Aromatase inhibitors for the treatment of endometriosis

Mary Ellen Pavone, Bulun SE, Serdar E Bulun
Fertility and sterility · 2012 · vol. 98(6) , pp. 1370–1379 · doi:10.1016/j.fertnstert.2012.08.053 · PMID:22999792 · PMC3513666 · W2021118491
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⚙ AI-generated summary by claude@2026-06+body, 2026-06-14 ⓘ

Endometriotic tissues predominantly express aromatase via promoter II, leading to abnormal estradiol production, which may be targeted by aromatase inhibitors for treatment.

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This review examines aromatase biology and the rationale for aromatase inhibitors in estrogen-dependent conditions, focusing on evidence that endometriotic tissues overexpress aromatase via the proximal promoter II (PII) and show impaired progesterone-driven estrogen metabolism due to defective stromal HSD17B2 induction, resulting in high local estradiol. It outlines the generations of aromatase inhibitors (with letrozole/anastrozole/exemestane as potent third-generation agents) and summarizes known side effects and bone-loss mitigation strategies, while noting that in premenopausal women estrogen suppression can trigger increased FSH and requires ovarian downregulation via combination therapy. Across small pilot, case report, retrospective, and open-label trials in reproductive-aged women with various forms of endometriosis, combinations such as letrozole plus norethindrone acetate (or OCPs) often improved pain and symptom scores during treatment, but symptoms frequently recurred after discontinuation; adverse effects were also reported, and long-term outcomes are limited. This paper is centrally about endometriosis — it specifically reviews the molecular basis for aromatase overexpression in endometriotic lesions and summarizes clinical evidence for aromatase inhibitors (often combined with progestins) to treat endometriosis-related pain.

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Abstract

ObjectiveTo review the use of aromatase inhibitors (AIs) for the treatment of endometriosis.DesignLiterature review.Conclusion(s)Most studies show that in reproductive-age women, the combination of AI with conventional therapy alleviates endometriosis-related pain. In postmenopausal women, using an AI alone has been shown to be an effective treatment, although more studies are needed in this subgroup. Side effects of using AIs appear to be tolerable in most women, although special consideration should be given to monitoring bone mineral density. More studies need to be done examining pregnancy rates and outcomes after AI treatment for endometriosis. In addition, larger randomized clinical trials using AIs need to be done. In summary, AIs may be effective in treating endometriosis-related chronic pelvic pain in both reproductive-age and postmenopausal women.
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Side

Most side effects associated with the use of third generation AI (e.g. letrozole, anastrazole) are relatively benign, with mild headache, joint stiffness or pain, nausea, and diarrhea as the most common. When compared to GnRH analogues, hot flashes are milder and more infrequent ( 33 , 35 ). Long-term use may place women at increased risk for developing bone fractures, osteopenia, and osteoporosis. Most of these long-term studies have been done in women using an AI as adjuvant therapy for hormone-receptor positive breast cancer. Fracture rates in patients treated with AI have ranged from 2.5% in one study to 11% in the ATAC (Anastrazole or Tamoxifen Alone or in Combination) study ( 35 , 36 ). A number of studies have shown that AI-induced bone loss can be averted or improved by the concomitant use of bisphosphonates ( 37 – 41 ). Because bisphosphonates are not recommended in premenopausal women, studies have also been done looking at add back with progestins and oral contraceptive pills. These studies, which combine AI with either norethindrone acetate (in addition to calcium and vitamin D) or oral contraceptive pills, have shown no significant changes in bone mineral density (BMD) during their use ( 20 , 42 ). However, a trial using the combination of the GnRH agonist goserelin plus the AI anastrazole showed significant bone loss after six months of treatment ( 43 ). It was noted that the observed BMD loss was significantly greater in the goserelin plus anastrazole arm as compared to the goserelin-alone arm and that this effect persisted even after cessation of treatment. However, none of these patients became osteopenic or osteoporotic. Other side effects include hot flushes and hot flashes, headache, back pain, leg cramps, and arthralgia. Most of these side effects occur with prolonged use ( 33 ).

Summary

Aromatase inhibitors may be effective in alleviating endometriosis-related chronic pelvic pain (Table 4). Treating chronic pelvic pain caused by endometriosis is often challenging for patients and physicians. Both the growth and survival of endometriotic tissue relies on estrogens. Conventional treatment strategies for endometriosis target ovarian E 2 production but have little effect on estrogens produced from other sources. AIs target extraovarian E 2 production but in doing so stimulate ovarian E 2 production by causing an increase in FSH. Therefore, combining AI with conventional therapies should effectively block both ovarian and extraovarian E 2 production and be effective in treating endometriosis. The studies reviewed have demonstrated that in reproductive-aged women, the combination of an AI with conventional therapy does alleviate endometriosis related pain. In postmenopausal women, using an AI alone has been shown to be an effective treatment, although more studies are needed in this subgroup. Side effects using AIs appear to be tolerable in most women, although special consideration should be given to monitoring BMD. More studies need to be done examining pregnancy rates and outcomes following aromatase inhibitor treatment for endometriosis. In addition, larger multi-center randomized trials using aromatase inhibitors for the treatment of endometriosis related chronic pelvic pain need to be done. In summary, aromatase inhibitors may be effective in treating endometriosis related chronic pelvic pain in both reproductive-aged and postmenopausal women.

Abnormal

Aromatase is expressed in certain human cells including the ovarian granulosa cell, the placental syncytiotrophoblst, the testicular Leydig cell, and other extraglandular sites such as adipose tissue, the brain, and skin fibroblasts ( 15 , 17 ). The highest levels of aromatase are in the ovarian granulosa cells in premenopausal women, whereas adipose tissue becomes a major site of aromatase expression in post-menopausal women ( 24 , 25 ). The principal product of ovarian granulosa cells during the follicular phase of the menstrual cycle is estradiol. In adipose tissue a weaker estrogen, estrone, is produced from androstenedione of adrenal origin in relatively large quantities. At least half of this estrone is eventually converted to estradiol in extra-ovarian tissues ( 26 ). In the ovary, the biologically active estradiol is produced from cholesterol through serial enzymatic actions in two cell types, namely the theca and granulosa cells, which cooperate in a paracrine fashion ( Figure 1 ) ( 1 , 17 ). There are two rate-limiting steps in this process: entry of cholesterol into the mitochondria of theca cells, regulated by steroidogenic acute regulatory (STAR) protein; and conversion of androstenedione to estrone by aromatase in granulosa cells ( Figure 1 ). Thus, targeting this final step in estradiol production using selective inhibitors effectively eliminates estrogen biosynthesis ( 17 ). As previously mentioned, estrogen production via aromatase also occurs in tissues throughout the body. In humans, transcription of the aromatase gene is highly regulated under the control of alternatively used, tissue-specific promoters. There are at least 10 distinct promoters in the aromatase gene regulating its transcription ( Figure 2 ) ( 17 , 27 ). There is a tissue-and-hormone specific activation of promoters via alternative splicing that gives rise to aromatase species with variable first exons but identical coding regions. For example, the adipose tissue uses alternate exon I.3 and I.4 while the brain uses I.f ( 17 , 21 ). Enhancers can react with upstream elements of these alternate exons to stimulate the rate of transcription of the aromatase gene. Therefore, aromatase expression is highly regulated in a very tissue-specific method. Endometriotic tissues, both extraovarian as well as ovarian endometriomas, have been shown to almost exclusively use promoter II (labeled PII in Figure 2 ), which is the proximal promoter responsive to prostaglandin E2 (PGE2) and cyclic adenosine monophosphate to express aromatase. Thus, PII is the likely mediator of abnormal aromatase expression in these endometriotic tissues ( 17 , 21 ). In addition, there are other molecular differences between normal endometrium and endometriotic tissues contributing to abnormal exposure to estrogens. More subtle abnormalities also occur in the endometrium of women with endometriosis. As previously mentioned, both the eutopic endometrium of women with endometriosis as well as ectopic endometriotic lesions have been found to express STAR and aromatase ( 1 ). Steroidogenic factor 1 (SF1), a transcription factor that is expressed in endometriotic tissue but absent in endometrium, is integral for the expression of STAR and aromatase. SF1, whose expression depends on the presence of prostaglandin E2 in endometriotic cells, assembles enhancer transcriptional complexes, which then bind to the promoters of STAR and aromatase genes to induce their expression ( 1 , 11 , 28 , 29 ). Additionally, in normal endometrium, progesterone acts on stromal cells to induce secretion of paracrine factors that act on neighboring epithelial cells to induce the expression of the enzyme 17 beta-hydroxysteroid dehydrogenase type 2 (HSD17B2). This enzyme catalyzes the conversion of E 2 to estrone, a less biologically-active estrogen. In endometriotic tissue, progesterone does not induce epithelial HSD17B2 expression due to a defect in stromal cells ( 30 – 32 ). The end result is deficient metabolism of E 2 in endometriosis giving rise to high local concentrations of estradiol. Thus, in endometriotic tissues, there is both an overproduction of estradiol and an aberrant conversion to a less biologically active estrogen. In addition, inflammatory and immune responses, angiogenesis, and apoptosis are all altered to favor survival pathways in endometriotic tissue via various mechanisms that are beyond the scope of this review ( 1 ).

Aromatase

Endometriosis in postmenopausal women is a rare condition. Endometriosis is always estrogen-dependent. In premenopausal women, the ovaries are the main source of estrogen production, while in postmenopausal women estrogens are derived either from extra-ovarian production or from exogenous administration. There have been reports linking hormone replacement therapy with postmenopausal endometriosis ( 33 , 53 , 54 ). However, most estrogen production in postmenopausal women originates from extra-ovarian sources including adipose tissue, skin, and the adrenal gland. Adipose tissue likely accounts for the majority of postmenopausal estrogen production via aromatization of androgens produced from the adrenal gland ( 55 ). Treatment for postmenopausal endometriosis should be surgical because there is a potential for malignancy or malignant transformation ( 56 , 57 ). However, there are recurrences of endometriosis following surgical resection, and some patients may not be candidates for surgery. Therefore, there is a need for medical therapies. Treatments with GnRH analogues, progestins, and danazol have not been as effective for treatment of postmenopausal endometriosis ( 33 ). Because of their ability to block extra-ovarian estrogen production, AIs have been used to treat postmenopausal endometriosis. There have been several case reports published successfully using AIs in postmenopausal women with endometriosis ( 33 , 55 , 58 – 62 ). All patients had undergone either surgical or natural menopause, with several patients having been exposed to hormone replacement therapy. Most women were previously treated for endometriosis with either surgery, GnRH agonists, or progestins. In these case reports, administration of either letrozole or anastrazole for 4–18 months improved endometriosis related pain. Subjective symptoms decreased and quantitative parameters, including endometriotic lesion size (by physical exam findings or imaging techniques), were also reduced. Only one patient reported hot flushes ( 59 ). Co-administration of bisphosphonates was given in two patients ( 55 , 58 ), and one reported letrozole associated bone loss, with a slight reduction of BMD after 9 months of anastrazole treatment ( 55 ). Although data is limited, AIs may be a promising new therapy for the treatment of postmenopausal endometriosis.

Pregnancy

A prospective randomized trial of 144 infertile patients with laparoscopic and histologic diagnosis of endometriosis was published by Alborzi et al. ( 63 ). In this study, patients underwent laparoscopic surgery to diagnose and treat endometriosis. Patients were then randomized to receiving letrozole 2.5mg/day for two months, triptorelin 3.75mg IM every four weeks for two months or no medication for two months. The authors found no statistically significant differences in pregnancy rates between the three groups (23.5% in the letrozole group, 27.5% in the triptorelin group, 28.1% in the no medication group). In addition, there was no significant difference in rates of recurrence for endometriosis, although recurrence was based on patient complaints and sonographic evidence, not laparoscopic evaluation. The rate of functional cyst development was significantly higher in the letrozole treated women ( 63 ). Additional studies investigating pregnancy rates and pregnancy outcomes following treatment for endometriosis using an AI are needed.

Combination

A prospective randomized trial was done by Soysal et al. of 80 women to evaluate the efficacy of using either a combination of anastrazole and goserelin, or goserelin alone for six months, after conservative surgery for severe endometriosis ( 43 ). Patients were randomized to receive a combination of anastrazole 1 mg/day plus subcutaneous depot injections of 3.6mg goserelin every 4 weeks or goserelin plus a placebo tablet for the same amount of time. Patients were treated for 24 weeks and evaluated at 6, 12, 18, and 24 months after the end of medical treatment. The primary outcomes of this trial were the recurrence rate and impact of allocated treatments on Total Pelvic Symptom Score (TPSS) during the follow-up period of 24 months after the end of medical treatment. Other outcome measures examined were the impact of allocated treatment regimens on menopausal quality of life and on lumbar spine bone mineral density ( 43 ). Both treatment protocols proved to be statistically effective in reducing the TPSS during the study period ( 43 ). However, the authors found a statistically significant advantage of goserelin plus anastrazole as compared to goserelin only in terms of median time to detect symptom recurrence. In addition, three cases out of 40 recurred in the goserelin plus anastrazole arm (7.5%), whereas 14 cases of 40 cases recurred in the goserelin only group during the follow up period of 24 months ( 43 ). The authors found that goserelin plus anastrazole did lower E 2 concentrations significantly more than goserelin alone. Menopausal quality of life surveys showed no statistically significant differences, which may indicate that this lower E 2 level did not cause more climacteric symptoms. Goserelin plus anastrazole did show a greater bone loss at the spine at the completion of six months of therapy. However, by 24 months after therapy, no significant difference was noted ( 43 ). Thus, AIs in combination with GnRH analogues have been shown to increase pain-free interval and decrease symptom recurrence rate following surgery in premenopausal women.

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Condition tags

endometriosis

MeSH descriptors

Aromatase Inhibitors Endometriosis Endometriosis Infertility, Female Infertility, Female Ovulation Induction Aromatase Inhibitors Aromatase Inhibitors Endometriosis Female Humans Infertility, Female Ovulation Induction Ovulation Induction

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