun was honoured this morning as the Herbert H. Thomas lecturer at the 66th Annual Meeting of the ASRM.  His plenary lecture “Targeting Steroidogenesis in Endometriosis” reviewed the importance of ovarian steroid hormones in the growth and maintenance of endometriotic lesions.

Picture of Professor Bullun

Professor Serdar Bulun

Professor Bulun explained how increased cell survival, inflammation, and deficient differentiation in endometriosis have been linked to a stromal-cell defect involving the excessive formation of oestrogen and prostaglandin, as well as progesterone resistance, all of which originate from two distinct epigenetic changes that affect the transcription factors: steroidogenic factor-1 (SF1) and oestrogen receptor beta (ER-beta).

Specific DNA sequences called the CpG islands at the promoters of the genes encoding SF1 and ER-beta are heavily methylated and silence these genes in the endometrium; whereas the lack of DNA methylation results in extraordinarily high levels of SF1 and ER-beta in endometriotic tissue.

In response to the exposure of endometriotic cells to prostaglandin E2, SF1 coordinately binds to the promoters of multiple steroidogenic genes, including that of aromatase, which is a protein in the body that is responsible for producing oestrogen. Normally, aromatase is found in the ovaries, and to a much lesser extent in the skin and fat, but recent research has shown that it is also found in high levels in the ectopic endometriotic tissue of women with endometriosis – which contributes to the growth of their endometriotic lesions.  This causes the formation of large quantities of local oestradiol. Oestradiol acts by way of ER-beta to stimulate COX-2, leading to the overproduction of prostaglandin E2.

Inflammation and oestrogen are therefore linked in a feedback cycle involving the over-expression of genes that encode the aromatase and COX-2 enzymes and the continuous formation of the products of aromatase and COX-2, oestradiol and prostaglandin E2, in endometriotic tissue. Furthermore, oestrogen receptor beta suppresses progesterone-receptor levels, resulting in progesterone resistance and disruption of a paracrine pathway that inactivates oestradiol.  Large amounts of oestradiol will therefore accumulate, owing to its increased formation and deficient inactivation in endometriotic tissue.

This working model is clinically relevant because the targeting of aromatase, COX-2, ER-beta, or progesterone receptors reduces pelvic pain and ablates visible endometriotic tissue.

Professor Bulun was thus tempted to speculate that genetic predisposition or the exposure to environmental toxins of foetal progenitor cells destined to form adult female pelvic organs may result in epigenetic events, including promoter hypomethylation and over-expression of SF1 and ER-beta, that can play critical roles in the pathogenesis of endometriosis.

In summary Professor Bulun provided a rationale for new, specific drug targets, including the aromatase, SF1 or ER-beta, which might be more effective than the general actions seen in the GnRH analogues, oral contraceptives and progestins currently used to treat the symptoms of endometriosis.

He also introduced the concept that retinoic acid, a vitamin-A derivative, which binds to related classes of nuclear retinoid receptors, appears to shift from a suppressive to a growth-promoting pathway in endometriosis cells. The development of new drugs that normalise the retinoic acid pathway may be therapeutic in endometriosis in the future.

Professor Bulun’s work on steroidogenesis in endometriosis is also the subject of a paper published last year in The New England Journal of Medicine (Bulun SE, N Engl J Med 2009;360(3):268-79)

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