Sage Journals: Discover world-class research

Abstract

Endometriosis is an estrogen-dependent disease and estrogen-related pathways are imbalanced in women with endometriosis. One of the key enzymes in estrogen synthesis is aromatase. Inhibiting this pathway at several points is a promising idea for the treatment of endometriosis. The third generation of aromatase inhibitors is becoming more potent in efficacy, with fewer side effects than previous generations, but cotreatment with other hormones is needed to inhibit ovarian stimulation. Other components that promote estrogen synthesis such as COX-2 can also be potentially targeted. Selective estrogen-receptor modulators could also be interesting in view of their tissue-specific effect. However, all these new drugs are still in an early phase of development. At present, it is too early to conclude that aromatase inhibitors, COX-2 inhibitors or selective estrogen-receptor modulators really present any added value compared with the existing drugs that can be used to achieve hormonal suppression in the medical treatment of endometriosis.

Keywords

aromatase inhibitor COX-2 inhibitor estrogen production endometriosis SERM

Endometrium is a tissue with continuous regeneration according to the menstrual cycle. The function of this tissue is to provide the appropriate environment for the implanting blastocyst after decidual transformation. In this regard, there is cell–cell communication, rapid proliferation, invasion and response to hormonal regulation in the endometrium. Estrogen is a key component of these very complex and diverging processes. Estrogens initiate the growth and structural development of functional endometrial tissue, including formation of the stromal and glandular cell network, and angiogenesis. Estrogens activate genes with an estrogen response element (ERE) in the regulatory site of their promoter. In this review, we analyze new treatment strategies for endometriosis utilizing the estrogen-pathway inhibition concept at different intervention points.

Estrogen pathway

Estrogen production in normal pathways

The main sources for estrogen are ovarian granulosa cells in the ovarian follicles from women during their reproductive age. Around menopause, the adipose tissue partly takes over the estrogen production from the ovary. The individual estrogen production of a single adipose cell is small, but the accumulated amount is stored in the tissue to maintain a permanent estrogen level in the peripheral circulation.

The biochemical and genetic background of estrogen synthesis in association with endometriosis has been reviewed recently [1,2] and is shown in Figure 1. Understanding regular estrogen production is important to distinguish it from its pathogenic form in endometriosis and to recognize possible intervention points. Briefly, in the ovary, the first step of estrogen synthesis is the entry of cholesterol from the cytosol into the mitochondrion, regulated by the steroidogenic acute regulatory protein (StAR) [3]. In the mitochondrion, cholesterol is converted to androstenedione, which is catalyzed either to progesterone or to the biologically active estrogen, estradiol, by six enzymes. In a key step, androstenedione is converted to estrone. The catalytic enzyme for this step is aromatase (P450arom/gene CYP19A1), a member of the cytochrome family, located in the smooth endoplasmic reticulum. Estrone itself has only a low estrogenic capacity. It is then further converted by a hydroxysteroid dehydrogenase enzyme (17β-HSD type 1) to physiologically potent estradiol. Subsequently, estrogen is secreted into the peripheral circulation and is ready to act on its target tissues, such as the endometrial tissue. Inside the cell, estrogen binds to its receptor in the cytoplasm and is transported into the nucleus to activate endometrium-related genes. This activation results in estrogen-dependent cell growth. Estrogen excess is eliminated by 17β-HSD type 2, an enzyme that neutralizes estrogen by converting it back into estrone.

Figure 1.

Regulation of the estrogen pathway in the ovary and in endometriotic lesions.

While the ovaries produce estrogen directly from cholesterol, adipose tissue produces – by the use of aromatase – estrone from the circulating androstenedione, which is then further converted to estrogen in other extraovarian tissues.

The key enzyme of the estrogen-synthesis pathway after cholesterol has entered the mitochondrion is aromatase cytochrome P450 (CYP). The presence of CYP mRNA or protein is a good indicator of estrogen production. The genetic background and regulation of the aromatase gene (CYP19A1) is well known [2,4,5]. The promoter region of the aromatase gene is reasonably complex. Several tissue-specific promoters (n = 10) regulate the expression of this gene, resulting in different hnRNA, which, with alternative splicing, then matures into the same mRNA form. The main consequence of distinct tissue-specific promoters is the different strength in transcription activation and different activation signals to which they can respond. In the ovary, promoter II acts as a regulator sequence that is inducible by prostaglandin E2 (PGE-2). The activation takes place via cAMP, activating the steroidogenic factor 1 (SF1), which, in cooperation with other coactivators (e.g., CCAAT-enhancer-binding protein [C/EBP]α and cAMP-response-element-binding protein [CREB]), induces aromatase expression. By contrast, in adipose tissue, promoter I.4 is in charge for the aromatase regulation. The promoter I.4 is coregulated by glucocorticoids and cytokines from the class I cytokine family (e.g., IL-6, IL-11, leukemia inhibitory factor, oncostatin-M and TNF-α).

Normal endometrium & estrogen

During estrogen stimulation, the endometrium undergoes proliferation. Endometrium contains estrogen receptors, the catalytic enzyme to reduce estrone to estrogen (17β-HSD-1) and another hydroxysteroid dehydrogenase enzyme (17β-HSD-2) that controls estrogen levels by converting it back to estrone. Other gene products with a key function in estrogen synthesis, such as aromatase, are not traceable or are only traceable at a very low level (StAR) in the endometrium from women without endometriosis (Table 1) [2,6 –8]. The other, nonregulational enzymes of the estrogen pathway seem to be present in a housekeeping manner [8]. The high level of regulatory proteins, such as chicken ovalbumin upstream promoter transcription factor (COUP-TF), Wilms tumor-1 (WT-1) and C/EBPβ, keep the estrogen synthesis shut down (Figure 1).

Table 1.

The expression of aromatase and other key enzymes related to estrogen synthesis in endometriosis tissue and in endometrium from women with and without endometriosis.

Tissue	Presence of endometriosis	StAR	CYP expression	17β-HSD-1	17β-HSD-2
Eutopic endometrium	No	Present: very low level [8]*,††	Undetectable [11]*	Present [23]*	Present [109]*
	Undetectable [107]*,†		Present [23]†
		Undetectable [22]*	Undetectable [16]†
			Undetectable [13]*,†
			Undetectable [108]*,†
Eutopic endometrium	Yes	Not examined	Present: low level [11]*	Present [23]*	Present [23]†
			Present [110]**		Present [110]*
			Present [13]*,†
			Present [108]*,†
			Undetectable [16]†
Endometriotic lesion		Present [8]*,†	Present [11]*	Present [23]*	Undetectable [23]†
		Present [22]*	Present [16]†		Undetectable[110]*
			Present [110]*
			Present [13]*,†
			Present [111]*
Peritoneum	Yes	Not examined	Undetectable [16]†	Not examined	Not examined
			Undetectable [11]*
Peritoneum	No	Not examined	Undetectable [11]*	Not examined	Not examined
Adipose tissue	No	Not examined	Present [112]*	Undetectable [113]*	Undetectable [113]*
			Present [16]†
Ovary	No	Present [114]	Present [114]	Present [114]	Present [114]

RNA-based method.

†

lmmunochemical-based method.

CYP: Cytochrome P450; HSD: Hydroxysteroid dehydrogenase; StAR: Steroidogenic acute regulatory protein.

At the end of the menstrual cycle, the endometrium begins to become necrotic and the menstrual endometrial tissue is cleared from the body through the vagina, but can also regurgitate into the peritoneal cavity in 70–90% of cases [9]. In healthy women, this regurgitated endometrium is thought to be cleared up by immune scavenger mechanisms, but this has never been substantiated by scientific evidence.

Estrogen & its relationship with endometriosis

Endometriosis is defined as the growth of endometrium outside the uterine cavity or myometrium. This endometriotic tissue is characterized by local estradiol biosynthesis, in contrast with the eutopic endometrium derived from patients without endometriosis.

Estrogen production in endometriotic lesions versus eutopic endometrium from control patients

As discussed earlier, in order to produce estrogen, eutopic endometrium from disease-free women only expresses enzyme (17β-HSD-1) to convert estrone to estradiol estrogen [2,6,7] and express some cascadial enzymes in a housekeeping manner [8]. By contrast, endometriotic lesions are equipped with all the enzymes needed for estrogen synthesis from cholesterol to estrone and the final step to estradiol conversion [2,8,10]. In endometriotic lesions, estrogen is synthesized in stromal cells induced by PGE-2 via the cAMP pathway, such as in the ovary [6,11].

In vitro, PGE-2 or cAMP at a low level are capable of turning on CYP aromatase expression in endometriosis-derived stromal cells, but not in cultured endometrial cells from disease-free women [6,12]. Indeed, aromatase is expressed in endometriotic lesions in vivo, but is undetectable in normal endometrium, peritoneum or decidua (Table 1) [7,10,11,13 –16]. It is also worth noting that aromatase expression appears to be cycle dependent (more pronounced during the secretory phase) in some patients, but not in others [16]. In some endometriotic lesions, up to 39% in one study [16], aromatase expression is undetectable when assessed by immunohistochemical staining and aromatase-enzyme activity. These characteristics might indicate that these aromatase-lacking endometriotic lesions have a different (possibly less active) biological activity.

By analyzing the activating mechanisms that regulate gene transcription, it turns out that at promoter II, several differences can be observed between eutopic endometrium from women without endometriosis and those with endometriotic lesions [15,17 –19]. In the eutopic endometrium of disease-free women, COUP-TF inhibits the expression of P450arom, SF-1 transcription factor is not present (even in stimulated conditions), and other repressors are also present. However, in endometriotic tissue, SF-1 is expressed and over-rules the COUP-TF suppression, which is downregulated in a competitive way [20]. The SF-1 repressor WT-1 also shows a lower level in endometriotic tissue compared with normal endometrium from nondiseased women [15,21]. The main regulatory problem may be even more upstream on the signaling pathway, towards the COUP-TF WT-1 direction and the genes involved in the regulation of estrogen synthesis [14]. Indeed, PGE-2 affects not only the expression of aromatase, but the whole estrogen pathway. Activated genes in endometriotic lesions range from StAR [22], which regulates the cholesterol entry to the mitochondrion, to genes involved in the catalytic pathway. Other coactivators are also elevated, such as C/EBPα, which cooperates with SF-1 to induce aromatase. However, C/EBPβ, known to repress the expression of SF-1, is scarcely present in endometriotic lesions [14].

Not only are estrogen-pathway gene-repression mechanisms abnormal in endometriotic tissue, but endometriotic lesions also lack the 17β-HSD-2-catalyzed reaction that converts estradiol back to its inactive form (estrone) [23]. Furthermore, endometriotic stromal cells are resistant to progesterone because of the under-expression of progesterone receptor-β [15,24,25], and therefore are not sensitive to the PGE-2-stimulated inhibitory effect of progesterone on estrogen synthesis that is observed in the endometrium of women without endometriosis.

Other mechanisms may also support the development of endometriosis. Indeed, via a positive-feedback effect, estrogen can upregulate PGE-2 via the estrogen receptor [26 –28]. PGE-2 can in turn increase estrogen production from a low initial level to a higher level, allowing ectopic endometrial tissue survival, and perhaps the formation of endometriotic lesions. PGE-2 has a positive feedback on its own production by upregulating COX-2 in prostaglandin synthesis. Cytokine IL-1β also affects PGE-2 levels by stabilizing the mRNA structure of the COX-2 gene in endometrial stromal cells. Furthermore, IL-1β not only stabilizes, but also increases COX-2 expression in endometriosis [29,30]. Other cytokines such as IL-6, IL-11 and TNF-α also stimulate the cAMP level and might thereby stimulate aromatase activity in endometriotic tissue [31 –34]. Based on the currently available evidence, it appears that endometriotic lesions are characterized by both an activation of the complete estrogen-synthesis pathway, and an absence of proteins that are able to inactivate estrogen locally.

Some alterations have been discovered in protein expression regarding the estrogen-synthesis pathway in eutopic endometrium from women with endometriosis compared with nondiseased controls. Whereas aromatase expression has been reported to be absent in eutopic endometrium from nondiseased women, expression of aromatase is detectable in eutopic endometrium from women with endometriosis, but at much lower levels than in the endometriotic lesions (see Table 1 for references). Indeed, COX-2, a key enzyme in prostaglandin synthesis, shows elevated levels in eutopic and ectopic endometrium from patients with endometriosis compared with endometrium from controls [29,35 –39]. However, PGE-2 itself is produced in a cyclic manner during the cycle and is not abnormally expressed in endometrium from women with endometriosis compared with controls [40].

Recently, a working hypothesis based on the retrograde menstruation theory [41] has been proposed by Bulun and colleagues [1]. Briefly, aberrant endometrium with a low level of aromatase expression owing to a possible genetic abnormality is shed into the peritoneal cavity at the time of menstruation. These cells cause subclinical pelvic inflammation and then get some boost from cytokines and PGE-2 derived from the normal immunological scavenger cells, which leads to local estrogen production via an exaggerated feedback circle [6]. The lack of estrogen-neutralizing enzyme (17β-HSD-2), gene-suppressor cofactors and progesterone receptor B prevents the elimination of excess estrogen. Consequently, the survival of endometrial cells leading to the development of endometriosis is supported by estrogen-dependent cell proliferation, together with additional supportive mechanisms such as defective immune functions and/or aberrant expression of other genes.

Concept of estrogen inhibition

The relationship between estrogen and endometriosis seem to be pivotal in the development of the disease. Endometriosis has two main symptoms, chronic pain and infertility, which are caused by endometriotic lesions, adhesions and inflammation in the peritoneal cavity. Current medical treatment aims at altering the menstrual cycle by inducing a state of pseudopregnancy pseudo-menopause or chronic anovulation [6] to inhibit ectopic endometrial growth [42].

There are two main ideas to influence estrogen and its effect on endometriosis. One way is to suppress the production of estrogen by inhibiting its synthetic and regulatory pathway. The other way is to influence estrogen receptors to block estrogen-dependent gene expression.

Estrogen synthesis inhibition

The central repression of estrogen production is achieved by using gonadotropin-releasing hormone (GnRH) analogues that block the synthesis in the ovary by downregulating the pituitary–hypothalamic unit. The treatment results in an approximately 50% reduction in symptoms, with a short-term pain reduction, but in the long-term, pain recurrence can be observed in up to 75% of the cases [43]. GnRH analogues also have considerable side effects, including the loss of bone mass [44].

Recurrence of endometriosis can be partially explained by estrogen synthesis in the adipose tissue and by low-level autocrine estrogen production in the endometriotic cells, which, in a positive-feedback loop, could increase the final estrogen level as explained earlier [3]. Since extra-ovarian estrogen production is not under hormonal control, other sites for inhibition should be considered to aim at this estrogen source.

Aromatase inhibitors

Suppression of extra-ovarian estrogen production in endometriotic lesions and fat tissue could mean a potential treatment of endometriosis. Since aromatase, the key enzyme in estrogen synthesis in ovary, adipose tissue or endometriotic tissue, is encoded by one single gene (the P450arom gene), the inhibition of this gene or its production can cause an effective suppression of estrogen production in all sources [45].

The first generation of aromatase inhibitors (aminoglutethimide and testolactone) [46] was used to block estrogen synthesis in postmenopausal women with breast cancer [47]. The blocking effect was not strictly specific: aminoglutethimide inhibited many other enzymes in steroid biosynthesis, resulted in a medical adrenalectomy [48] and led to important side effects such as lethargy, rashes, nausea and fever [49]. Furthermore, the inhibition was not complete [50].

The second generation of aromatase inhibitors, such as formestane, proved to be effective in the treatment of breast cancer in post-menopuasal women and showed a higher specificity for aromatase, with fewer side effects [51]. These second-generation aromatase inhibitors are defined as the type I group and are mainly steroidal inhibitors [52]. They are derivatives of androstenedione, capable of binding to aromatase as a substrate analogue, inhibiting the conversion to estrogen [53].

The third type of aromatase inhibitors (anastrozole, letrozole, exemestane and vorozole) are 1000- to 10,000-times more potent than the original aminoglutethimide [54]. These compounds are more specific for the aromatase enzyme and produce fewer side effects (headache, nausea and diarrhea). Hot flushes are infrequent [55] and the inhibitory effect is longer; therefore, daily administration is not necessary [56]. These third-generation aromatase inhibitors belong to the type II group of nonsteroidal inhibitors. Type II inhibitors act via binding to P450arom. Aromatase is a member of the cytochrome oxidase family, which contains a heme prosthetic group in covalent association with the protein catalytic part to provide the electron exchange for the redox reaction. Type II inhibitors block this reaction by binding to the heme part [57]. As a physiological consequence, both anastrozole and letrozole cause apoptosis in cultured eutopic endometrial cells [58].

Aromatase inhibitors were first developed for breast cancer treatment [59] and have only recently been considered for the treatment of endometriosis [60]. In one case report, administration of anastrozole successfully relieved pain, caused lesion regression, led to a reduction in estradiol levels in the peripheral circulation, and mRNA levels for aromatase became undetectable in the endometriotic lesion [60]. A number of other publications have been published with respect to the treatment of endometriosis with aromatase inhibitors, as presented in Table 2. Although treatment with aromatase inhibitors has shown promising results, a concomitant treatment is needed in premenopausal women, for several reasons (Table 2). During treatment with aromatase inhibitors, substantial levels of estrogen are still present since the dose used is adequate to shut down peripheral but not ovarian estrogen synthesis. Indeed, lower peripheral estrogen levels following inhibition of extra-ovarian estradiol production stimulate, via a negative-feedback system, the pituitary secretion of luteinizing hormone and follicle-stimulating hormone, resulting in ovarian follicular development and ovarian estrogen production [2,61]. In animal models, only a very high dose of aromatase inhibitor results in a complete block of ovarian estrogen production [62]. Aromatase inhibitors alone are also ineffective in premenopausal women with breast cancer [63]. Therefore, combined treatments of aromatase inhibitors with other hormonal medication (GnRH agonists, progestins, oral contraceptives, and so on) suppressing ovarian estrogen production have been evaluated in women with endometriosis, as shown in Table 2. However, most of these studies are case reports or uncontrolled studies. In the only published randomized trial, a combined treatment with GnRH agonist and aromatase inhibitor therapy was compared with a treatment with GnRH agonist (goserelin) alone in premenopausal women with endometriosis. The combined treatment resulted in a better improvement of pain scores (54.7 vs 10%) and a lower recurrence rate (7.5 vs 35%) than treatment with GnRH agonist only. Patients who received combined treatment had a nonsignificant decrease in bone density [64]. In another study, vaginal administration of anastrazole (0.25 mg) was used in ten premenopausal patients with histologically confirmed rectovaginal endometriosis who were resistant to conventional therapy [65]. Cotreatment with daily calcium and cholecalciferol was provided to prevent loss of bone density. However, a regression in lesion size was observed in only 30% of cases and pain scores were unchanged, possibly owing to the inadequate dose of anastrozole [65]. In summary, the therapeutic effect of aromatase inhibitors without hormonal cotreatment is unknown in women with endometriosis. When premenopausal women with endometriosis are treated with aromatase inhibitors, cotreatment with other hormones is needed to inhibit ovarian stimulation. Preliminary evidence suggests that combined treatment with luteinizing-hormone-releasing hormone analogues and aromatase inhibitors may be superior to medical treatment with luteinizing-hormone-releasing hormone analogues only.

Table 2.

List of aromatase therapies in endometriosis treatment.

Agents	Clinical phase	Study type	n	Cotreatment	Effects on endometriosis	Ref.
Anastrozole 1 mg/day		Case report	1	Alendronate 10 mg/day Calcium 1.5 g/day	Regression in lesion	[60]
Anasrozole 1 mg/day	Phase II	Prospective, open-label	15	Ethinyl estradiol 20 μg/day Levonorgestrel 0.1 mg/day	Decreased pain	[115]
Anasrozole 1 mg/day		Case report	2	Rofecoxib 12.5 mg/day Calcitriol 0.5 μg/day Progesterone 200 mg/day	Decreased pain Regression in lesion	[116]
Anastrozole 0.25 mg/day		Case report	10	Calcium 1.2 g/day Cholecalciferol 800 IE/day	Partly regression in lesion	[65]
Anastrozole 1 mg/day		Prospective, randomized, controlled	40	Goserelin 3.6 mg/day Calcium 600 mg Vitamin D 400 IU	Decreased pain	[64]
Letrozole 2.5 mg/day	Phase II	Open-label, nonrandomized, proof-of-concept	10	Progestin 2.5 mg Calcium citrate 1.250 mg Vitamin D (800 IU)	Decreased pain Regression in lesion	[117]
Letrozole 2.5 mg/day		Case report	1	Calcium 1 g/day Vitamin D 400 IU	Decreased pain	[118]

Most of the reports show a statistically insufficient number of participants, as they are preliminary observations. Although treatments are versatile in combinations and dose, they tend to show advantage in pain relief and regression of the lesions, suggesting the value of concept in combinatory therapy.

COX-2 inhibitors

Inhibition of COX-2 synthesis can reduce PGE-2 synthesis and estrogen production, and could support treatment of endometriosis with aromatase inhibitors [30]. NSAIDs, such as aspirin, ibuprofen and diclofenac, have an inhibitory effect on COX-2 and have been used in the treatment of abdominal pain or dysmenorrhea with variable success, which can possibly be explained by their unspecific inhibition of COX-2 [30]. Novel selective inhibitors of COX-2 such as rofecoxib, valdecoxib and celecoxib target intracellular COX-2 and appear to have less gastrointestinal side effects than the NSAIDs [66 –68].

In a rat model with induced endometriosis, celecoxib was effective in the prevention of ectopic implants [33]. In a clinical study, treatment of women with minimal-to-mild endometriosis with rofecoxib resulted in significant pain reduction [69]. Unfortunately, rofecoxib and valdecoxib have been withdrawn from the market owing to severe side effects.

Selective estrogen-receptor modulators

Except for raloxifene, which has a specific binding site on target DNA (raloxifene responsive element) [70], selective estrogen-receptor modulators (SERMs) interact with estrogen receptors and block the hormonal signaling pathway. Although SERMs have been proposed in the treatment of endometriosis [55,71], no clinical study is known to have been performed to evaluate their safety and efficacy in patients with endometriosis so far.

The SERMs are polycyclic aromatic compounds with a different chemical structure compared with estrogen, which are capable of binding to estrogen receptors. The SERMs are double-faced agents, having distinct effects on different tissues. In breast cancer they act as estrogen antagonists, while in the bone and on the vasculature they display their agonist activity [72,73]. All SERMs bind to the estrogen receptor and sterically change its conformation, but each SERM acts in a distinct way [74 –76]. This unique conformation calls forth the feature allowing the receptor to cooperate with different coregulators (e.g., SRC-1, SRC-2 and SRC-3/AIB1), resulting in different biological outcomes [77,78]. The presence or relative abundance of these coregulators and the availability of regulatory sequences are tissue specific and depend on other factors affecting the cell, such as cytokines [79].

Tamoxifen was the first clinically relevant SERM in breast cancer treatment that obtained US FDA approval in 1999, after it had been proven to be efficient in reducing the chances of developing the disease by 50% in high-risk pre-and post-menopausal women [80,81]. Tamoxifen proved to be effective in reducing breast cancer risk on a long-term basis (7 years) by 49% in a randomly selected patient group [82]. In another study, the same agent was found to reduce the risk of invasive breast cancer by 66% in elderly women with osteoporosis during 8 years of follow-up [83], and was also protective against osteoporosis [84]. Tamoxifen is carcinogenic in rats [85,86] and may cause cancer in the submucosal layer of the human uterus [87], but this risk is reduced in women owing to the liver metabolism of tamoxifen [88]. According to a Phase III trial in women with breast cancer, another aromatase inhibitor, letrozole, had fewer side effects (less intense weight gain, dyspnea, thromboembolic events and vaginal bleeding) than tamoxifen [89].

Executive summary

Endometriosis is an estrogen-dependent disease and an endometrial lesion can produce its own estrogen owing to increased expression of aromatase, and lack of repression proteins. However, aromatase expression/activity can be very low or absent in a considerable number of endometriosis lesions.

When premenopausal women with endometriosis are treated with aromatase inhibitors, cotreatment with other hormones is needed to inhibit ovarian stimulation. The therapeutic effect of aromatase inhibitors without hormonal cotreatment is unknown in women with endometriosis.

COX-2 inhibitors can decrease estrogen production in endometriotic lesions, but their clinical effect in women with endometriosis is unknown, and considerable concern exists regarding their side effects.

Selective estrogen-receptor modulators are potent in decreasing pain and regression of endometriosis lesions in animal models, but have not yet been tested in a clinical environment.

At present, it is too early to conclude that aromatase inhibitors, COX-2 inhibitors or selective estrogen-receptor modulators really present any added value compared with the existing drugs that can be used to achieve hormonal suppression in the medical treatment of endometriosis.

Raloxifene (formerly keoxifene) was developed in the early 1980s as a breast cancer drug, but was less effective than tamoxifen and was not developed further. Later, when tamoxifen turned out to be carcinogenic, raloxifene was studied again, since it does not have carcinogenic effects [90]. Women with increased cardiovascular risk treated with raloxifene are reported to have a reduced incidence of cardiovascular events [91]. It is hypothesized that raloxifene may exert this beneficial effect through nitric oxide release [92]. In vitro exposure of endothelial cells to raloxifene can increase mRNA and protein expression of COX genes that are involved in prostaglandin and prostacyclin synthesis, and this activation is not inhibited by blocking estrogen receptors, suggesting the existence of a yet undiscovered estrogen-receptor-independent mechanism [93].

Toremifene is a relatively new SERM with an action and side effects similar to tamoxifen [94], but with less carcinogenic potential. It has been used successfully in the treatment of cyclical mastalgia with a pain reduction of 77% compared with 35% in placebo-treated control patients [95].

The complex action of raloxifen and other SERMs requires a more careful evaluation, especially regarding possible side effects. The development of SERMs is ongoing. Several new compounds are being evaluated in animal studies, including arzoxifene (LY 353,381Â·HCl) [96,97], a long-acting raloxifene analogue that protects against bone loss, reduces serum cholesterol levels in rats [96,98], and may provide better results in the treatment of induced mammary cancer than raloxifene [99]. Another compound, EM-652 [loo], seems to have similar positive properties [101]. The compound GW-5638, a tamoxifen analogue, is a total estrogen-receptor antagonist with minimal uterotropic activity [102], whereas molecule SP500263 is a structurally unrelated new SERM [103] with effects comparable with the previously mentioned drugs in the murine breast cancer xenograft model [104].

The value of SERMs in the treatment of endometriosis has been tested in animal models. In rats, raloxifene was tested in various doses (1, 3 or 10 mg/kg) to assess its effect on the regression of endometriotic lesions. Raloxifene was effective in reducing the size of the implanted endometrium only at a 10 mg/kg dose [105]. In conclusion, SERMs are promising drugs, but require more study in the context of endometriosis. The fact that SERMs have different effects in different tissue types makes them interesting agents for further endometriosis research, for example, blocking estrogen-mediated growth of endometriotic lesions and at the same time supporting bone-mass remediation.

Future perspective

Estrogen-pathway inhibition is not the only promising concept in endometriosis therapy There are many other emerging alternatives for hormonal therapy in women with endometriosis, such as levonorgestrel-releasing intrauterine system or selective progesterone-receptor modulators. Furthermore, there is increasing interest in developing nonhormonal medical treatment for endometriosis [106].

Footnotes

The authors have no relevant financial interests, including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties related to this manuscript.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Bulun

Lin

Imir

: Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol. Rev. 57(3), 359–383 (2005).

Describes a complex hypothesis of how retrograde menstruation could cause endometriosis.

Attar

Bulun

: Aromatase and other steroidogenic genes in endometriosis: translational aspects. Hum. Reprod. Update 12(1), 49–56 (2006).

Broad review of aromatase regulation.

Stocco

Wang

Manna

: Multiple signaling pathways regulating steroidogenesis and StAR expression: more complicated than we thought. Mol. Endocrinol. 19(11), 2647–2659 (2005).

Broad review of positive-feedback loop between estrogen and progesterone in endometriosis.

Bulun

Takayama

Suzuki

Sasano

Yilmaz

Sebastian

: Organization of the human aromatase p450 (CYP19) gene. Semin. Reprod. Med. 22(1), 5–9 (2004).

Bulun

Imir

Utsunomiya

: Aromatase in endometriosis and uterine leiomyomata. J. Steroid Biochem. Mol. Biol. 95(1–5), 57–62 (2005).

10.

Noble

Takayama

Putman

: Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J. Clin. Endocrinol. Metab. 82(2), 600–606 (1997).

11.

Zeitoun

Bulun

: Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil. Stenl. 72(6), 961–969 (1999).

12.

Tsai

Lin

Sun

Chan

: Regulation of steroidogenic acute regulatory protein expression and progesterone production in endometriotic stromal cells. J. Clin. Endocrinol. Metab. 86(12), 5765–5773 (2001).

13.

Halme

Hammond

Hulka

Raj

Talbert

: Retrograde menstruation in healthy women and in patients with endometriosis. Obstet. Gynecol. 64(2), 151–154 (1984).

14.

Bulun

Yang

Fang

: Role of aromatase in endometrial disease. J. Steroid Biochem. Mol. Biol. 79(1–5), 19–25 (2001).

15.

Noble

Simpson

Johns

Bulun

: Aromatase expression in endometriosis. J. Clin. Endocrinol. Metab. 81(1), 174–179 (1996).

16.

Ebert

Bartley

David

Schweppe

: Aromatase inhibitors – theoretical concept and present experiences in the treatment of endometriosis. Zentralbl. Gynakol. 125(7–8), 247–251 (2003).

17.

Kitawaki

Noguchi

Amatsu

: Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol. Reprod. 57(3), 514–519 (1997).

18.

Yang

Fang

Takashi

: Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAT/enhancer binding proteins: decreased C/EBPβ in endometriosis is associated with overexpression of aromatase. J. Clin. Endocrinol. Metab. 87(5), 2336–2345 (2002).

19.

Gurates

Bulun

: Endometriosis: the ultimate hormonal disease. Semin. Reprod. Med. 21(2), 125–134 (2003).

20.

Velasco

Rueda

Aden

: Aromatase expression in endometriotic tissues and cell cultures of patients with endometriosis. Mol. Hum. Reprod. 12(6), 377–381 (2006).

21.

Raises doubts that all endometriotic lesions produce estrogen.

22.

Bulun

Zeitoun

Takayama

Sasano

: Molecular basis for treating endometriosis with aromatase inhibitors. Hum. Reprod. Update 6(5), 413–418 (2000).

23.

Bulun

Zeitoun

Takayama

Simpson

Sasano

: Aromatase as a therapeutic target in endometriosis. Trends Endocrinol. Metab. 11(1), 22–27 (2000).

24.

Bulun

Fang

Imir

: Aromatase and endometriosis. Semin. Reprod. Med. 22(1), 45–50 (2004).

25.

Zeitoun

Takayama

Michael

Bulun

: Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of SF-1 and COUP-TF to the same cis-acting element. Mol. Endocrinol. 13(2), 239–253 (1999).

26.

Gurates

Sebastian

Yang

: WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells. J. Clin. Endocrinol. Metab. 87(9), 4369–4377 (2002).

27.

Sun

Hsiao

Hsu

Tsai

: Transactivation of steroidogenic acute regulatory protein in human endometriotic stromalcells is mediated by the prostaglandin EP2 receptor. Endocrinology 144(9), 3934–3942 (2003).

28.

Zeitoun

Takayama

Sasano

: Deficient 17β-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17β-estradiol. J. Clin. Endocrinol. Metab. 83(12), 4474–4480 (1998).

29.

Attia

Zeitoun

Edwards

Johns

Carr

Bulun

: Progesterone receptor isoform A but not B is expressed in endometriosis. J. Clin. Endocrinol. Metab. 85(88), 2897–2902 (2000).

30.

Leyendecker

Herbertz

Kunz

Mall

: Endometriosis results from the dislocation of basal endometrium. Hum. Reprod. 17(10), 2725–2736 (2002).

31.

Miller

Kurtzman

Anderson

: Interleukin-1 family expression in human breast cancer: interleukin-1 receptor antagonist. Cancer Invest. 18(4), 293–302 (2000).

32.

Frasor

Danes

Komm

Chang

Lyttle

Katzenellenbogen

: Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144(10), 4562–4574 (2003).

33.

Tamura

Deb

Sebastian

Okamura

Bulun

: Estrogen up-regulates cyclooxygenase-2 via estrogen receptor in human uterine microvascular endothelial cells. Fertil. Steril. 81(5), 1351–1356 (2004).

34.

Wang

Lin

Chen

Chang

Tsai

: Distinct regulation of cyclooxygenase-2 by interleukin-1{β} in normal and endometriotic stromal cells. J. Clin. Endocrinol. Metab. 90(1), 286–295 (2004).

35.

Ebert

Bartley

David

: Aromatase inhibitors and cyclo oxygenase-2 (COX-2) inhibitors in endometriosis: new questions – old answers? Eur. J. Obstet. Gynecol. Reprod. Biol. 122(2), 144–150 (2005).

36.

Review of COX-2 inhibition.

37.

Simpson

Mahendroo

Means

: Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr. Rev. 15, 342–355 (1994).

38.

Zhao

Nicole

Bulun

Mendelson

Simpson

: Aromatase P450 gene expression in human adipose tissue. Role of a Jak/STAT pathway in regulation of the adipose-specific promoter. J. Biol. Chem. 270(27), 16449–16457 (1995).

39.

Michael

Kilgore

Morohashi

Simpson

: Ad4BP/SF-1 regulates cyclic AMP-induced transcription from the proximal promoter (PII) of the human aromatase P450 (CYP19) gene in the ovary. J. Biol. Chem. 270(22), 13561–13566 (1995).

40.

Michael

Simpson

: A CRE-like sequence that binds CREB and contributes to cAMP-dependent regulation of the proximal promoter of the human aromatase P450 (CYP19) gene. Mol. Cell. Endocrinol. 134(2), 147–156 (1997).

41.

Jones

Kelly

Critchley

: Chemokine and cyclooxygenase-2 expression in human endometrium coincides with leukocyte accumulation. Hum. Reprod. 12(6), 1300–1306 (1997).

42.

Ota

Igarashi

Sasaki

Tanaka

: Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis. Hum. Reprod. 16(3), 561–566 (2001).

43.

Chishima

Hayakawa

Sugita

: Increased expression of cyclooxygenase-2 in local lesions of endometriosis patients. Am. J. Reprod. Immunol. 48(1), 50–56 (2002).

44.

Fagotti

Ferrandina

Fanfani

: Analysis of cyclooxygenase-2 (COX-2) expression in different sites of endometriosis and correlation with clinico-pathological parameters. Hum. Reprod. 19(2), 393–397 (2004).

45.

Matsuzaki

Canis

Pouly

Wattiez

Okamura

Mage

: Cyclooxygenase-2 expression in deep endometriosis and matched eutopic endometrium. Fertil. Steril. 82(5), 1309–1315 (2004).

46.

Smith

Kelly

: The release of PGF2 α and PGE2 from separated cells of human endometrium and decidua. Prostaglandins Leukot. Essent. Fatty Acids 33, 91–96 (1988).

47.

Sampson

: Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am. J. Obstet. Gynecol. 14, 422–469 (1927).

48.

Melega

Balducci

Bulletti

Galassi

Jasonni

Flamigni

: Tissue factors influencing growth and maintenance of endometriosis. Ann. NY Acad. Sci. 622, 256–265 (1991).

49.

Surrey

Hornstein

: Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstet. Gynecol. 99(5 Pt 1), 709 (2002).

50.

Pierce

Gazvani

Farquharson

: Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up. Fertil. Steril. 74(5), 964–968 (2000).

51.

Simpson

Clyne

Rubin

: Aromatase – a brief overview. Annu. Rev. Physiol. 64, 93–127 (2002).

52.

Overview of aromatase inhibitors.

53.

Thompson

Siiteri

: Utilization of oxygen and reduced nicotinamide adeninedinucleotide phosphate by human placental microsomes during aromatization of androstenedione. J. Biol. Chem. 249(17), 5364–5372 (1974).

54.

Santen

Santner

Davis

Veldhuis

Samojlik

Ruby

: Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma. J. Clin. Endocrinol. Metab. 47(6), 1257–1265 (1978).

55.

Santen

Lipton

Kendall

: Successful medical adrenalectomy using aminoglutethimide: a role of altered drug metabolism. J. Am. Med. Assoc. 230(12), 1661–1665 (1974).

56.

Lipton

Santen

: Proceedings: medical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer. Cancer 33(2), 503–512 (1974).

57.

Harris

Dowsett

Jeffcoate

McKinna

Morgan

Smith

: Endocrine and therapeutic effects of aminoglutethimide in premenopausal patients with breast cancer. J. Clin. Endocrinol. Metab. 55(4), 718–722 (1982).

58.

Goss

Powles

Dowsett

Hutchison

Brodie

Gazet

Coombes

: Treatment of advanced postmenopausal breast cancer with the aromatase inhibitor, 4-hydroxyandrostenedione: Phase II report. Cancer Res. 46(9), 4823–4826 (1986).

59.

Bhatnagar

Hausler

Schieweck

Lang

Bowman

: Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J. Steroid Biochem. Mol. Biol. 37(6), 1021–1027 (1990).

60.

Karaer

Oruc

Koyuncu

: Aromatase inhibitors: possible future applications. Acta. Obstet. Gynecol. Scand. 83(8), 699–706 (2004).

61.

Yue

Mor

Naftolin

: Aromatase inhibitors in breast cancer. In: Endocrine Therapy of Breast Cancer. Robertson

JFR

Nicholson

Hayes

(Eds). Martin Dunitz, London, UK, 75–106 (2002).

62.

Santen

: To block estrogen synthesis or action: that is the question. J. Clin. Endocrinol. Metab. 87(7), 3007–3012 (2002).

63.

Selective estrogen-receptor modulator review in endometriosis.

64.

Santen

: Inhibition of aromatase: insights from recent studies. Steroids 68(7–8), 559–567 (2003).

65.

Brodie

Njar

: Aromatase inhibitors and breast cancer. Semin. Oncol. 23(4 Suppl. 9), 10–20 (1996).

66.

Meresman

Bilotas

Abello

Buquet

Tesone

Sueldo

: Effects of aromatase inhibitors on proliferation and apoptosis in eutopic endometrial cell cultures from patients with endometriosis. Fertil. Steril. 84(2), 459–463 (2005).

67.

Masamura

Adlercreutz

Harvey

: Aromatase inhibitor development for the treatment of breast cancer. Breast Cancer Res. Treat. 33(1), 19–26 (1995).

68.

Takayama

Zeitoun

Gunby

Sasano

Carr

Bulun

: Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil. Steril. 69(4), 709–713 (1998).

69.

Carlson

: Sequencing of endocrine therapies in breast cancer – integration of recent data. Breast Cancer Res. Treat. 75(Suppl. 1), S27–S32 (2002).

70.

Sinha

Kaseta

Santner

Demers

Bremmer

Santen

: Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat. Breast Cancer Res. Treat. 48(1), 45–51 (1998).

71.

Santen

Samojlik

Wells

: Resistance of the ovary to blockade of aromatization with aminoglutethimide. J. Clin. Endocrinol. Metab. 51(3), 473–477 (1980).

72.

Soysal

Ozer

Gul

Gezgin

: The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum. Reprod. 19(1), 160–167 (2004).

73.

Heller

Grimm

van Trotsenburg

Nagele

: Role of the vaginally administered aromatase inhibitor anastrozole in women with rectovaginal endometriosis: a pilot study. Fertil. Steril. 84(4), 1033–1036 (2005).

74.

Howe

Subbaramaiah

Brown

Dannenberg

: Cyclooxygenase-2: a target for prevention and treatment of breast cancer. Endomcr. Relat. Cancer 8(2), 97–114 (2001).

75.

Hayes

Rock

: COX-2 inhibitors and their role in gynecology. Obstet. Gynecol. Surv. 57(11), 768–780 (2002).

76.

Fedele

Berlanda

: Emerging drugs for endometriosis. Expert Opin. Emerg. Drugs 9(1), 167–177 (2004).

77.

Cobellis

Razzi

de Simone

: The treatment with a COX-2 specific inhibitor is effective in the management of pain related to endometriosis. Eur. J. Obstet. Gynecol. Reprod. Biol. 116(1), 100–102 (2004).

78.

Yang

Venugopalan

Hardikar

Glasebrook

: Identification of an estrogen response element activated by metabolites of 17β-estradiol and raloxifene. Science 273(5279), 1222–1225 (1996).

79.

Vignali

Infantino

Matrone

: Endometriosis: novel etiopathogenetic concepts and clinical perspectives. Fertil. Steril. 78(4), 665–678 (2002).

80.

Describes the concept of selective estrogen-receptor modulators in endometriosis.

81.

Barrett-Connor

Cox

Anderson

: The potential of SERMs for reducing the risk of coronary heart disease. Trends Endocrinol. Metab. 10(8), 320–325 (1999).

82.

Cosman

Lindsay

: Selective estrogen receptor modulators clinical spectrum. Endocr. Rev. 20(3), 418–434 (1999).

83.

Brzozowski

Pike

Dauter

: Molecular basis of agonism and antagonism in the estrogen receptor. Nature 389(6652), 753–758 (1997).

84.

Moras

Gronemeyer

: The nuclear receptor lidand-binding domain; structure and function. Curr. Opin. Cell Biol. 10(3), 384–391 (1998).

85.

Liu

Park

Bentrem

: Structure–function relationships of the raloxifene–estrogen receptor-α complex for regulating transforming growth factor-α expression in breast cancer cells. J. Biol. Chem. 277(11), 9189–9198 (2002).

86.

Schiff

Massarweh

Shou

Osborne

: Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin. Cancer Res. 9(1 Pt 2), S447–S454 (2003).

87.

Shao

Brown

: Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy. Breast Cancer Res. 6(1), 39–52 (2004).

88.

Lewis

Jordan

: Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat. Res. 591(1–2), 247–263 (2005).

89.

Fisher

Costantino

Wickerham

: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90(18), 1371–1388 (1998).

90.

Cuzick

Powles

Veronesi

: Overview of the main outcomes in breast-cancer prevention trials. Lancet 361(9354), 296–300 (2003).

91.

Fisher

Constantino

Wickerham

: Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 97(22), 1652–1662 (2005).

92.

Martino

Cauley

Barrett-Connor

; CORE Investigators: Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J. Natl Cancer Inst. 96(23), 1751–1761 (2004).

93.

Love

Mazess

Barden

: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N. Engl. J. Med. 326(13), 852–856 (1992).

94.

White

de Matteis

Davies

: Genotoxic potential of tamoxifen and analogues in female Fischer F344/n rats, DBA/2 and C57BL/6 mice and in human MCL-5 cells. Carcinogenesis 13(12), 2197–2212 (1992).

95.

Phillips

: Understanding the genotoxicity of tamoxifen? Carcinogenesis 22(6), 839–845 (2001).

96.

Cohen

: Tamoxifen and endometrial cancer: tamoxifen effects on the human female genital tract. Semin. Oncol. 24(Suppl. 1), 55–64 (1997).

97.

Comoglio

Gibbs

White

: Effect of tamoxifen feeding on metabolic activation of tamoxifen by the liver of the rhesus monkey: does liver accumulation of inhibitory metabolites protect from tamoxifen-dependent genotoxicity and cancer? Carcinogenesis 17(8), 1687–1693 (1996).

98.

Mouridsen

Gershanovich

Sun

: Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a Phase III study of the International Letrozole Breast Cancer Group. J. Clin. Oncol. 19(10), 2596–2606 (2001).

99.

Cummings

Eckert

Krueger

: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple outcomes of raloxifene evaluation. J. Am. Med. Assoc. 281(23), 2189–2197 (1999).

100.

Barrett-Connor

Grady

Sashegyi

; MORE Investigators (Multiple Outcomes of Raloxifene Evaluation): Raloxifene and cardiovascular events in osteoporotic postmenopausal women four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 287(7), 847–857 (2002).

101.

Simoncini

Genazzani

: Raloxifene acutely stimulates nitric oxide release from human endothelial cells via an activation of endothelial nitric oxide synthase. J. Clin. Endocrinol. Metab. 85(8), 2966–2969 (2000).

102.

Oviedo

Hermenegildo

Tarín

Cano

: Raloxifene promotes prostacyclin release in human endothelial cells through a mechanism that involves cyclooxygenase-1 and-2. Fertil. Steril. 83(6), 1822–1829 (2005).

103.

Howell

Johnston

Howell

: The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer. Best Pract. Res. Clin. Endocrinol. Metab. 18(1), 47–66 (2004).

104.

Gong

Song

Jia

: A double-blind randomized controlled trial of toremifen therapy for mastalgia. Arch. Surg. 14(1), 43–47 (2006).

105.

Sato

Turner

Wang

Adrian

Rowley

Bryant

: LY353381.HCl: a novel raloxifene analog with improved SERM potency and efficacy in vivo. J. Pharmacol. Exp. Ther. 287(1), 1–10 (1998).

106.

Munster

Buzdar

Dhingra

: Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer. J. Clin. Oncol. 19(7), 2002–2011 (2001).

107.

Bryant

Zeng

: Long-term dosing of arzoxifene lowers cholesterol, reduces bone turnover, and preserves bone quality in ovariectomized rats. J. Bone Miner. Res. 17(12), 2256–2261 (2002).

108.

Glatt

Davis

Meinl

Hermersdorfer

Venitt

Phillips

: Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis 19(10), 1709–1713 (1998).

109.

Gutman

Couillard

Roy

Labrie

Candas

Labrie

: Comparison of the effects of EM-652 (SCH57068), tamoxifen, toremifene, droloxifene, idoxifene, GW-5638 and raloxifene on the growth of human ZR-75–1 breast tumors in nude mice. Int. J. Cancer 99(2), 273–281 (2002).

110.

Martel

Picard

Richard

Belanger

Labrie

: Prevention of bone loss by EM-800 and raloxifene in the ovariectomized rat. J. Steroid Biochem. Mol. Biol. 74(1–2), 45–53 (2000).

111.

Willson

Henke

Momtahen

: 3-[4-(l,2-diphenylbut-1-enyl)phenyl]acrylic acid: a non-steroidal estrogen with functional selectivity for bone over uterus in rats. J. Med. Chem. 37(11), 1550–1559 (1994).

112.

Brady

Doubleday

Gayo-Fung

: Differential response of estrogen receptors α and β to SP500263, a novel potent selective estrogen receptor modulator. Mol. Pharmacol. 61(3), 562–572 (2002).

113.

Brady

Desai

Gayo-Fung

: Effects of SP500263, a novel, potent antiestrogen, on breast cancer cells and in xenograft models. Cancer Res. 63(5), 1439–1446 (2002).

114.

Yao

Shen

Capodanno

: Validation of rat endometriosis model by using raloxifene as a positive control for the evaluation of novel SERM compounds. J. Invest. Surg. 18(4), 177–183 (2005).

115.

Mihalyi

Meuleman

Mwenda

Kyama

D'Hooghe

: Emerging drugs in endometriosis. Expert Opin. Emerg. Drugs 11(3), 503–524 (2006).

116.

Bulun

Simpson

Word

: Expression of the CYP19 gene and its product aromatase cytochrome P450 in human leiomyoma tissues and cells in culture. J. Clin. Endocrinol. Metab. 78, 736–743 (1994).

117.

Kitawaki

Kusuki

Koshiba

Tsukamoto

Fushiki

Honjo

: Detection of aromatase cytochrome P-450 in endometrial biopsy specimens as a diagnostic test for endometriosis. Fertil. Steril. 72(6), 1100–1106 (1999).

118.

Casey

MacDonald

Andersson

: 17β-hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium. J. Clin. Invest. 94, 2135–2141 (1994).

119.

Matsuzaki

Canis

Pouly

Dechelotte

Mage

: Analysis of aromatase and 17β-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression in deep endometriosis and eutopic endometrium using laser capture microdissection. Fertil. Steril. 85(2), 308–313 (2006).

120.

Heilier

Donnez

van Kerckhove

Lison

Donnez

: Expression of aromatase (P450 aromatase/CYP19) in peritoneal and ovarian endometriotic tissues and deep endometriotic (adenomyotic) nodules of the rectovaginal septum. Fertil. Steril. 85(5), 1516–1518 (2006).

121.

Bulun

Simpson

: Competitive reverse transcription-polymerase chain reaction analysis indicates levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J. Clin. Endocrinol. Metab. 78(2), 428–432 (1994).

122.

Quinkler

Sinha

Tomlinson

Bujalska

Stewart

Arlt

: Androgen generation in adipose tissue in women with simple obesity – a site-specific role for 17β-hydroxysteroid dehydrogenase type 5. J. Endocrinol. 183(2), 331–342 (2004).

123.

Sasano

Okamoto

Mason

: Immunolocalization of aromatase, 17α-hydroxylase and side-chain-cleavage P-450 in the human ovary. J. Reprod. Fertil. 85, 163–169 (1989).

124.

Amsterdam

Gentry

Jobanputra

Wolf

Rubin

Bulun

: Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil. Steril. 84(2), 300–304 (2005).

125.

Shippen

West

Jr : Successful treatment of severe endometriosis in two premenopausal women with an aromatase inhibitor. Fertil. Steril. 81(5), 1395–1398 (2004).

126.

Ailawadi

Jobanputra

Kataria

Gurates

Bulun

: Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil. Steril. 81(2), 290–296 (2004).

127.

Razzi

Fava

Sartini

de Simone

Cobellis

Petraglia

: Treatment of severe recurrent endometriosis with an aromatase inhibitor in a young ovariectomised woman. BJOG 111(2), 182–184 (2004).

Selective Estrogen-Receptor Modulators and Aromatase Inhibitors: Promising New Medical Therapies for Endometriosis?

Abstract

Keywords

Estrogen pathway

Estrogen production in normal pathways

Normal endometrium & estrogen

Estrogen & its relationship with endometriosis

Estrogen production in endometriotic lesions versus eutopic endometrium from control patients

Concept of estrogen inhibition

Estrogen synthesis inhibition

Aromatase inhibitors

COX-2 inhibitors

Selective estrogen-receptor modulators

Future perspective

Footnotes

References