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DR. BULUN is Professor Friends of Prentice Distinguished Physician and Chief, Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Chicago, Ill.
DR. ATTAR is a Visiting Scholar in the Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, Ill.
Blocking the activity of aromatase may be the key to controlling the often-intractable pain of endometriosis. Here, pioneers in the use of aromatase inhibitors review use of the drugs in premenopausal and postmenopausal patients.
Endometriosis is very troubling to obstetrician/gynecologists and their patients. For patients, this chronic disease is the number one cause of hysterectomy, and only about half the women with it in the United States can expect to get long-term relief from pain with more conservative measures.1 For ob/gyns, endometriosis is a management challenge because it is at once extremely common and exceedingly hard to manage with available therapies.
Characterized by the presence of endometrium-like tissue in ectopic sites outside the uterus-primarily the pelvic peritoneum and ovaries-endometriosis is linked to chronic pelvic pain, pain during sex, and infertility.2 Existing hormonal treatments and conservative surgery often fail, leading to a clear need for novel and effective approaches. Aromatase inhibitors (AIs) may be that solution. Before we get into a discussion of results with AIs, we need to set the stage with an understanding of aromatase's role in endometriosis.
Aromatase is an enzyme that catalyzes the final and key step of estrogen production in a number of human cells.3,4 Studies by us and other investigators have shown that it is abundant in endometriotic tissue and responsible for local production of estrogen there.5-10 Estrogen biosynthesis can be effectively eliminated by disrupting or inhibiting the one gene-CYP19-that encodes aromatase in humans.3 Estrogen, of course, is essential for development and persistence of endometriosis, and blocking its activity is the foundation for use of GnRH to treat the condition. Results with AIs in endometriosis underscore the role of aromatase in this condition.11,12
Aromatase in action
In humans, aromatase is expressed in the ovary, placenta, testis, brain, and various peripheral tissues, including skin and fat.17 In premenopausal women, it's primarily expressed in the ovarian follicle; FSH induces aromatase, which leads to estradiol production, in a cyclic fashion.17 The ovary's principal product is the potent estrogen, estradiol. Ovarian aromatase expression is primarily mediated by FSH receptors, cAMP production, and activation of its proximal promoter II.17 Aromatase is also expressed in adipose tissue. There, large quantities of estrogenically weak estrone are produced from androstenedione that originates in the adrenals. At least half of this peripherally produced estrone eventually is converted to biologically active estradiol in peripheral tissues.18
To date, [aromatase overexpression has been shown to be critical to four estrogen-responsive human diseases: breast cancer, endometriosis, endometrial cancer, and uterine fibroids.] And in these diseases, AIs have proven useful in therapy.
The endometrium and aromatase expression
Pain and infertility, the primary devastating symptoms of endometriosis, are associated with growth and inflammation in endometriotic tissue. Estrogen, growth factors, and metalloproteinases enhance the growth and invasion of endometriotic tissue, whereas prostaglandins and cytokines mediate pain, inflammation, and infertility.32,33