Selective Estrogen Receptor Modulators. Antonio Cano

Chapter 12. Benign Gynecological Diseases and SERMs

• Stefano Palomba

• Fulvio Zullo



The most common benign gynecological diseases, for prevalence and related economic costs, are probably uterine leiomyomas and endometriosis (Stewart 2001; Missmer et al. 2003). Notwithstanding the fact that both conditions are characterized by a sex-hormone-related development and by the possibility of a medical treatment consisting of hormonal manipulation, at present the main approach to these conditions is surgical excision (Palomba et al. 2006a; Olive et al. 2001).

The present chapter describes current knowledge regarding the effects of selective estrogen receptor modulators (SERMs) on these two gynecological conditions.

First we shall describe the effects of tamoxifen, a first-generation SERM used as adjuvant treatment in women with breast cancer, on uterine leiomyomas and endometriosis. Considerable space will be devoted to raloxifene, a second-generation SERM administered for the prevention and treatment of postmenopausal women recently tested for the treatment of these two sex- hormone-related diseases. Unfortunately, at present no or very little data are available on the new third-generation SERMs such as lasofoxifene, idroxifene, droloxifene, ospemifene, azomifene, fulvestrant, and MDL 103.323.


Uterine Leiomyomas

Uterine leiomyomas are the most frequent benign disease of the female reproductive apparatus. At least 20-25% of women of fertile age and 50% of women studied in postmortem have uterine leiomyomas (Stewart 2001; Palomba et al. 2005a). In between 20 and 50% of cases, the uterine leiomyomas cause a clinically relevant symptomatology (such as menorrhagia, infertility, recurrent abortion, pelvic pain, and so on) and treatment is required (Stewart 2001; Palomba et al. 2006a). Thus, this disease is one of the main causes of health expense in the field of gynecology (Stewart 2001; Palomba et al. 2006a). In fact, symptomatic uterine leiomyomatosis is the surgical indication for about 2/3 of hysterectomies, and these data are all the more relevant considering the fact that hysterectomy is the most frequent intervention of major surgery (Stewart 2001; Palomba et al. 2006a).

Despite the fact that the pathogenesis of uterine leiomyomas is still poorly defined, it has been demonstrated that uterine leiomyomas are estrogen- dependent monoclonal tumors (Chegini et al. 1996; Englund et al. 1998; Hi- gashijima et al. 1996). The primum movens is probably a genetic mutation and thus an alteration of the intratumoral estrogenic metabolism (Pasqualini et al. 1990; Yamamoto et al. 1984; Bulun et al. 1994; Benassayag et al. 1999). The transcription and expressivity of the estrogen receptor (ER), in fact, is increased in myoma tissue when compared to healthy myometrium (Yamamoto et al. 1984; Bulun et al. 1994). A specific distribution of ER subtypes has been demonstrated (Benassayag et al. 1999). The simple action of estrogens does not seem, moreover, to be the only pathogenic cause. Progesterone could play a pivotal role in the transformation of the normal myometrial cell to a myomatous cell (Rein et al. 1995; Tiltman 1985). High progesterone levels, such as those detected in the luteal phase of the menstrual cycle or in the administration of medroxyprogesterone acetate, are related to an increase in mitotic activity of the myoma cells (Kawaguchi et al. 1989; Rein 2000). Finally, in myomatous tissue, as in ERs, there is an overexpression of the progesterone receptor (Englund et al. 1998).


Treatments of Uterine Leiomyomas

To date, the standard treatment for uterine leiomyomas is their laparo- tomic/laparoscopic excision in women who want to preserve their fertility, whereas the use of a more extensive surgery, such as the hysterectomy, is reserved for disseminating uterine leiomyomatosis, generally in the peri- menopausal period (Stewart 2001; Palomba et al. 2006a).

Moreover, given the pathogenesis of uterine leiomyomas (see below), it is clear that future treatments of fibroids will be essentially medical and consist of hormonal therapies. In recent years, in fact, several medical therapies have been proposed for the treatment of this benign disease (Table 12.1). In clinical practice it is very common to administer oral contraceptives in patients affected by uterine leiomyomas. Even if few data are available regarding the effects of estroprogestin associations on uterine leiomyomas (Friedman et al. 1995; Marshall et al. 1998), in clinical practice is very common to administer oral contraceptives in patients affected by uterine leiomyomas. They should be administered to regularize menstrual bleeding so as to decrease the duration of bleedings and the severity of menorrhagia (Friedman et al. 1995). Moreover, some studies have also determined that oral contraceptives can cause tumoral growth (Barbieri 1997; Marshall et al. 1998). The use of mifepristone (RU486), a drug with a weak antiprogestin action, at a dosage of 10 mg/d, induces the reduction of progesterone receptors and leiomyoma dimensions (Murphy et al. 1993; Kertel et al. 1994). Also, the use of gestrinone at doses of 2.5 or 5 mg two to three times a week has been proposed as treatment for uterine leiomyomas (Coutinho et al. 1989; Coutinho 1989, 1990). Danazol is also effective for treating patients with uterine leiomyomas (De Leo et al. 1999). In particular, it has been demonstrated that 400 mg daily of danazol for 4 months leads to a decrease of about 25% in the size of leiomyomas due to the actions of hypoestrogenism and antiprogestin (De Leo et al. 1999). Moreover, in both therapeutic regimens the treatment has several side effects related to the androgenic action of the drugs such as weight gain, seborrhea, acne, and hirsutism (Palomba et al. 2006a).

Virtually the only medical therapeutic approach that is currently used in clinical practice is the administration of GnRH agonists (GnRH-a) (Palomba et al. 2006a). GnRH-a, a group of drugs with an agonist action on the GnRH receptor, induces, after a rapid and initial synthesis and secretion of gonadotropins (the “flare up” effect), a profound down-regulation of the pituitary followed by postreceptor message blockage of the gonadotropin synthesis and secretion with inhibition of follicular development, anovulation, and a reversible hypogonadotropic hypogonadism state (Palomba et al. 2005a). GnRH-a induce a significant reduction in the size of leiomyomas within only 8-10 weeks, achieving the highest reduction after the 14th week of treatment. After this period, the volume reduction achieves a steady state. Even if some evidences seem to show a direct action of the GnRH-a on leiomyoma tissue (Palomba et al. 2005a), after treatment withdrawal, estrogen levels will return to their normal range within about 1 month and the leiomyomas will resume their pretreatment sizes within about 3 months (Palomba et al. 2005a). The disease will again be symptomatic in relation to the regrowth of the leiomyomas.

Table 12.1. Medical therapies for uterine leiomyomas (Palomba et al. 2000a)

The hypoestrogenism induced by GnRH-a causes several climacteric-like symptoms such as hot flashes, vaginal dryness, reduction in libido, metabolic alterations, cognitive deficit, and, above all, bone loss, which varies from 0.8% to 7% after 12 months of GnRH-a administration (Palomba et al. 2005a). Notwithstanding the metabolic alterations, which have been studied recently in women treated with GnRH-a (Palomba et al. 2004b), at present there is no clear evidence regarding the cardiovascular risk related to GnRH-a treatment (Palomba et al. 2005a).

For GnRH-a administration beyond 6 months, it has been postulated that the addition of low doses of steroids (“add-back therapy”) may avoid the adverse effects of prolonged hypoestrogenism without reducing the efficacy of the analog alone (Pickersgill 1998; Palomba et al. 1998; Palomba et al. 1999). Furthermore, with respect to the high costs of treatment, the use of GnRH- a plus add-back therapy has little clinical impact (Palomba et al. 2005a).

Finally, new hypotheses of treatment were recently published (Minakuchi et al. 1999; De Leo et al. 2001; Palomba et al. 2002b; Shozu et al. 2003; Gainer et al. 2005; Spitz 2003). At present, only SERMs, i.e., raloxifene, seem to hold any real promise in terms of future development.


SERMs and Uterine Leiomyomas


Tamoxifen, a first-generation SERM, is a nonsteroidal triphenylethylene derivate routinely used in clinical practice for the treatment and prevention of breast cancer in high-risk populations (Robertson 2004). This drug produces an estrogen antagonist effect on the breast and an estrogen agonist effect on the reproductive organs, e.g., uterus, ovary, and endometrium (Robertson 2004).

The first data on the effects of tamoxifen on uterine leiomyomas were obtained in a rat model. They showed that tamoxifen increased tumor latency and decreased tumor size (Howe et al. 1995). These findings were confirmed more recently by Walker et al. (2000). In the same period, moreover, several case reports were published showing an increase in uterine leiomyoma dimensions following tamoxifen administration (Dilts et al. 1992; Leo et al. 1994; Ugwumadu et al. 1994).

The scientific data on the effects of tamoxifen on uterine leiomyomas are generally extrapolated from safety data on the use of tamoxifen in women with breast cancer, and for this reason the studies available are essentially clinical studies on human models.

In premenopausal women with uterine leiomyomas, Lumsden et al. (1989a) showed that 20 mg/d tamoxifen prolongs the luteal phase, increasing the secretion of gonadotropins by antagonizing the effects of estradiol at the central level, but it has no effect on the dimensions of uterine tumors. On the contrary, when tamoxifen was administered in women treated with GnRH-a, despite the profound pituitary-ovarian suppression, no significant changes in uterine and leiomyoma volume were observed during combined therapy, suggesting that tamoxifen acts as an estrogen agonist in hypoestrogenic women (Lumsden et al. 1989b).

The effects of tamoxifen on uterine leiomyomas have been studied also in postmenopausal patients with breast cancer (Schwartz et al. 1998). After an average treatment of about 1 year, uterine and leiomyoma volumes increased significantly, confirming an agonistic effect of tamoxifen on the uterus. No significant difference in agonist effect on the uterus has been detected between tamoxifen and toremifene (Tomas et al. 1995).

Notwithstanding these somewhat discouraging data, a clinical trial has been designed to study the efficacy of tamoxifen in women affected by uterine fibroids (Sadan et al. 2001). In this, the most recent, study, Sadan et al. demonstrated that 20 mg/d tamoxifen confers no benefit in premenopausal women with symptomatic leiomyomas.


Raloxifene hydrochloride is a synthetic nonsteroidal drug derived from the benzothiophene and afferent to SERMs. It is known that raloxifene acts on metabolism, the skeleton, and the cardiovascular system as an estrogenic agonist (Khovidhunkit et al. 1999; Ettinger et al. 1999; Walsh et al. 1998), whereas it shows an estrogenic antagonist effect on reproductive organs such as the breast and the uterus (Cummings et al. 1999; Goldstein et al. 2000; Cohen et al. 2000). Data on the central nervous system are still unclear (Lacreuse et al. 2002; Yaffe et al. 2001).

Raloxifene is a SERM with desirable mixed agonist/antagonist effects. In fact, unlike tamoxifen, it does not cause uterine stimulation, and it seems to have no effect on the reproductive system.

Preclinical Studies

Black et al. (1994) first reported that raloxifene was effective in terms of bone loss prevention and lipid pattern without any stimulatory effect on the uterus. Specifically, the histological examination of uteri from ovariectomized rats treated with raloxifene alone shows poor effects on myometrial thickness and a uterine weight slightly higher than untreated ovariectomized rats (Black et al. 1994).

Later, Fuchs-Young et al. (1996) demonstrated that raloxifene inhibited proliferation of rat leiomyoma cells in culture. In the same year, in one of the first reviews of the pharmacology of raloxifene, Bryant et al. (1996) showed that raloxifene exerted on animal models a dose-related capacity for blocking estrogen-induced stimulation of uterine weight gain.

More recently, it has been demonstrated that raloxifene induces a fast regression of abdominal-wall estrogen-induced leiomyomas in guinea pigs (Porter et al. 1998). Finally, Walker et al. (2000) have confirmed that treatment with tamoxifen or with a raloxifene analog reduces the size of leiomyomas and their incidence by 40-60% in the rat.

Clinical Studies

The first clinical data on the humans were published by Palomba et al. (2001). Based on previous experimental studies (Black et al. 1994; Fuchs-Young et al. 1996; Bryant et al. 1996; Porter et al. 1998), the effect of raloxifene administration on uterine leiomyomas was tested in postmenopausal women. These data (Palomba et al. 2001) confirmed that raloxifene was effective in reducing leiomyoma dimensions. In particular, after six cycles of raloxifene administration, a significant reduction in mean uterine and uterine leiomyoma size was observed (Fig. 12.1). This reduction was not observed in subjects treated with placebo. During raloxifene administration, a high rate of amenorrhea with a low number of spotting episodes was observed. No significant differences were observed in the length and severity of abnormal uterine bleedings among women treated with raloxifene in comparison with those treated with placebo tablets (Palomba et al. 2001).

A relevant finding of this study was the selective action of raloxifene on leiomyoma tissue highlighted by a significant increase in the difference between uterine and leiomyoma sizes (nonleiomyoma tissue size) (Fig. 12.1) (Palomba et al. 2001). In particular, in postmenopausal women raloxifene seems to induce a significant reduction in leiomyoma size, without any significant action on a normal myometrium. The reduction in uterine size, in fact, is due essentially to a reduction in leiomyoma dimensions. An explanation for these data may be the selective action of raloxifene on leiomyoma tissue. The selective action of raloxifene on leiomyoma tissue, just as on other target tissues, is probably due to the varying distribution of ER subtypes. In fact, as was already specified in previous chapters, at least two ERs exist in humans, encoded by two independent ER genes (Paech et al. 1997; Kuiper et al. 1997). ERα binds estrogens with high affinity and low capacity, while ERβ binds estrogens with low affinity and high capacity (Paech et al. 1997; Kuiper et al. 1997). The estradiol activation of the two different ERs gives two different regulatory signals inducing, respectively, activation and inhibition of transcription (Paech et al. 1997; Kuiper et al. 1997). Furthermore, to date no clear consensus exists about the presence of sex hormone receptors in leiomyomas (Palomba et al. 2005a).

An excellent experimental work (Benassayag et al. 1999) showed an overexpression of the genes regulated by sex hormones in leiomyoma tissue, such as in pregnant compared with nonpregnant myometrium. In leiomyoma tissue, like the pregnant myometrium, higher levels of ERa and ERβ mRNA were detected (Benassayag et al. 1999). Notwithstanding the high level of ERa mRNA present in leiomyoma tissue, high concentrations of ERa for estradiol have not been shown (Benassayag et al. 1999). This result may be explained by the presence of ERa variants lacking estradiol binding sites for posttranscriptional modification or a faulty translation of ERa mRNA. In contrast, the concentrations of ER,β were two- to threefold higher in leiomyoma in comparison with nonpregnant myometrium (Benassayag et al. 1999). The differential expression of these two ER genes could play a pivotal role in the normal or abnormal growth of the myometrium.

To date, experimental data regarding the cellular mechanisms by which raloxifene acts on uterine and leiomyoma tissue are provided by only two papers (Walker et al. 2000; Palomba et al. 2005b). In the first study (Walker et al. 2000) it was shown in a rat model that the effect of raloxifene analog LY 326315 in reducing leiomyoma incidence and size is mediated exclusively by a decrease in cell proliferation without any action on the apoptotic index. In contrast, in the second study (Palomba et al. 2005b) a significant effect of raloxifene on both cell indexes was observed. In particular, a 3-month course of 180 mg/d raloxifene induced a significant decrease in proliferating cell nuclear antigen (PCNA)/total cells (TC) and in Bcl-2/Bax ratios in comparison with placebo showing that raloxifene acts on uterine leiomyomas, reducing cell proliferation and enhancing cell apoptosis (Palomba et al. 2005b). In addition, the raloxifene effect on the apoptotic index seems to be specific to leiomyoma tissue. In fact, no difference in the apoptotic index was observed in the myometrium of subjects treated with raloxifene when compared to control samples (Palomba et al. 2005b).

The discrepancy between these two studies (Walker et al. 2000; Palomba et al. 2005c) are probably due to the different models used. This suggestion is supported by the absence of a correspondence between beneficial effects of tamoxifen on uterine leiomyomas in the rat (Walker et al. 2000) and findings obtained in clinical studies in humans (Leo et al. 1994; Ugwumadu et al. 1994; Lumsden et al. 1989a,b; Schwartz et al. 1998; Tomas et al. 1995; Sadan et al. 2001) . In fact, it has been clearly shown, as detailed earlier, that tamoxifen in women with breast cancer exerts a proliferative estrogenlike effect on uterine leiomyomas (Leo et al. 1994; Ugwumadu et al. 1994; Lumsden et al. 1989a,b; Schwartz et al. 1998; Tomas et al. 1995; Sadan et al. 2001).

Raloxifene has been shown also to exert a more mild but significant effect on normal myometrium in terms of cell proliferation inhibition, as suggested by a PCNA/TC ratio that is lower in raloxifene than in placebo groups (Palomba et al. 2005b). This finding could explain the observation of a reduced incidence in new tumors observed in premenopausal women treated with 180 mg/d raloxifene (Palomba et al. 2002a). To define the relationship, if any, between prolifer ation and apoptotic indexes and raloxifene’s effect on uterine and leiomyoma dimensions, a linear correlation between PCNA/TC and Bcl-2/Bax ratios and the percent change in uterine and leiomyomas sizes was performed (Palomba et al. 2005c). Proliferation and apoptotic indexes resulted significantly related to the percent change in the dimension of leiomyomas alone, whereas no significant relationship was observed with a percent change in uterine size (Palomba et al. 2005c).

At present, no explanation of these data is available. A possible hypothesis could be that raloxifene acts on cell proliferation and apoptosis, decreasing the intratumoral insulin growth factor (IGF)-1 concentrations with an antagonist effect on ERs (Gao et al. 2001). In fact, several data suggest that IGF-1 may be involved in the regulation of leiomyoma growth as a local mediator of the growth-promoting actions of sex hormones (Gao et al. 2001). The altered expression of different ER subtypes in leiomyomas could play a role (Benassayag et al. 1999; Brandon et al. 1995).

To test the real efficacy in clinical practice of raloxifene in the treatment of uterine leiomyomas, a randomized, placebo-controlled study was performed in premenopausal women with asymptomatic uterine leiomyomas using conventional (60 mg/d) and high (180 mg/d) doses of raloxifene (Palomba et al. 2002a). No significant effect on uterine and leiomyoma sizes was observed after six cycles of raloxifene administration at either dose (Palomba et al. 2002a). However, our results should not be considered completely negative (Table 12.2). In fact, after six cycles of raloxifene treatment at the high dosage, in only two women was an increase in tumor size detected, whereas in a high percentage of cases the leiomyoma size was unmodified. Indeed, it seems that the use of 180 mg/d raloxifene acts more to prevent tumoral growth than to reduce leiomyoma size. A higher incidence of new leiomyomas has been observed in the groups treated with 60 mg/d raloxifene or with placebo, suggesting a dose- related response of raloxifene treatment (Table 12.2) (Palomba et al. 2002a). Unfortunately, it was not possible to perform an appropriate statistical analysis to evaluate the raloxifene effect on the prevention of leiomyomas for the small group of women and the short treatment period.

A possible explanation for these results may be twofold. First, the raloxifene doses were too low to reduce or reverse the proliferative effect of serum estradiol in normal ovulatory women. In fact, in postmenopausal women serum estradiol levels are about tenfold lower in comparison with normally cycled premenopausal women. Second, it is possible that in postmenopausal women ERs have a different intratumoral pattern in terms of concentration, expression, and affinity in comparison with premenopausal women.

No significant effect was observed on endometrial thickness or on the length and severity of uterine bleedings after raloxifene treatment at doses of 60 and 180 mg/d in premenopausal women (Palomba et al. 2002a). Unfortunately, during the different phases of the menstrual cycle, only the plasma FSH, estradiol, and progesterone levels were studied. In contrast, in the study of Baker et al. (1998) the endocrine effects of raloxifene in premenopausal women were studied extensively. No alteration in LH surge, FSH, progesterone, and estradiol levels was detected while raloxifene was being administered at doses of 400 mg/d for 5 d during the follicular, periovulatory, and luteal phases and at doses of 100 or 200 mg/d for 28d/month in healthy premenopausal women (Baker et al. 1998). Indeed, all women ovulated regularly, and only in some cases was an increase of estradiol and FSH levels observed (Baker et al. 1998).

Table 12.2. Number and percentage of women with unmodified, decreased, and increased uterine and leiomyoma sizes after 3 and 6 cycles of 60 mg/d raloxifene (group A), 180 mg/d raloxifene (group B), and placebo (group C) (Palomba et al. 2002a)


Unmodified (%)

Decreased (%)

Increased (%)

Group A(n = 29)

3rd cycle

27 (93.1)


2 (6.9)

6th cycle

22 (75.9)

1 (3.4)

6 (20.7)

Group B (n = 30)

3rd cycle

27 (90.0)

1 (3.3)

2 (6.7)

6th cycle

26 (86.7)

2 (6.7)

2 (6.7)

Group C (n = 29)

3rd cycle

25 (86.2)

1 (3.4)

3 (10.3)

6th cycle

21 (72.4)

1 (3.4)


More recently, in a randomized, open-label, controlled clinical trial Janseng et al. (Jerecek et al. 2004) demonstrated that high doses (180 mg/d) of raloxifene inhibited leiomyoma growth in premenopausal women. However, several criticisms have been made of this study (Palomba et al. 2004a). In perimenopausal women with low sex hormone levels, high doses of raloxifene could probably only inhibit leiomyoma growth and not have any clinical effect on uterine and leiomyoma dimensions (Palomba et al. 2004a).

Based on these findings, our team has studied the efficacy of raloxifene as an “add-back therapy” in women with uterine leiomyomas treated with GnRH-a (Palomba et al. 2002b; Palomba et al. 2002c). In this study’s protocol, we compared, in a randomized, single-blind, placebo-controlled fashion, the administration of GnRH-a plus raloxifene vs. GnRH-a alone (Palomba et al. 2002b; Palomba et al. 2002c). A significant decrease in uterine, leiomyoma, and nonleiomyoma sizes was detected in both treatment groups in comparison with the baseline (Fig. 12.2) (Palomba et al. 2002b). Significantly lower leiomyoma sizes were observed in the GnRH-a plus raloxifene group than in the GnRH- a alone group, but no difference was observed in leiomyoma-related symptoms between groups throughout the study period (Fig. 12.2) (Palomba et al. 2002b).

Fig. 12.2. Variation (%) from baseline in uterine and leiomyoma sizes and in ∆ size after 6 cycles of treatment in groups A (GnRH analog plus raloxifene) and B (GnRH analog plus placebo). Values are reported as mean ± SD. a p < 0.05 vs. baseline;b p < 0.05 vs. baseline and group A (Palomba et al. 2002b). Permission to publish from Oxford University Press

In this view, the effectiveness of raloxifene on leiomyoma reduction in postmenopausal women and in premenopausal women treated with GnRH- a could explain partially the ineffectivess of raloxifene in normally cycled women. Specifically, it seems, as supposed, that raloxifene achieves a clinical result only in patients with low serum estrogen levels.

In this sample of women treated with GnRH-a, raloxifene proved to be efficacious also in the prevention of GnRH-a-related bone loss (Palomba et al. 2002c). In fact, no significant variation in bone metabolism and mineral density was detected during treatment with GnRH-a plus raloxifene (Palomba et al. 2002c). The safety and effectiveness of GnRH-a plus raloxifene treatment were also tested following a long-term study (Palomba et al. 2004c) that showed improvements in mood and quality of life (Palomba et al. 2004d). Unfortunately, raloxifene did not reduce GnRH-a-related vasomotor symptoms.

In a subanalysis of the study (Palomba et al. 2004b), it was observed that GnRH-a altered serum lipoprotein and homocycsteine levels and increased insulin resistance. In contrast, when raloxifene was added to GnRH-a, these acute metabolic changes were prevented or reduced (Palomba et al. 2004b). However, raloxifene did not reduce the cognitive deficits observed during GnRH analog administration (Palomba et al. 2004d).

Finally, raloxifene has been successfully used in a symptomatic premenopausal woman with benign metastasizing leiomyomas (Rivera et al. 2004). In particular, 60 mg/d raloxifene, in coadministration with anastrozole 1 mg/d, induced a regression of the symptoms within few days, but a worsening of the symptomatology was observed when the woman stopped the treatment (Rivera et al. 2004). Raloxifene (120 mg/d) plus anastrozole (2 mg/d) was again administered inducing a regression of symptoms. After a 2-year followup, the woman remained clinically well (Rivera et al. 2004).

Other New-Generation SERMs

Lasofoxifene is a new potent nonsteroidal SERM that binds with high affinity to ERs acting as a tissue-selective estrogen antagonist or agonist (Maeda et al. 2004).

In preclinical studies designed to evaluate the effects of lasofoxifene on the uterus, a slight increase in wet uterine weight was observed in immature and aged female rats, but this difference was not observed in dry uterine weight, suggesting that the increased uterine weight was due to increased water content in the tissue (Maeda et al. 2004). When lasofoxifene was administered in combination with estrogens, it blocked the hypertrophic effects of estrogen specifically in the uterus. In immature and aged female rats, lasofoxifene did not affect uterine weight or uterine histology (Maeda et al. 2004).



Endometriosis is an estrogen-dependent disorder mostly occurring in reproductive-age women characterized by a growth of the endometrium outside the uterine cavity (Oral et al. 1997; Child et al. 2001). Explanations of how the tissue stains this abnormal placement are controversial, although the predominant theory is that retrograde menstruation is the cause (Oral et al. 1997; Child et al. 2001). Additional factors that maybe pivotal in the disease’s pathogenesis include immunologic abnormalities, endometrial disorders, and peritoneal dysfunction (Oral et al. 1997; Child et al. 2001).

The main manifestations and symptoms of endometriosis are infertil- ity/subfertility and pelvic pain (Missmer et al. 2003; Olive et al. 2001). Retrospective data have, in fact, shown that women with subfertility are at a high risk of having endometriosis, and prospective studies have demonstrated that endometriosis is related to a low relative risk for pregnancy (D’Hooghe et al. 2003; Akande et al. 2004).

In addition, about 15% of cases of pelvic pain are due to endometriosis, and most primary care physicians consider pelvic pain to be a common clinical problem that accounts for as much as 25% of routine gynecologic office visits (Hurd 1998). Endometriosis is frequently associated with several types of pelvic pain such as dysmenorrhea, chronic pelvic pain, deep dyspareunia, and, occasionally, painful defecation (Hurd 1998). Specifically, endometriosis was found in 37 to 74% of women undergoing laparoscopy for chronic pelvic pain (Demco 1998; Porpora et al. 1997).

The severity of pelvic pain and the incidence of infertility are not related to the localization of the lesions or to the stage of the disease (Gruppo Ital- iano per lo Studio dell’Endometriosi 2001), as categorized according to the revised American Fertility Society (r-AFS) guidelines (American Fertility Society 1985). In fact, the r-AFS classification system is inadequate to express the severity of the symptomatology because it does not reflect the disease in terms of cellular mass or activity.


Treatments of Endometriosis

The treatment of endometriosis is strongly related to its clinical manifestations. In women with infertility, the surgical treatment is probably the main therapeutic approach (Olive et al. 2001). In particular, if the endometriosis is of sufficient severity to cause distortion of the pelvis, the anatomic alteration could probably be treated by surgery (Olive et al. 2001). More controversial is the situation in women with early-stage endometriosis (Check 2003a,b,c). In fact, the effect of surgery is probably significant but too small to be acceptable (Marcoux et al. 1997; Parazzini 1999; Jacobson et al. 2004). In these cases a medical approach to infertility, such as induction of ovulation plus intrauterine insemination or assisted reproductive techniques, could be more appropriate (Olive et al. 2001).

When pelvic pain is the characterizing symptom of the disease, medical treatment could have a significant role. Several medical treatments have been proposed to treat secondary chronic pelvic pain due to endometriosis (Stones et al. 2004). Moreover, few data are available regarding the effectiveness of the treatments for endometriosis on the quality of life of these patients that seems to be deeply impaired (Carter 1998).

Medical treatment of endometriosis has focused on the hormonal alteration of the menstrual cycle in an attempt to produce a pseudopregnancy, pseudomenopause, or chronic anovulation (Olive et al. 2001).

Like the medical treatment of uterine leiomyomas, danazol, gestrinone, mifepristone, and GnRH-a, with or without add-back therapy, have been proposed for the treatment of endometriosis as well (Olive et al. 2001; Stones et al. 2004), but unlike leiomyomas, oral contraceptive pills, in cyclic or continuous administration, and medroxyprogesterone acetate also seem to be effective (Olive et al. 2001; Stones et al. 2004). A significant benefit in terms of pelvic pain relief also is obtained with the use of nonsteroidal anti-inflammatory drugs (Olive et al. 2001; Stones et al. 2004).

Furthermore, about 20% of women with chronic pelvic pain due to endometriosis are not responsive to medical treatment, and in these cases surgery represents the final diagnostic and therapeutic option (Olive et al. 2001; Stones et al. 2004). Several procedures have been described to treat medically unbeatable pelvic pain (Carter 1998). Nonconservative procedures, such as hysterectomy (Rannestad et al. 2001; Lefebvre et al. 2002), are effective in terms of pain relief, but they can be associated to the decrease in the quality of life (MacDonald et al. 1999), and considered unacceptable to women who wish to preserve intact their reproductive apparatus.

The goal of conservative surgery is to remove all apparent endometriosis from the abdomen and pelvis and restore normal anatomical relations. Several data show that the conservative surgical treatment of endometriosis is effective, in terms of pain relief and quality of life in women with secondary pelvic pain (Sutton et al. 1994; Palomba et al. 2006b). In addition, other surgical procedures can be used as a first course of action or added to surgical endometriosis treatment (Palomba et al. 2006b). These procedures, known as pelvic denervations, consist essentially in the interruption of a majority of cervical and uterine sensory nerve fibers (Palomba et al. 2006b).

Recently, several other medical treatments of endometriosis have been proposed (Olive 2002; D’Hooghe 2003; Chwalisz et al. 2002; Saito et al. 2003). However, their use is currently only potential.


SERMs and Endometriosis

The estrogen agonist effects of tamoxifen on eutopic endometrium have been widely described (Riggs et al. 2003; Fotiou et al. 1998). Several data have confirmed that tamoxifen acts also on ectopic endometrium as an estrogen agonist (Cohen et al. 1997; Parrott et al. 2001; Rose et al. 2000; Abad de Velasco et al. 2003; Chang et al. 2003; Bese et al. 2003).

A high incidence of histologically diagnosed adenomyosis has been detected in postmenopausal women with breast cancer taking tamoxifen when compared with those not taking tamoxifen (53.6% vs. 18.2%) (Cohen et al. 1997). Toremifene seems to exert the same effect as tamoxifen in the induction of adenomyotic foci in the rat (Parrott et al. 2001). In addition, in hypoestrogenic premenopausal women with breast cancer, tamoxifen has been shown to stimulate massively and rapidly an ectopic endometrium (Rose et al. 2000; Abad de Velasco et al. 2003; Chang et al. 2003; Bese et al. 2003), inducing a rapid condition requiring surgical treatment. Tamoxifen-induced endometriosis can be severe, making necessary a demolitive surgery (Bese et al. 2003).

Based on these considerations, a history of endometriosis should be considered a contraindication for treatment with tamoxifen, and considerable attention should be paid to the widespread use of tamoxifen as prophylactic treatment for the prevention of breast cancer in premenopausal women.

Raloxifene seems to have pharmacological proprieties that make its administration useful in women with endometriosis. Raloxifene, in fact, has been investigated in animal models with good results. Furthermore, just as with the other novel therapies for endometriosis, original articles on the effect of raloxifene on this condition are still lacking.

Recently, a Japanese research group published preclinical safety and efficacy data of an oral antiestrogen (TZE-5323) (Saito et al. 2003). This drug has been shown to have a strong affinity for human ERα and ERβ and a dose- dependent capacity to inhibit estradiol-stimulated transcriptional activation (Saito et al. 2003). In the experimental endometriosis model in rats, TZE-5323 dose-dependently reduced the volume of the endometrial implant with an effectiveness similar to that of danazol and leuprorelin acetate without causing significant changes in bone mineral density and in serum estradiol levels (Saito et al. 2003).



At present, the only SERMs routinely used in clinical practice are tamoxifen and raloxifene. Tamoxifen is used essentially as adjuvant treatment in women with breast cancer. Its use is related to estrogenic effects on the uterus. Specifically, tamoxifen can be associated with an increase not only in endometrial hyperplasia and cancer risk but also in uterine leiomyoma dimensions and in a risk of developing active endometriotic lesions.

Raloxifene is actually used for the treatment and prevention of postmenopausal osteoporosis. Also, if raloxifene has been shown to have any effect on uterine leiomyomas in vitro and in animal models, to date no concrete efficacy has been demonstrated in normally cycled premenopausal women. Moreover, the addition of raloxifene to GnRH-a administration can be useful for limiting GnRH-a-related side effects and increasing the rate of reduction in tumor size.

Regarding the use of SERMs in women with endometriosis, the efficacy of raloxifene or other compounds is only potential. Experimental studies to determine if SERMs have a greater potency against uterine leiomyomas and endometriosis are currently in progress.


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