Aromatase inhibitors: The next wave in treatment of endometriosis？

Erkut Attar, MD   Serdar E. Bulun, MD      

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

AIs are unique drugs that decrease both peripheral and local estradiol production in endometriosis. They are at least as effective as existing medical treatments for endometriosis in both premenopausal and postmenopausal women.^{12-16 In premenopausal women, we and other investigators are using AIs in combination with ovarian suppression.12,13,16} Recent results suggest that AIs may be better at suppressing local estrogen formation in endometriotic tissue than GnRH, and hence more effective.

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.

Figure 1. Two types of AIs

There are two types of AIs: competitive inhibitors and inactivators of the aromatase enzyme.^19,20 Currently, three highly specific AIs are available in the US. The competitive AIs are anastrozole and letrozole, and the inactivator compound is exemestane (Figure 1). Both classes have been associated with a decline in blood and tissue estrogen to below postmenopausal levels.^21-30 AIs have been primarily investigated in postmenopausal women with breast cancer, but the drugs now are being assessed in premenopausal patients who have undergone ovarian ablation/suppression.³¹

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

A number of molecular abnormalities have been demonstrated in endometriosis.⁹ The most striking is the presence of significant levels of aromatase activity and expression of protein and mRNA in the stromal cell component of endometriosis. In contrast, aromatase expression is either absent or barely detectable in the eutopic endometrium of disease-free women.^7,34-37 [The aromatase activity is mediated by a positive feedback cycle that favors expression of the key gene for estrogen formation, expression of cyclooxygenase-2 (COX-2) that favors prostaglandin formation, and consequent continuous local production of estradiol and PGE₂ in endometriotic tissue (Figure 2).^35-37] The aberrantly expressed transcription factor steroidogenic factor-1 (SF-1) is responsible for PGE₂-cAMP-dependent activation of aromatase in endometriosis.³⁷

The eutopic endometrium of women with endometriosis contains low but significant levels of aromatase mRNA and enzyme activity and represents an intermediate state of this disease. Aromatase expression and enzyme activity appear to be amplified more than 100-fold in endometriotic tissue that resides on pelvic peritoneal surfaces.^34,35 [COX-2 expression, which is important for PGE₂ synthesis, also is markedly increased in both eutopic endometrium and endometriotic tissue of women with endometriosis.^38,39]

Figure 2. Mechanism of local estrogen and prostaglandin biosynthesis in endometriosis

Results with AIs in postmenopausal and premenopausal patients

Aromatase expression and local estrogen biosynthesis in endometriotic implants prompted us and other investigators to use third-generation inhibitors to target aromatase in endometriosis. Anastrozole and letrozole now have been used successfully to treat endometriosis in both postmenopausal and premenopausal women.^11-14,40,41

Postmenopausal patients. We introduced AIs into treatment of endometriosis in 1998 by publishing a case report about a postmenopausal patient.¹¹ The woman had undergone surgical removal of her uterus and both ovaries and therefore was surgically postmenopausal, yet she continued to have a persistent pelvic mass and severe pain.¹¹ An AI effectively eradicated the mass and eliminated her pain.¹¹ This was followed by another case report, which suggested that an AI was the medical treatment of choice for postmenopausal endometriosis, a relatively rare condition.⁴⁰

Figure 3. The effects of AIs in premenopausal women

Premenopausal patients. [In premenopausal endometriosis, some form of ovarian suppression needs to be added to AI;] otherwise, estrogen depletion in the hypothalamus causes increased FSH and LH secretion and ovarian stimulation (Figure 3). Thus, phase II trials in this setting have involved administration of an AI together with a GnRH agonist, a progestin, progesterone, or a combination oral contraceptive (COC).^12,13,16,41 The function of the latter medications is to suppress gonadotropins. All four studies showed a significant benefit for AIs in reducing pelvic pain.

One pilot study without a control group showed laparoscopic evidence of eradication of visible pelvic endometriotic implants and significantly decreased pain.¹² Most notably, [a randomized study (n=80) that combined an AI with a GnRH agonist showed recurrence of pain in only 45% of patients in the GnRH agonist-plus-AI arm versus 90% in the GnRH agonist-only arm within 24 months after treatment completion.¹³] Combining an AI with an oral progestin or a COC gave rise to similar results, and we predict that many patients and physicians will prefer these simpler oral regimens.^12,16,40-42 Table 1 summarizes the published regimens in the treatment of endometriosis.

Side effects. The side-effect profile for AIs is reasonably benign. Some patients have experienced mild headache, nausea, and diarrhea. The hot flashes associated with AIs appear to be milder and less frequent than those produced by GnRH analogs. The regimens that combine AIs with add-back progestins or COC do not appear to be associated with significant bone loss after 6 months of treatment.^{12,16 In a randomized, prospective study, goserelin plus anastrozole caused significantly higher bone loss at the spine than goserelin only after 6 months of treatment. However, at 24-month follow-up, no significant difference between these groups was observed.13}

 Table 1. Clinical studies of AIs for endometriosis

The reports from the clinical trials suggest four things about AIs:

1. They effectively treat endometrosis-induced pelvic pain that is resistant to existing therapies.
[2. An AI is the medical treatment of choice for persistent postmenopausal endometriosis.]
3. In premenopausal women with endometriosis, AIs must be given with a GnRH analog, progestin, or COC for ovarian suppression.
4. The side effect profiles of AIs are quite favorable, and for most regimens, do not include bone loss.

Thus, AIs represent one of the most promising new treatments for pain associated with endometriosis.

Conclusion

AI-based treatment of endometriosis represents the most promising novel option among the available drugs on the market. The drugs effectively treat pelvic pain that is resistant to existing therapies. In premenopausal women, current AI regimens require ovarian suppression with a GnRH analog, progestin, or COC. We predict that ob/gyns will be more likely to combine an AI with a progestin or OC than with a GnRH analog because the latter is more complicated, expensive, has more side effects, and cannot be given for as long. The side effect profiles of oral regimens are quite favorable and do not include bone loss.

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