Selective Estrogen Receptor Modulators. Antonio Cano

Chapter 12. Benign Gynecological Diseases and SERMs

• Stefano Palomba

• Fulvio Zullo

12.1

Introduction

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.

12.2

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).

12.2.1

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.

12.2.2

SERMs and Uterine Leiomyomas

12.2.2.1

Tamoxifen

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.

12.2.2.2

Raloxifene

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)

-(0)

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)

7(24.1)

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).

12.2.2.3

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).

12.3

Endometriosis

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.

12.3.1

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.

12.3.2

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).

12.4

Conclusions

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.

References

1. Abad de Velasco L, Cano A (2003) Acute abdomen due to endometriosis in a premenopausal woman taking tamoxifen. Eur J Obstet Gynecol Reprod Biol 109:234-235

2. Akande VA, Hunt LP, Cahill DJ, Jenkins JM (2004) Differences in time to natural conception between women with unexplained infertility and infertile women with minor endometriosis. Hum Reprod 19:96-103

3. American Fertility Society (1985) Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 43:351-355

4. Baker VL, Draper M, Paul S, Allerheiligen S, Glant M, Shifren J, Jaffe RB (1998) Reproductive endocrine and endometrial hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles. J Clin Endocrinol Metab 83: 6-13

5. Barbieri RL (1997) Reduction in the size of a uterine leiomyoma following discontinuation of an estrogen-progestin contraceptive. Gynecol Obstet Invest 43:276-277

6. Benassayag C, Leroy MJ, Rigourd V, Robert B, Honore JC, Mignot TM (1999) Estrogen receptors (ERalpha/ERbeta) in normal and pathological growth of the human myometrium: pregnancy and leiomyoma. Am J Physiol 276:1112-1118

7. Bese T, Simsek Y, Bese N, Ilvan S, Arvas M (2003) Extensive pelvic endometriosis with malignant change in tamoxifen-treated postmenopausal women. Int J Gynecol Cancer 13:376-380

8. Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC (1994) Raloxifene (LY139481 HCL) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovriectomized rats. J Clin Invest 93:63-69

9. Brandon DD, Erickson TE, Keenan EJ, Strawn EY, NovyMJ, Burry KA (1995) Estrogen receptor gene expression in human uterine leiomyomata. J Clin Endocrinol Metab 80:1876-1881

10. Bryant HU, Glasebrook AL, Yang NN, Sato M (1996) A pharmacological review of raloxifene. J Bone Miner Metab 14:1-9

11. Bulun SE, Simpson ER, Word RA (1994) Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissue and cells in culture. J Clin Endocrinol Metab 78:736-743

12. Carter JE (1998) Surgical treatment for chronic pelvic pain. J Soc Laparoendoscop Surgeons 2:129-133

13. Chang CK, Chen P, Leu FJ, Lou SM (2003) Florid polypoid endometriosis exacerbated by tamoxifen therapy in breast cancer. Obstet Gynecol 102:1127-1130

14. Check JH (2003a) The association of minimal and mild endometriosis without adhesions and infertility with therapeutic strategies. Clin Exp Obstet Gynecol 30:13-18

15. Check JH (2003b) The association of minimal and mild endometriosis without adhesions and infertility with therapeutic strategies. Clin Exp Obstet Gynecol 30:19-34

16. Check JH (2003c) The association of minimal and mild endometriosis without adhesions and infertility with therapeutic strategies. Clin Exp Obstet Gynecol 30:35-39

17. Chegini N, Rong H, Dou Q, Kipersztok S, Williams RS (1996) Gonadotropin-releasing hormone (GnRH) and GnRH receptor gene expression in human myometrium and leiomyomata and the direct action of GnRH analogs on myometrial smooth muscle cells and interaction with ovarian steroids in vitro. J Clin Endocrinol Metab 81:32153221

18. Child TJ, Tan SL (2001) Endometriosis: aetiology, pathogenesis and treatment. Drugs 61:1735-1750

19. Chwalisz K, Garg R, Brenner RM, Schubert G, Elger W (2002) Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann NY Acad Sci 955:373-388

20. Cohen FJ, Watts S, Shah A, Akers R, Plouffe L (2000) Uterine effects of 3-year raloxifene therapy in postmenopausal women younger than age 60. Obstet Gynecol 95:104-110

21. Cohen I, Beyth Y, Shapira J, Tepper R, Fishman A, Cordoba M, Bernheim J, Yigael D, Altaras MM (1997) High frequency of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen. Gynecol Obstet Invest 44:200-205

22. Coutinho EM (1989) Gestrinone in the treatment of myomas. Acta Obstet Gynecol Scand 150:39-46

23. Coutinho EM (1990) Treatment of large fibroids with high doses of getrinone. Gynecol Obstet Invest 30:44-47

24. Coutinho EM, Goncalves MT (1989) Long-term treatment of leiomyomas with gestri- none. Fertil Steril 51:939-946

25. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC (1999) Effects of raloxifene on breast cancer risk in postmenopausal women. J Am Med Assoc 281:2189-2197

26. De Leo V, La Marca A, Morgante G (1999) Short-term treatment of uterine fibromyomas with danazol. Gynecol Obstet Invest 47:258-262

27. De Leo V, La Marca A, Morgante G, Severi FM, Petraglia F (2001) Administration of somatostatin analogue reduces uterine and myoma volume in women with uterine leiomyomata. Obstet Gynecol 75:632-633

28. Demco L (1998) Mapping the source and character of pain due to endometriosis by patient-assisted laparoscopy. J Am Assoc Gynecol Laparosc 5:241-245

29. D’Hooghe TM (2003) Immunomodulators and aromatase inhibitors: are they the next generation of treatment for endometriosis? Curr Opin Obstet Gynecol 15: 243-249

30. D’Hooghe TM, Debrock S, Hill JA, Meuleman C (2003) Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med 21:243-254

31. Dilts PV Jr, Hopkins MP, Chang AE, Cody RL (1992) Rapid growth of leiomyoma in patient receiving tamoxifen. Am J Obstet Gynecol 166:167-168

32. Englund K, Blanck A, Gustavsson I, Lundkvist U, Sjoblom P (1998) Sex steroids receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinol Metab 83:92-96

33. Ettinger B, Black DM, Mitlak BH, Knickerbocker RH, Nickelsen T, Genant NK (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. J Am Med Assoc 282:637-645

34. Fotiou S, Tserkezoglou A, Hadjieleftheriou G, Apostolikas N, Karydas I, Stravolemos K (1998) Tamoxifen associated uterine pathology in breast cancer patients with abnormal bleeding. Anticancer Res 18:625-629

35. Friedman AJ, Thomas PP (1995) Does low-dose combination oral contraceptive use affect uterine size or menstrual flow in premenopausal with leiomyomas? Obstet Gynecol 85:631-635

36. Fuchs-Young R, Howe S, Hale L, Miles R, Walker C (1996) Inhibition of estrogen stimulated growth of uterine leiomyomas by selective estrogen receptor modulators. Mol Carcinog 17:151-159

37. Gainer EE, Ulmann A (2003) Pharmacologic properties of CDB(VA)-2914. Steroids 68:1005-1011

38. Gao Z, Matsuo H, Wang Y, Nakago S, Maruo T (2001) Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 86:5593-5599

39. Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK (2000) A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol 95:95-103

40. Gruppo Italiano per lo Studio dell’Endometriosi (2001) Relationship between stage, site and morphological characteristics of pelvis endometriosis and pain. Hum Reprod 16:2668-2671

41. Higashijima T, Kataoka A, Nishida T, Yakushiji M (1996) Gonadotropin-releasing hormone agonist therapy induces apoptosis in uterine leiomyoma. Eur J Obstet Gynecol Reprod Biol 68:169-173

42. Howe SR, Gottardis MM, Everitt JI, Walker C (1995) Estrogen stimulation and tamoxifen inhibition of leiomyoma cell growth in vitro and in vivo. Endocrinology 136:4996-5003

43. Hurd WW (1998) Criteria that indicate endometriosis is the cause of chronic pelvic pain. Obstet Gynecol 92:1029-1032

44. Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C (2004) Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Library, Issue 4. Update Software, Oxford

45. Jirecek S, Lee A, Pavo I, Crans G, Eppel W, Wenzl R (2004) Raloxifene prevents the growth of uterine leiomyomas in premenopausal women. Fertil Steril 81:132-136

46. Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T (1989) Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol 160:637-641

47. Kertel LM, Murphy AA, Morales AJ, Yen SS (1994) Clinical efficacy of antiprogesterone RU 486 in the treatment of endometriosis and uterine fibroids. Hum Reprod 9:116-120

48. Khovidhunkit W, Shoback DM (1999) Clinical effects of raloxifene hydrocloride in women. Ann Intern Med 130:431-439

49. Kuiper GGJM, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors a and в. Endocrinology 138:863-870

50. Lacreuse A, Wilson ME, Herndon JG (2002) Estradiol, but not raloxifene, improves aspects of spatial working memory in aged ovariectomized rhesus monkeys. Neurobiol Ag 23:589-600

51. Lefebvre G, Allaire C, Jeffrey J (2002) Clinical Practice Gynaecology Committee and Executive Committeee and Council, Society of Obstetricians and Gynaecologists of Canada. SOGC clinical guidelines. Hysterectomy. J Obstet Gynaecol Can 4:37-61

52. Leo L, Lanza A, Re A, Tessarolo M, Bellino R, Lauricella A, Wierdis T (1994) Leiomyomas in patients receiving tamoxifen. Clin Exp Obstet Gynecol 21:94-98

53. Lumsden MA, West CP, Baird DT (1989a) Tamoxifen prolongs luteal phase in premenopausal women but has no effect on the size of uterine fibroids. Clin Endocrinol 31:335-343

54. Lumsden MA, West CP, Hillier H, Baird DT (1989b) Estrogenic action of tamoxifen in women treated with luteinizing hormone-releasing hormone agonists (goserelin)-lack of shrinkage of uterine fibroids. Fertil Steril 52:924-929

55. MacDonald SR, Klock SC, Milad MP (1999) Long-term outcome of nonconservative surgery (hysterectomy) for endometriosis-associated pain in women < 30 years old. Am J Obstet Gynecol 180:1360-1363

56. Maeda T, Ke HZ, Simmons H, Thompson D (2004) Lasofoxifene, a next generation estrogen receptor modulator: preclinical studies. Clin Calcium 14:85-93

57. Marcoux S, Maheux R, Berube S (1997) Laparoscopy surgery in infertile woman with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 337:217-222

58. Marshall LM, Spiegelman D, Goldman MB, Manson JE, Colditz G, Barbieri RL, Stampfer MJ, Hunter DJ (1998) A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril 70:432-439

59. Minakuchi K, Kawamura N, Tsujimura A (1999) Remarkable and persistent shrinkage of uterine leiomyoma associated with interferon alfa treatment for hepatitis. Lancet 353:2127-2128

60. Missmer SA, Cramer DW (2003) The epidemiology of endometriosis. Obstet Gynecol Clin North Am 30:1-19

61. Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SSC (1993) Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metab 76:513-517

62. Olive DL (2002) Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet Gynecol Surv 57:S55-63

63. Olive DL, Pritts EA (2001) Treatment of endometriosis. N Engl J Med 345:266-275

64. Oral E, Arici A (1997) Pathogenesis of endometriosis. Obstet Gynecol Clin North Am 24:219-233

65. Paech K, Webb P, Kuiper GGJM, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS (1997) Differential ligand activation of estrogen receptors ERa and ERe at AP1 sites. Science 277:1508-1510

66. Palomba S, Zullo F (2006b) Pelvic denervations procedures as surgical management of pelvic pain due to endometriosis. In: Sutton C, Jones K, Adamdson GD (eds) Modern Management of Endometriosis. Taylor and Francis, London; 167-176; Palomba et al. 2006a

67. Palomba S, Affinito P, Tommaselli GA, Nappi C (1998) A clinical trial on the effects of ti- bolone association with gonadotropin-releasinghormone analogues for the treatment of uterine leiomyomata. Fertil Steril 70:111-118

68. Palomba S, Affinito P, Di Carlo C, Bifulco G, Nappi C (1999) Long term administration of tibolone plus gonadotropin-releasing hormone agonist for treatment of uterine leiomyomas: effectiveness and effects on vasomotor symptoms, bone mass, and lipid profile. Fertil Steril 72:889-895

69. Palomba S, Sammartino A, Di Carlo C, Affinito P, Zullo F, Nappi C (2001) Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 76:38-43

70. Palomba S, Orio F Jr, Morelli M, Russo T, Pellicano M, Zupi E, Lombardi G, Nappi C, Benedetti Panici PG, Zullo F (2002a) Raloxifene administration in premenopausal women with uterine leiomyomas: a pilot study. J Clin Endocrinol Metab 87:3303-3308

71. Palomba S, Russo T, Orio F jr, Tauchmananovà L, Zupi E, Benedetti Panici PG, Nappi C, Lombardi G, Colao A, Zullo F (2002b) Effectiveness of combined GnRH analogue plus raloxifene administration in the treatment of uterine leiomyomas: a prospective, randomized, single-blind, placebo-controlled clinical trial. Hum Reprod 17:3213-3219

72. Palomba S, Orio F Jr, Morelli M, Russo T, Pellicano M, Nappi C, Mastrantonio P, Lombardi G, Colao A, Zullo F (2002c) Raloxifene administration in women treated with gonadotropin releasing hormone agonist for uterine leiomyomas: effects on bone metabolism. J Clin Endocrinol Metab 87:4476-4481

73. Palomba S, Zullo F, Orio F Jr, Lombardi G (2004a) Does raloxifene inhibit the growth of uterine fibroids? Fertil Steril 81:1719-1720

74. Palomba S, Russo T, Orio F Jr, Sammartino A, Sbano FM, Nappi C, Colao A, Mastran- tonio P, Lombardi G, Zullo F (2004b) Lipid, glucose, and homocysteine metabolism in women treated with a gonadotropin-releasing hormone agonist with or without raloxifene. Hum Reprod 19:415-421

75. Palomba S, Orio F Jr, Russo T, Falbo A, Cascella T, Doldo P, Nappi C, Lombardi G, Mastrantonio P, Zullo F (2004c) Long-term effectiveness and safety of GnRH agonist plus raloxifene administration in women with uterine leiomyomas. Hum Reprod 19:1308-1314

76. Palomba S, Orio F Jr, Falbo A, Russo T, Amati A, Zullo F (2005b) Gonadotropinreleasing hormone agonist with or without raloxifene: effects on cognition, mood, and quality of life. Fertil Steril 84:154-161

77. Palomba S, Falbo A, Russo T, Zullo F (2005a) Emerging drugs in uterine leiomyomas. Exp Opin Emerg Drugs (in press)

78. Palomba S, Falbo A, Russo T, Zullo F (2006a) GnRH analogs use for the treatment of symptomatic leiomyomas. Gynecol Surg 2:7-13

79. Palomba S, Orio F Jr, Russo T, Falbo A, Tolino A, Lombardi G, Cimini V, Zullo F (2005b) Anti-proliferative and pro-apoptotic effects of raloxifene on uterine leiomyomas in postmenopausal women. Fertil Steril (in press)

80. Parazzini F (1999) Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell’En- dometriosi. Hum Reprod 14:1332-1334

81. Parrott E, Butterworth M, Green A, White INH, Greaves P (2001) Adenomyosis: a result of disordered stromal differentiation. Am J Pathol 159:623-630

82. Pasqualini JR, Cornier E, Grenier J, Vella C, Schatz B, Netter A (1990) Effect of de- capeptyl, an agonost analog of gonadotropin-releasing hormone on estrogens, estrogen sulfates, and progesterone receptors in leiomyomata and myometrium. Fertil Steril 53:1012-1017

83. Pickersgill A (1998) GnRH agonists and add-back therapy: is there a perfect combination? Br J Obstet Gynaecol 105:475-485

84. Porpora MG, Gomel V (1997) The role of laparoscopy in the management of pelvic pain in women of reproductive age. Fertil Steril 68:765-769

85. Porter KB, Tsibris JC, Porter GW, Fuchs-Young R, Nicosia SV, O’Brien WF (1998) Effects of raloxifene in a guinea pig model for leiomyomas. Am J Obstet Gynecol 179:1283-1287

86. Rannestad T, Eikeland OJ, Helland H (2001) The quality of life in women suffering from gynecological disorders is improved by means of hysterectomy. Absolute and relative differences between pre- and postoperative measures. Acta Obstet Gynecol Scand 80:46-51

87. Rein MS (2000) Advanced in uterine leiomyoma research: the progesterone hypothesis. Environ Health Perspect 108:791-793

88. Rein MS, Barbieri RL, Friedman AJ (1995) Progesterone: a critical role in pathogenesis of uterine myomas. Am J Obstet Gynecol 172:14-18

89. Riggs BL, Hartmann LC (2003) Selective estrogen-receptor modulators: mechanisms of action and application to clinical practice. N Engl J Med 348:618-629

90. Rivera JA, Christopoulos S, Small D, Trifiro M (2004) Hormonal manipulation of benign metastasizing leiomyomas: report of two cases an review of the literature. J Clin Endocrinol Metab 89:3183-3188

91. Robertson JF (2004) Selective oestrogen receptor modulators/new antioestrogens: a clinical perspective. Cancer Treat Rev 30:695-706

92. Rose PG, Alvarez B, Maclennan GT (2000) Exacerbation of endometriosis as a result of premenopausal tamoxifen exposure. Am J Obstet Gynecol 183:507-508

93. Sadan O, Ginath S, Sofer D, Rotmensch S, Debby A, Glezerman M, Zakut H (2001) The role of tamoxifen in the treatment of symptomatic uterine leiomyomata: a pilot study. Eur J Obstet Gynecol Reprod Biol 96:183-186

94. Saito T, Yoshizawa M, Yamauchi Y, Kinoshita S, Fujii T, Mieda M, Sone H, Yamamoto Y, Koizumi N (2003) Effects of the novel orally active antiestrogen TZE-5323 on experimental endometriosis. Arzneimittelforschung 53:507-514

95. Schwartz LB, Rutkowski N, Horan C, Nachtigall LE, Snyder J, Goldstein SR (1998) Use of transvaginal ultrasonography to monitor the effects of tamoxifen on uterine leiomyoma size and ovarian cyst formation. J Ultrasound Med 17: 699-703

96. Shozu M, Murakami K, Segawa T, Kasai T, Inoue M (2003) Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor. Fertil Steril 79:628-631

97. Spitz IM (2003) Progesterone antagonists and progesterone receptor modulators: an overview. Steroids 68:981-993

98. Steward EA (2001) Uterine fibroids. Lancet 357:293-298

99. Stones RW, Mountfiel dJ (2004) Interventions for treating chronic pelvic pain in women. Cochrane Library, Issue 2. Update Software, Oxford

100. Sutton CJ, Ewen SP, Whitelaw N (1994) Prospective, randomized double-blind controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild and moderate endometriosis. Fertil Steril 62:696-700

101. Tiltman AJ (1985) The effect of progestins on the mitotic activity of uterine fibromy- omas. Int J Gynecol Pathol 4:89-96

102. Tomas E, Kauppila A, Blanco G, Apaja-Sarkkinen M, Laatikainen T (1995) Comparison between the effects of tamoxifen and toremifene on the uterus in postmenopausal breast cancer patients. Gynecol Oncol 59:261-266

103. Ugwumadu AH, Harding K (1994) Uterine leiomyomata and endometrial proliferation in postmenopausal women treated with the anti-oestrogen tamoxifen. Eur J Obstet Gynecol Reprod Biol 54:153-156

104. Walker CL, Burroughs KD, Davis B, Sowell K, Everitt JI, Fuchs-Young R (2000) Preclinical evidence for therapeutic efficacy of selective estrogen receptor modulators for uterine leiomyoma. J Soc Gynecol Invest 7:249-256

105. Walsh BW, Kuller LH, Wild RA, Paul S, Farmer M, Lawrence JB, Shah AS, Anderson PW (1998) Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. J Am Med Assoc 279:1445-1451

106. Yaffe K, Krueger K, Sarkar S, Grady D, Barrett-Connor E, Cox DA, et al. (2001) Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 344:12071213

107. Yamamoto T, Takamori K, Okada H (1984) Estrogen biosynthesis in leiomyomata and myometrium of the uterus. Horm Metab Res 16:678-679



If you find an error or have any questions, please email us at admin@doctorlib.info. Thank you!