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138 Current Women’s Health Reviews, 2012, 8, 138-149 Endometriosis: The Role of Pharmacotherapy

Chrysanthi Sardeli1,*, Angelos Daniilidis2, Antonios Goulas1, Georgios Papazisis1, Dimitrios Kouvelas1 and John Tzafettas

1Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki; 22nd Department of Obstetrics and Gynecology, School of Medicine, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece

Abstract: Objective: This review discusses the general principles on which classic and novel approaches in the pharmacotherapy of endometriosis are based and presents the types of drugs involved. Design: Review article. Data sources: Relevant studies were retrieved from Pubmed, Scopus and ISI –Web of knowledge databases. Eligibility criteria: All articles in English, French, German and Danish languages that contained the following keywords: endometriosis, pharmacotherapy, pain relief, chronic pelvic pain & , were retrieved and read and all relevant data were included in this review. Results: Endometriosis is an -dependent, benign gynaecologic disorder, characterized by the presence of tissue morphologically and biologically similar to normal outside its normal location. The underlying aetiology and pathophysiology are poorly understood. Dyspareunia, , chronic pelvic pain and infertility are characteristic and debilitating manifestations of the . Several pharmacotherapeutic approaches are available. Currently available pharmacotherapies are not curative but symptomatic and aim either at decreasing ovarian estrogen production or at antagonizing estrogen action. Recurrence is the rule after cessation of treatment while pharmacotherapy is not suitable for women seeking conception. Conclusions: No curative pharmacotherapeutic options for treating endometriosis are currently available and most options complicate the course of treatment due to adverse events and short-term results. Novel approaches aim to take advantage of recent advances in endometriosis research but limited data are available regarding chronic use and long-term safety and efficacy. Keywords: Chronic pelvic pain, endometriosis, pain relief, pharmacotherapy.

INTRODUCTION data suggest that, besides hormonal dependency, several immunologic, angiogenetic and apoptotic pathways [7-10] Endometriosis is an estrogen-dependent, benign may be involved in the pathogenesis of endometriosis. This gynaecologic disorder, characterized by the ectopic presence has led to the development and investigation of novel of endometrial tissue that is morphologically and biologically pharmacological strategies [11, 12]. similar to eutopic endometrium, most commonly in the pelvic peritoneum and the ovary [1]. It affects mainly This review discusses the general principles on which women of reproductive age, regardless of race or social classic and novel pharmacotherapeutic approaches are based, status, and has a negative impact on physical, mental and and provides an outline of the types of drugs involved. social aspects of life [2, 3]. Surgical and medical manage- ment of endometriosis has traditionally focused on symptom CLASSIC APPROACHES IN THE PHARMACO- relief, such as pain. The observation that symptoms improve THERAPY OF ENDOMETRIOSIS during or has led to targeting classic , progestins and estrogen-progestagen pharmacotherapies (, progestins, oral contraceptives combinations, and GnRH have long been prescribed (OCs), -releasing receptor (GnRH) analogs) to endometriosis patients. These drug classes target the either on ovarian suppression and subsequent decrease of estrogen-dependency of the disease by creating an ovarian estrogen production or the antagonizing of estrogen unfavourable hormonal environment and restricting action [4-6]. These modalities are all similarly effective in proliferation of endometriotic tissue [13-15]. The symptomatic relief but are not curative, and their use is disadvantage of such pharmacologic modalities is that they associated with significant adverse effects while it is not are not curative but symptomatic and at treatment cessation, suitable for women planning to conceive. Symptoms usually recurrence of symptoms is usually the rule [16]. recur after cessation of treatment. Recently published DANAZOL Danazol is an orally administered weak synthetic *Address correspondence to this author at the Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, GR-54124, (recommended dose of 600-800 mg/day) that acts Thessaloniki, Greece; Tel: +302310999353; Fax: +302310999335; through suppression of the hypothalamic-pituitary-ovarian E-mail: [email protected] axis, accompanied by increased serum free and

1875-6581/12 $58.00+.00 © 2012 Bentham Science Publishers Endometriosis: The Role of Pharmacotherapy Current Women’s Health Reviews, 2012, Vol. 8, No. 2 139 decreased serum estrogen levels, inducing anovulation and (for 6 months to 1 year) in women with symptomatic and amenorrhea [17, 18]. Use of danazol is associated with endoscopically confirmed endometriosis resulted in , mood changes, , fluid retention, substantial decrease of dysmenorrhea and chronic pelvic atrophy, voice deepening, , and adverse lipid pain, without causing serious adverse effects [28]. There profiles [18-20]. Although danazol is less expensive than were no significant differences in pain relief when oral GnRH analogs, its androgenic anabolic effects are much less administration of acetate 10 mg/day was tolerable than the hypoestrogenic effects of GnRH analogs, a compared to oral administration of 2 mg/day for 6 fact that negatively affects patient compliance [20, 21]. months [29]. More recently, a randomized prospective study demonstrated that low-dose is Danazol has been proven effective in reducing effective in reducing the intensity of pain symptoms caused endometriosis-associated pain as demonstrated by various studies and a recent Cochrane Database metaanalysis [22], by rectovaginal endometriosis [30], an effect verified by another recent pilot study [31] in a similar patient this benefit however disappears after cessation of use. Two population. recently published studies examining the use of alternative routes of administration are of interest. In the first one, Norethisterone acetate controls well uterine and, intrauterine insertion of a danazol-containing device resulted at low doses, has limited effects on the lipoprotein profile in substantial decrease in dysmenorrhea, dyspareunia, and [32, 33], probably due to low conversion to . pelvic pain, while there was negligible systemic absorption However, data on the effect of long-term administration of and no systemic adverse effects [23]. In the second norethisterone acetate on bone mineral density is somewhat study, vaginal administration of 200mg of danazol caused a controversial. In one study, adolescent users of injectable gradual decrease, and, after continuous use for 6 months, norethisterone enantate for contraception were found to have disappearance of dysmenorrhea, dyspareunia, and pelvic lower increases in BMD over time compared with users of pain and a decrease in dyschezia and the size of pre-existing depot or OCs [34]. Another study, rectovaginal nodules with few vaginal adverse effects however, by the same group regarding the use of reported [24]. New drug forms and alternative routes of norethisterone acetate, depot medroxyprogesterone or OCs administration will perhaps renew interest in this drug but in women older than 40 years of age showed no untoward more data on safety and efficacy are needed. effect on BMD [35].

PROGESTINS Progestins, the most frequently used of which are 19- Cyproterone, a derivative of 17-hydroxyprogesterone nortestosterone derivatives, and with anti-androgenic and antigonadotropinic properties [21], medroxyprogesterone (MPA), act by causing decidualization usually combined with ethinylestradiol as an oral of endometrial tissue and, ultimately, atrophy. Doses range contraceptive, was first suggested as an option in the between 20 and 100 mg/day. Breakthrough bleeding, , treatment of endometriosis in 1987 [36] and subsequently weight gain, , , and breast tenderness are used in 1989 [37]. In a small later study [38] oral frequent adverse effects for this . High doses of administration of cyproterone 10 mg/day for 20 days progestins cause untoward changes in high density- followed by 10 days with no treatment for a 6 month period, lipoprotein (HDL) cholesterol and apolipoprotein A-1. considerably diminished dysmenorrhea in all patients. In This adverse effect occurs more commonly with 19- repeat laparoscopy minimal residual lesions or even absence nortestosterone derivatives [25]. The clinical significance of of disease was seen. In the only RCT published, continuous these changes during short-term treatment is unclear. oral administration of cyproterone 12.5 mg/day compared with a 0.15 mg/ethinylestradiol 0.02 mg containing OC for 6 months in women with recurrent Gestrinone is a not commonly used anti-progestagenic moderate-to-severe pelvic pain after conservative surgery that exerts its action by blocking follicular develop- [39] resulted in a significant reduction in dysmenorrhea, ment and subsequent production. Furthermore, it deep dyspareunia and non menstrual pelvic pain. Both binds to androgen receptors as an , and to treatments improved health-related quality of life (HR- receptors, where it acts both as an agonist and QOL), psychological profile and sexual satisfaction with no an antagonist, producing a progesterone withdrawal effect at differences between treatment groups and metabolic or other the endometrial cells [21, 25]. Administered orally 5–10 adverse effects were minimal. mg/day or 2-3 times/week, it is associated with androgenic, anti-progestagenic and anti-estrogenic adverse effects that Medroxyprogesterone include decrease in HDL cholesterol, increase in LDL Medroxyprogesterone is a 17-hydroxy derivative of cholesterol, weight gain, hirsutism, seborrhoea and [25- progesterone displaying androgenic activity and minor 27]. Gestrinone has been shown to be effective in alleviating effects on the lipoprotein profile [21]. Numerous studies endometriosis-associated pain, in a mode similar to danazol have shown that use of medroxyprogesterone in women with or GnRH analogs [26, 27]. symptomatic endometriosis is more efficacious than placebo, Norethisterone Acetate and no less efficacious than GnRH agonists, in reducing pain and improving HR-QOL. However, erratic bleeding episodes Norethisterone acetate (or norethindrone acetate) is a are more frequent and protracted. progestogene derivative of 19-nortestosterone [21]. Its use 140 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Sardeli et al.

Two RCTs have shown that daily oral administration of without suppressing and may relieve menstrual medroxyprogesterone is more efficacious than placebo in pain [54]. Insertion of l-IUS in women with stage I-III reducing pain symptoms and improving well being but not endometriosis resulted in significant reduction of improving pregnancy rates [40] and equally efficacious dysmenorrhea, dyspareunia, number of days of pain, when compared with nasal administration of monthly blood loss and not in non-cyclic pelvic pain in without worsening anxiety-depression scores [41]. However those who completed 6 month follow-up. Fifty-six% of the different dosing regiments were used. women initially enrolled in the study retained the l-IUS for 3 years [55] and those who dropped out stated irregular Medroxyprogesterone is widely used today as a bleeding, pelvic pain and weight gain as reasons for having contraceptive in an injectable depot formulation (intra- muscular administration of medroxyprogesterone 150 mg/3 the l-IUS removed. Reduction in dysmenorrhea and monthly blood loss was even more pronounced. A single RTC [56] months) [21]. There is some controversy regarding the risk has compared the efficacy of the l-IUS against monthly for bone demineralization after long-term use of medro- administration of depot leurpolin 3.75 mg/28 days in xyprogesterone [42-48] but cessation of administration reverses any adverse effect on BMD [44, 47]. No changes in managing endometriosis-associated pain. Both treatments were equally effective in reducing pelvic pain and improving BMD are reported between users and never users of medro- QOL but bleeding scores were, as expected, higher in the l- xyprogesterone, and although use of medroxyprogesterone IUS group. for more than 2 years has been associated with low BMD [48], this effect seems to be less significant when medro- When inserted in parous previously conservatively xyprogesterone is compared to leuprolide [49]. There are, operated women with recurrent moderate-to severe however, no data regarding clinically significant bone menstrual pain, a study reported decreased dysmenorrhea, fractures occurring after medroxyprogesterone use (or any mild adverse effects and high patient satisfaction [57]. The other progestin, for that matter), as the only biomarker used same group has also studied the insertion of l-IUS as to date has been BMD. adjuvant therapy immediately after laparoscopic surgery [58], reporting significant reduction in dysmenorrhea, non Regarding endometriosis-associated pain, intramuscular menstrual pain and recurrence of moderate or severe administration of depot medroxyprogesterone for 1 year was dysmenorrhea and higher patient satisfaction at 1 year compared to the combination of a monophasic OC and low- dose danazol (50 mg/day) [50]. Pain symptoms were follow-up, compared to surgery only. significantly reduced in both groups, with medroxypro- The insertion of l-IUS results in good compliance and it gesterone having a greater positive effect on dysmenorrhea is cost-effective in the long run but it is associated with and patient satisfaction but at the same time provoking more adverse effects such as irregular bleeding, especially adverse effects. A lower-dose depot formulation of medro- prevalent in the first 3-6 months post-insertion, a fact that xyprogesterone containing 104 mg/3 months for requires specific patient counselling [59]. Lack of inhibition subcutaneous administration has been found equally of ovulation is potentially clinically relevant in the formation efficacious to leuprolide 11.25 mg in reducing pain of endometriomas, as is the risk for pelvic inflammation and symptoms at treatment cessation and at follow-up in two device expulsion. More research data are needed, especially different RCTs [51,52]. Both RTCs report a significantly in comparing this modality to other classic ones, but smaller reduction in BMD in patients receiving depot there seems to be a role for it in the pharmacotherapy of medroxyprogesterone and return to pre-treatment levels at endometriosis [60]. follow-up in the same group. Both treatments were associated with similar improvements in overall HR-QOL Other Progestins and productivity. acetate [61], [62], dienogest, Depot medroxyprogesterone is an effective, generally (19-nortestosterone derivative) [28, 63] and well tolerated, low cost alternative for the treatment of [64] have also been studied, mostly in observational or symptomatic endometriosis. However, one must be careful retrospective studies, producing only some degree of in patient selection because of the ensuing adverse effects symptom improvement. and the impossibility to cease treatment if these occur. Medroxyprogesterone use is associated with a prolonged ORAL CONTRACEPTIVE PILLS delay in the resumption of ovulation and uterine break- through bleeding that is protracted, recurring and difficult to Oral contraceptives, whether used in a cyclic or correct. Patients with residual symptomatic endometriosis continuous fashion, induce a pseudopregnancy state through following hysterectomy are probably the target group for this decidualization and atrophy of the endometrium [65] and therapeutic modality. have long been used for treatment of endometriosis- associated pelvic pain and dysmenorrhea [21]. Adverse Levonogestrel effects are usually mild to moderate, including abnormal bleeding, weight gain, nausea, and (the latter is a potent 19-nortestosterone derivative, being a rare but highly significant occurrence). exhibiting androgenic and anti-estrogenic effects on the endometrium [53]. An intrauterine device releasing 20 Already in 1989 cyclic low-dose use of OCs was mg/day of levonorgestrel (l-IUS) induces endometrial associated with decrease in intrauterine pressure and pain atrophy with subsequent oligomenorrhea or amenorrhea reduction on the first day of menstruation [66, 67]. Several Endometriosis: The Role of Pharmacotherapy Current Women’s Health Reviews, 2012, Vol. 8, No. 2 141 studies have reported an association between OC use and pregnancy treatment. As adolescents and young adults have decreased dysmenorrhea. Although one study suggested that only recently begun using these extended cycle regimens, OCs containing a potent progestin (such as levonorgestrel) long-term safety remains unknown. might be more beneficial in the treatment of dysmenorrhea [68], other studies showed OCs with less potent progestins GnRH AGONISTS (such as desogestrel and ) to be equally effective GnRH agonists inhibit secretion of FSH and LH, thus [69-73]. creating a hypoestrogenic state that resembles postmenopause. Administration of a monophasic OC (desogestrel 0.15 GnRH agonists are reasonably effective in reducing all types mg/ethinylestradiol 0.02 mg) administered cyclically has of endometriosis-associated pain [85], the effect however been compared to subcutaneous administration of depot may be exerted via several other pathways besides hormonal (3.6 mg/28 days) on endometriosis-associated dependency. Inhibition of ovulation can cause reduced symptoms [74]. Both treatments reduced non menstrual exposure of endometriotic lesion to growth factors with pain and deep dyspareunia, with goserelin being superior angiogenic, mitogenic and chemotactic properties, such to the OC. OC users reported a significant reduction in as midkine. Inhibition of menstrual bleeding reduces amenorrhea. Both treatments resulted in symptom recurrence mechanical uterine distention and stress, reducing the 6 months after cessation of treatment. Another study [75] negative effects of inflammatory factors on ectopic endo- investigated whether intramuscular administration of metrium [86]. GnRH agonists have a direct effect on 3.75 mg/28 days administered for 4 months before endometriotic cells by inhibiting cell proliferation and beginning cyclic OC use would improve results compared increasing apoptosis [87]. Treatment is however symptomatic with use of an estrogen-progestin combination (gestodene and recurrence occurs after cessation of treatment [88]. 0.75 mg/ethinylestradiol 0.03 mg) for 12 months. No Two recently published Cochrane Database meta- differences were reported in pelvic pain. A recent randomized, placebo-controlled, double-blind study has analyses have found GnRH agonists to be effective in demonstrated the efficacy of OCs in providing relief from reducing endometriosis-associated pain (dysmenorrhea, endometriosis-associated pain [76]. Patients with severe dyspareunia and non menstrual pelvic pain) [85], with little dysmenorrhea were randomized to either a monophasic OC or no difference in efficacy between GnRH agonists and (norethisterone 1mg/ethinylestradiol 0.035 mg) or placebo. other drugs for endometriosis (danazol, OCs, gestrinone) but Total dysmenorrhea, non menstrual pain and endometrioma markedly different adverse effect profiles [89]. Adverse volume were significantly reduced in OC users. effects occur in a dose-dependent fashion and include , hot flushes, vaginal dryness, decreased Post-operative recurrence of endometriomas is high , breast tenderness, insomnia, and depression/ and can be effectively lowered via postoperative use of OCs emotional lability. They may be administered intranasally, [77]. This significant reduction in risk of recurrence of subcutaneously and intramuscularly, at intervals ranging endometriomas represents an important benefit of prolonged between twice/day to once every 3 months. GnRH agonists suppression of ovulation [21]. Endometriosis has also been use cannot exceed the 6 months limit as prolonged exposure associated with an increased risk for endometrioid and increases the risk for BMD reduction and [90, clear cell epithelial ovarian . It is hypothesized that 91], especially in adolescents [92]. The threshold hypothesis, shared risk factors, such as persistent ovulation, retrograde which states that estrogen requirements are greater for the menstruation, chronic peritoneal inflammation and immune endometrium than brain, bone, and other tissues, has given or steroid imbalances [78] are responsible. A recent pooled rise to the use of add-back therapy using progesterone data analysis from 4 population-based, case-control studies or a combination of estrogen and progesterone, thereby showed that long-term use of OCs reduces the risk of ovarian eliminating GnRH analogs adverse effects without cancer independently of a history of endometriosis, the decreasing efficacy [93]. Administration of GnRH agonists, reduction being marked in women with a history of with or without add back therapy as an adjuvant to surgery, endometriosis [78]. may reduce postoperative adhesion formation [94] but Cyclic use of OCs allows monthly uterine bleeding and other benefits like extending pain-free intervals are some patients on OCs might continue to experience temporary [95, 96]. bothersome dysmenorrhea. There are several studies Adding add back therapy to a GnRH agonist somewhat demonstrating that women with menstrual related problems complicates dosing regiments and increases cost without during cyclic use of an OC may benefit from a switch to offering additional benefits in efficacy compared to OC or continuous use of OCs. Studies in adult women with progestin use only. menstruation-related problems showed that an extended cycle regimen (allowing menses every 3 or more months) GnRH Antagonists was easier to follow, well tolerated, and efficacious in reducing menstrual symptoms [79-83]. A 7-day patient- The recently available GnRH antagonists cause an determined cessation of treatment is suggested in case of instant, dose-dependent inhibition of FSH and LH secretion, breakthrough bleeding during continuous use of OCs. The without causing an initial flare-up, as do GnRH agonists, or extended cycle regimen can cause a potential decrease in promoting histamine release from the mast cells [97, 98]. endometrial stability and a possible harmful effect on lipid GnRH antagonists have theoretically the same indications profile [84]. Furthermore, sexually active adolescents and currently accepted for agonists although clinical evidence is young adults may not be able to recognize an unexpected still limited [99-101] showing no clear benefit between the 142 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Sardeli et al. two drugs classes. Adverse effects reported include mood substrate [107]. and are trizazole changes, hot flushes, loss of libido and vaginal dryness [99]. derivatives, which are 3rd generation reversible, competitive GnRH antagonists are more expensive and have more AIs, and, at doses of 1-5 mg/day, inhibit aromatase levels complex dosing regiments and route of administration and by 97-99%. thus are not expected to solve problems associated with AIs’ most common adverse effects include mild GnRH agonists use, at least for the time being. , nausea, and diarrhea, possibly hot flushes (milder and less frequent that those associated with GnRH analogue NOVEL PHARMACOLOGIC APPROACHES FOR use). There is a possible effect on lipid profile [108]. Long- ENDOMETRIOSIS term use of AIs carries the potential risk of osteopenia and Other drug classes are being tested or developed based on osteoporosis. Supplementation with and vitamin D recent research findings regarding the molecular mechanisms is also recommended in an attempt to prevent a decrease in responsible for endometriosis, hold promise for safer, more bone mineral density in patients on AIs [109]. selective, and more efficacious treatment of the disease, with In postmenopausal women, oral administration of examples such as , selective letrozole in small doses (milligrams/day) inhibits peripheral modulators, (SERMs), selective tissue aromatase by 99%. Both types of AIs reduce modulators, (SPRMs), GnRH antagonists, aromatase circulating estrogen to 1-10% of pre-treatment levels in inhibitors, pentoxifylline, tumor necrosis factor- (TNF-) postmenopausal women or in premenopausal women whose inhibitors, MMP inhibitors, and angiogenesis inhibitors, to ovaries have been rendered non-functional with other name but a few [11]. treatments [110]. Premenopausal women with endometriosis resistant to surgical or medical treatment have received AIs AROMATASE INHIBITORS in combination with a [110] or an OC [111]. Aromatase is a (CYP) Both studies showed positive effects of the treatments on the expressed in several human tissues (ovarian granulosa cells, disease symptoms without major adverse effects. The only placental syncytiotrophoblast cells, adipose tissue and skin RCT [108] published to date evaluating the clinical efficacy fibroblasts among others), that catalyzes the conversion of of an AI+GnRH analogue combination vs GnRH analogue androgens to [21,102]. Estrogen is not synthetized alone for 6 months in a post-surgical setting in 80 patients in normal endometrial tissue but there is both CYP19 with severe endometriosis showed that the combination is and aromatase activity in leiomymoas, superior in reducing pain at 24-month follow-up, without and endometriotic tissues [103]. Aromatase activity in deleterious effects on BMD or patient quality of life. endometriotic tissue is regulated by several pathways presented shortly here. The cyclic-AMP-inducible promoter ANTI-INFLAMATORY AND IMMUNOMODULATING II appears to be responsible for in vivo aromatase expression DRUGS in endometriotic tissue. The stimulatory transcription factor A substantial number of publications support the (SF-1), expressed only in endometriotic tissue but not inflammatory nature of endometriosis where elevated levels in normal endometrium, binds to aromatase promoter II of cytokines and growth factors in peritoneal fluid, absolute more avidly than the inhibitory factor COUP-TF (chicken number, concentration and activity of macrophages, ovalbumin upstream promoter transcription factor). Thus, alterations in B-cell activity and an increased incidence of SF-1 activates aromatase gene transcription in endometriosis autoantibodies have been demonstrated in women with overcoming the protective inhibition maintained normally by endometriosis [112-116]. The use of two different types of COUP-TF in normal endometrium [21,104]. These findings immunomodulators seems thus well substantiated. This form, as recently published, the molecular basis for the use novel approach encompasses drugs that reduce inflammatory of aromatase inhibitors (AIs) in the pharmacologic treatment components and drugs that enhance immune response. of endometriosis [103] inhibiting estrogen production in the brain, the ovary, endometriotic tissue and adipose tissue and Drugs Reducing Inflammatory Components skin. Anti-inflammatory drugs such as COX inhibitors or AIs have been used in the treatment of postmenopausal anticytokines are currently under investigation for . They are classified into type I inhibitors endometriosis treatment beyond pain management based on (suicidal or noncompetitive) and type II inhibitors the fact that endometriosis is an inflammatory condition (competitive) [105, 106]. Both types of inhibitors compete [21]. for binding to the active site. Type I AIs binding to the active site is followed by enzyme irreversibly COX expression is found to increase in endometriotic inhibiting aromatase activity [107]. and tissue [117-119]. Since cancer patients using COX-2 are selective 3rd generation type I AIs. Type II inhibitors exhibit significant reduction in tumour growth AIs bind reversibly to the active enzyme site, thus inhibiting [120] several researchers have published data on the use of aromatase activity. The inhibitor can unbind from the these drug class in animal endometriosis models, given that binding site, allowing renewed competition for binding to endometriosis although a benign condition behaves the active enzyme site between the inhibitor and the invasively. Celecoxib, indomethacin, rofecoxib, substrate. Thus, continued activity requires continuous and nimesulide have been used in murine models with presence of inhibitor, and the efficacy of competitive varying results [121, 122]. One placebo-controlled trial inhibitors depends on the affinities of the inhibitor and the published has evaluated the efficacy of rofecoxib (25 Endometriosis: The Role of Pharmacotherapy Current Women’s Health Reviews, 2012, Vol. 8, No. 2 143 mg/day) vs placebo administered for 6 months in C patients. It causes activation of natural killer endometriosis-associated pelvic pain followed by (NK) cell-mediated lysis and CD8+ T-cell expansion and conservative surgery [123]. Pelvic pain and dyspareunia stimulation [131]. Loxoribine enhances NK-cell activity, were significantly decreased and the effect persisted for 6 stimulates the proliferation of B cells, stimulates months after treatment without recurrence in the rofecoxib macrophage-mediated cytotoxicity and augments antibody group vs 16% recurrence rate was observed in the placebo responses [132]. Levamisole, used as an antihelminthic drug, group. minimally affects T helper-1 cell immune function in humans without alteration of serum cytokine levels [131, Tumour necrosis factor (TNF)-a, secreted by macro- 134]. These drugs have been tested in animal endometriosis phages, is increased in peritoneal fluid from women with models with good results [135-138], though without endometriosis, and it has therefore been suggested that counteracting TNF-a could have a positive effect. TNF-a is a reproducibility in humans [131]. pleiotropic cytokine that can have a variety of positive and SELECTIVE PROGESTERONE RECEPTOR adverse effects, dependent on the quantity produced, its MODULATORS tissue localization and the local activity of TNF binding proteins. Etanercept (a TNF-a receptor-immunoglobulin Progesterone receptors exist as two separate isoforms fusion protein) successfully decreases the extent of (hPRA and hPRB), expressed by a single gene through an spontaneously occurring active endometriosis in baboons alternative splicing mechanism, and located in the cell [124]. Use of infliximab (a chimeric anti-TNF-a monoclonal nucleus. The two isoforms have similar steroid- and antibody) when compared to placebo combined with DNA-binding properties but have distinct functions that are surgery in 21 women with severe pain and rectovaginal dependent on the cell type. Generally, hPRB is a much endometriosis, showed a 30% decrease in pain severity stronger transcription activator than hPRA. Under certain before surgery. No effect of infliximab use was observed for conditions, hPRA is inactive as a transcription factor but any of the outcome measures before surgery. After surgery, can act as a ligand-dependent repressor of other steroid pain scores decreased in both groups with no between-group receptors, including its sibling isoform, estrogen/androgen/ differences. These preliminary clinical data therefore suggest mineralocorticoid and receptors [139]. Both that TNF-a inhibitors do not affect the pain associated with isoforms’ expression is upregulated in response to estrogens endometriosis [21,125]. in human endometrium preceding ovulation, but their Pentoxifylline, a xanthine derivative, is another known expression is downregulated by progesterone during inhibitor of TNF-. Four studies have been published endometrial maturation. The precise effect of these two with mixed data regarding pentoxifylline efficacy. Oral on the endometrium probably depends on the administration of pentoxifylline 800 mg/day had little effect hPRA/hPRB ratio, in fact, selective ablation of hPRA results on in women with minimal or mild endometriosis in a gain of hPRB-mediated proliferative activity in the [126]. One prospective, double-blind, randomized, placebo- endometrium [139, 140]. controlled study that postoperative use of pentoxifylline 800 The key role progesterone plays in reproduction led to mg/day for 6 months did not improve or reduce symptom the development of synthetic progesterone receptor ligands. recurrence in women with different stages of endometriosis Selective progesterone receptor modulators (SPRMs) have [127]. A recently published RCT comparing the use of mixed agonist and antagonist properties and exist as pentoxifylline after conservative surgery to surgery only three different types: type I SPRMs prevent or attenuate reported symptom reduction at 2 and 3 months posto- progesterone receptor binding to the progesterone response peratively [128]. Finally, a recent prospective, randomized, element, type II SPRMs promote progesterone receptor controlled blind trial reported that postoperative binding to DNA response element, but their ability to administration of pentoxifylline 800 mg/day immediately alter gene expression is highly variable and may be after laparoscopy achieved a higher, albeit non-significant, site-specific and type III SPRMs inhibit DNA transcription increase in cumulative pregnancy probability 6 months after by influencing progesterone receptor binding to the pro- surgery as compared to placebo [129]. A recently published gesterone response element. Until now, only type II SPRMs Cochrane Database review concluded that there is not have been used in the treatment of endometriosis, and they enough evidence to support the use of pentoxifylline in the can exerts different effects, depending on dose, the presence management of premenopausal women with endometriosis or absence of progesterone and site of action [141]. in terms of subfertility and relief of pain outcomes [130]. SPRMs have the potential to selectively inhibit estrogen- Agents Enhancing Cell-Mediated Immunity dependent endometrial proliferation and induce reversible amenorrhea without the systemic effects of estrogen Several drugs exhibiting immune-enhancing properties deprivation [140, 142]. Moreover SPRMs reversibly suppress have been investigated in endometriosis, including endometrial bleeding via a direct effect on endometrial blood interleukin-12, interferon (IFN)-a-2b (cytokines), loxoribine vessels, exhibit the potential to suppress endometrial (a guanosine analogue) and levamisole (an acetylcholine prostaglandin production in a tissue-specific manner. Several nicotinic receptor analogue) [21]. These drugs are pleiotropic reasons have been suggested for their anti-proliferative stimulators of the components of the immune system, a fact effects: they could be secondary to inhibition of estrogen accounting for their significant adverse effects. receptor gene transcription by the hPRA isoform, or they IFNa-2b is particularly effective in regulating immune could be caused by atrophy of spiral arteries, by the blockade responses against viral infections, as demonstrated in chronic of progesterone-dependent growth factors, by the inhibition 144 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Sardeli et al. of angiogenesis, by cell cycle blockade or by modulation of inhibit the interaction of cytokines with their cellular apoptosis via growth factors [139] In addition, SPRMs have receptor; and drugs,which have a direct inhibitory effect on the ability to suppress endometrial prostaglandin production the endothelial cells [149]. in a tissue-specific manner, which provides a further Anti-angiogenic drugs such as VEGF inhibitors and rationale for the treatment of endometriosis related pain angiostatic agents (AGM1470 [TNP470], endostatin, [21,140]. ) have been shown to reduce the establishment, One randomized placebo-controlled study [143] has maintenance and progression of endometriotic lesions in evaluated the safety and efficacy of the type II ligand different laboratory and animal models [151]. in the treatment of endometriosis symptoms. Three Both aromatase and COX-2 result in the production of different doses of asoprisnil (5, 10 and 25 mg/day) PGE2 and estradiol, which are known to increase VEGF were administered for 12 weeks to 130 women with a expression and thus angiogenesis. Inhibition of these key laparoscopic diagnosis of endometriosis and moderate-to- is likely to result in inhibition of angiogenesis. severe pain at baseline. Interestingly, all doses of asoprisnil These drug classes are discussed elsewhere in this review. reduced non menstrual pelvic pain and dysmenorrhea with mild adverse effects. Asoprisnil induces non-physiologic PROGESTERONE ANTAGONISTS secretory effects in the glandular epithelium and presence of unusual "thick-walled" arterial vessels in the stroma on the Mifepristone (RU 486), (ZK 98 299) and human endometrium during treatment for up to 3 months. CDB 2914 are orally administered progesterone antagonists These effects are consistent with endometrial anti- (PAs), demonstrating a high affinity for progesterone and proliferative effects of asoprisnil, without evidence of glucocorticoid II receptors. PAs act by competing with the hyperplastic changes. Such histologic changes may cause agonist for progesterone receptor binding and promote the confusion in interpreting endometrial biopsies especially if activation steps of dimerization and binding to specific the pathologist is unaware of the drug administered and its progesterone response elements of target DNA. However, effects on endometrial histology [144]. The most commonly PAs induce an altered conformation in progesterone reported adverse effects associated with asoprisnil use receptors that are transcriptionally inactive, resulting in a are headache, abdominal pain, nausea, dizziness, and non-productive interaction of the receptor with DNA. This is metrorrhagia. caused by progesterone receptor recruitment of co-inhibitors (such as the nuclear receptor co-repressor (NcoR) and ANGIOGENESIS INHIBITING DRUGS silencing mediator of retinoic acid and thyroid hormone receptor (SMRT)) instead of co-activators [152, 153]. Again “borrowing” from cancer, vascularization of endometriotic tissue is probably one of the most important Mifepristone exerts a direct inhibitory effect on human factors in the process of tissue invasion by endometrial cells endometrial cells [154] and it can modulate the estrogen and [21]. The peritoneal milieu is highly angiogenic, and both progesterone receptor expression in both eutopic and ectopic quantitative and qualitative increases of factors promoting endometrium [155]. Mifepristone has effectively reduced the angiogenesis in peritoneal fluid from women with size of endometriotic lesions in a primate model [156]. Three endometriosis have been demonstrated [145] Several factors small clinical trials [157-159] have been published regarding control angiogenesis including inducers like fibroblast the administration of three different doses of mifepristone (5 growth factor, hepatocyte growth factor, transforming mg/day or 50 mg/day for 6 months or 100 mg/day for 3 growth factor-a and -b and inhibitors such as angiostatin, months). There was an improvement in symptoms in all endostatin and thrombospondin [146]. The most important patients included in the studies independently of the dose though appears to be the vascular endothelial growth factor and a 55% mean regression of visible endometriosis after 6 (VEGF) family of glycoproteins, which are thought to be months of treatment was observed following the 50 mg dose. involved in both physiological and pathological angiogenesis Administration of mifepristone 5 mg/day in an uncontrolled [147]. VEGF is expressed in endometriotic tissue, a pilot study [160] resulted in pain improvement but no change fact explaining the mechanism for the neovascularization in endometriosis lesions, suggesting this dosage is too low to that is observed around endometriotic lesions (especially achieve adequate efficacy. Mifepristone appears promising hemorrhagic red lesions) [148]. Elevated levels of VEGF-a for the treatment of endometriosis, since it does not induce is highly abundant in peritoneal fluid from women with the severe estrogen deficiency associated with AIs. However, endometriosis; the highest levels were seen during the the long-term safety of mifepristone is still unclear, due proliferative phase of the cycle, a time at which the to the properties of mifepristone. peritoneum is exposed to the retrograde endometrium [149]. Hypoadrenalism must be considered as a major adverse There is a positive correlation between the severity of effect of long-term treatment, especially with doses > 200 endometriosis and the level of VEGF-a in peritoneal fluid. mg/day. The cellular sources of VEGF in peritoneal fluid have not been precisely defined and, although there is evidence OTHER PHARMACOLOGICAL AND NON- suggesting that it is produced by endometriotic lesions, PHARMACOLOGICAL OPTIONS activated peritoneal macrophages also have the ability to Alternative treatment options, such as use of vitamin synthesize and secrete VEGF [150]. B1 and , have been suggested for primary Angiogenesis inhibitors can be divided into two distinct dysmenorrhea, but it is unclear if they are effective groups: drugs that sequester proangiogenic cytokines or for endometriosis-associated dysmenorrhea [2, 161, 162]. Endometriosis: The Role of Pharmacotherapy Current Women’s Health Reviews, 2012, Vol. 8, No. 2 145

Nutritional and alternative therapies such as reflexology, [10] Nasu K, Yuge A, Tsuno A, Nishida M, Narahara H. Involvement of traditional Chinese medicine [163], herbal treatments, and resistance to apoptosis in the pathogenesis of endometriosis. Histol homeopathy [164], have also been suggested to reduce Histopathol. 2009; 24(9): 1181-92. [11] Guo SW. Emerging drugs for endometriosis. Expert Opin Emerg endometriosis-associated pain, and despite lack of evidence Drugs 2008; 13(4): 547-71. from RCTs, ESHRE guidelines suggest that these therapies [12] Ozkan S, Arici A. Advances in treatment options of endometriosis. should not be discouraged if the patient feels that they may Gynecol Obstet Invest 2009; 67(2): 81-91. be beneficial for pain management [2]. [13] Valle RF, Sciarra JJ: Endometriosis: treatment strategies. Ann NY Acad Sci 2003; 997: 229-39. COMMENT [14] Giudice LC. Endometriosis. Lancet 2004; 364: 1789-99. [15] The Practice Committee of the American Society for Reproductive Recent advances in endometriosis research have Medicine: Treatment of pelvic pain associated with endometriosis. improved current knowledge regarding endometriosis Fertil Steril 2006; 86: 18-27. pathophysiology. As a result, several novel pharmacologic [16] Vercellini P, Cortesi I, Crosignani PG. Progestins for symptomatic endometriosis: a critical analysis of the evidence. Fertil Steril 1997; strategies for endometriosis involving old and new drugs are 68: 393-401. under investigation with promising potential, at least in [17] Crosignani P, Olive D, Bergqvist A, Luciano A. Advances in the preclinical testing. On the other hand, numerous Phase II/III management of endometriosis: an update for clinicians. Hum studies are either listed as suspended or completed without Reprod Update 2006; 12(2): 179-89. publication of positive or negative results. Based on the [18] Henzl MR, Corson SL, Moghissi K, Buttram VC, Berqvist C, complex and still not fully understood pathways involved Jacobson J. Administration of nasal nafarelin as compared with oral and the currently available data, it is – regrettably - safe to danazol for endometriosis: a multicenter double-blind comparative . N Engl J Med 1988; 318(8): 485-9. say that no miracle drug will be available in the near future. [19] Fraser IS, Shearman RP, Jansen RP, Sutherland PD. A comparative Management of endometriosis in general, and pharma- treatment trial of endometriosis using the gonadotrophin releasing cotherapy in particular, must be tailored to fit the individual hormone agonist, nafarelin, and the synthetic steroid, danazol. Aust patient’s history and needs, choosing drugs that are N Z J Obstet Gynaecol 1991; 31(2): 158-63. efficacious in reducing burden of disease and are cost [20] Rotondi M, Labriola D, Rotondi M, et al. Depot acetate effective, without forgetting the role of surgery for diagnosis, versus danazol in the treatment of infertile women with symptomatic endometriosis. Eur J Gynaecol Oncol 2002; 23: removal of lesions and/or pain management where indicated. 523-6. Progestins and OCs fit these requirements and GnRH [21] Vercellini P, Somigliana E, Viganò P, Abbiati A, Barbara G, agonists must be chosen for progestin or OC non-responders. Crosignani PG. Endometriosis: Current Therapies and New Newer drugs must be studied further in terms of efficacy and Pharmacological Developments. Drugs 2009; 69(6): 649-675. long-term safety. [22] Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2001; CONFLICT OF INTEREST 4: CD000068. [23] Cobellis L, Razzi S, Fava A, Severi FM, Igarashi M, Petraglia F. A Declared none. danazol-loaded intrauterine device decreases dysmenorrhea, pelvic pain, and dyspareunia associated with endometriosis. Fertil Steril ACKNOWLEDGEMENT 2004; 82(1): 239-40. [24] Razzi S, Luisi S, Calonaci F, Altomare A, Bocchi C, Petraglia F. Declared none. Efficacy of vaginal danazol treatment in women with recurrent deeply infiltrating endometriosis. Fertil Steril 2007; 88(4): 789-94. REFERENCES [25] Surrey ES. The role of progestins in treating the pain of endometriosis. J Minim Invasive Gynecol 2006; 13: 528-34. [1] Barbieri RL. Endometriosis 1990 - current treatment approaches. [26] Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani GB. Drugs 1990; 39(4): 502-10. Gestrinone versus danazol in the treatment of endometriosis. Fertil [2] Kennedy S, Bergqvist A, Chapron C, et al. ESHRE guidelines for Steril 1989; 51(5): 781-5. the diagnosis and treatment of endometriosis. Hum Reprod 2005; [27] Gestrinone Italian Study Group. Gestrinone versus a gonadotropin- 20: 2698-2704. releasing hormone agonist for the treatment of pelvic pain [3] Jones GL, Kennedy SH, Jenkinson C. Health-related quality of life associated with endometriosis: a multicenter, randomized, double- measurement in women with common benign gynecologic blind study. Fertil Steril 1996; 66: 911-9. conditions: A systematic review. American J Obstet Gynecol 2002; [28] Muneyyirci-Delale O, Karacan M. Effect of norethindrone acetate 187(2): 501-11. in the treatment of symptomatic endometriosis. Int J Fertil Womens [4] Valle RF, Sciarra JJ: Endometriosis: treatment strategies. Ann NY Med 1998; 43: 24-7. Acad Sci 2003; 997: 229-239. [29] Moore C, Kohler G, Muller A. The treatment of endometriosis with [5] Giudice LC: Endometriosis. Lancet 2004; 364: 1789-1799. dienogest. Drugs Today 1999; 35 (Suppl C): 41-52. [6] The Practice Committee of the American Society for Reproductive [30] Vercellini P, Pietropaolo G, De Giorgi O, Pasin R, Chiodini A, Medicine: Treatment of pelvic pain associated with endometriosis. Crosignani PG. Treatment of symptomatic rectovaginal endo- Fertil Steril 2006; 86: 18-27. metriosis with an estrogen-progestogen combination versus low- [7] Christodoulakos G, Augoulea A, Lambrinoudaki I, Sioulas V, dose norethindrone acetate. Fertil Steril (2005) 84: 1375-87. Creatsas G. Pathogenesis of endometriosis: the role of defective [31] Ferrero S, Camerini G, Ragni N, Venturini PL, Biscaldi E, ‘immunosurveillance’. The European Journal of Contraception & Remorgida V. Norethisterone acetate in the treatment of colorectal Reproductive Health Care 2007; 12: 1362-87. endometriosis: a pilot study. Hum Reprod 2010; 25(1): 94-100. [8] Khan KN, Kitajima M, Hiraki K, et al. Immunopathogenesis of [32] Riis BJ, Lehmann HJ, Christiansen C. Norethisterone acetate in pelvic endometriosis: role of hepatocyte growth factor, macrophages combination with estrogen: effects on the skeleton and other and ovarian . Am J Reprod Immunol 2008; 60(5): 383-404. organs: a review. Am J Obstet Gynecol 2002; 187: 1101-6. [9] Taylor RN, Yu J, Torres PB, et al. Mechanistic and therapeutic [33] Vercellini P, Crosignani PG, Somigliana E, Berlanda N, Barbara G, implications of angiogenesis in endometriosis. Reprod Sci. 2009 Fedele L. Medical treatment for rectovaginal endometriosis: what Feb;16(2):140-6. Epub 2008 Nov 11. is the evidence? Hum Reprod (2009) 24: 2504-14. 146 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Sardeli et al.

[34] Beksinska ME, Kleinschmidt I, Smit JA, Farley TM. Bone mineral treatment of endometriosis-associated pain. Hum Reprod 2006; 21: density in a cohort of adolescents during use of norethisterone 248-56. enanthate, depot-medroxyprogesterone acetate or combined [53] Salmi A, Pakarinen P, Peltola AM, Rutanen EM. The effect of oral contraceptives and after discontinuation of norethisterone intrauterine levonorgestrel use on the expression of C-Jun, enanthate. Contraception 2009; 79(5): 345-9. oestrogen receptors, progesterone receptors and Ki-67 in human [35] Beksinska ME, Smit JA, Kleinschmidt I, Farley TM, Mbatha F. endometrium. Mol Hum Reprod 1998; 4(12): 1110-5. Bone mineral density in women aged 40-49 years using depot- [54] Lockhat FB, Emembolu JO, Konje JC. The evaluation of medroxyprogesterone acetate, or the effectiveness of an intrauterine-administered progestogen combined oral contraceptives for contraception. Contraception (levonorgestrel) in the symptomatic treatment of endometriosis and 2005; 71(3): 170-5. in the staging of the disease. Hum Reprod 2004; 19: 179-84. [36] Fraser HM, Baird DT. Clinical applications of LHRH analogs. [55] Lockhat FB, Emembolu JO, Konje JC. The efficacy, side-effects Baillieres Clin Endocrinol Metab. 1987; 1(1): 43-70. and continuation rates in women with symptomatic endometriosis [37] Fedele L, Arcaini L, Bianchi S, Baglioni A, Vercellini P. undergoing treatment with an intra-uterine administered Comparison of cyproterone acetate and danazol in the treatment of progestogen (levonorgestrel): a 3 year follow-up. Hum Reprod pelvic pain associated with endometriosis. Obstet Gynecol 1989; 2005; 20: 789-93. 73(6): 1000-4. [56] Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E Silva JC, [38] Moran C, Alcivia JC, Garcia-Hernandez E, Castro J. Treatment of Podgaec S, Bahamondes L. Randomized clinical trial of a endometriosis with cyproterone acetate: preliminary report. Arch levonorgestrel-releasing intrauterine system and a depot GnRH Med Res 1996; 27: 535-8. analogue for the treatment of chronic pelvic pain in women with [39] Vercellini P, De Giorgi O, Mosconi P, Stellato G, Vicentini S, endometriosis. Hum Reprod 2005; 20(7): 1993-8. Crosignani PG. Cyproterone acetate versus a continuous [57] Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, monophasic oral contraceptive in the treatment of recurrent pelvic Crosignani PG.A Levonorgestrel releasing intrauterine system for pain after conservative surgery for symptomatic endometriosis. the treatment of dysmenorrhea associated with endometriosis: a Fertil Steril 2002; 77(1): 52-61. pilot study. Fertil Steril 1999; 72(3): 505-8. [40] Harrison RF, Barry-Kinsella C. Efficacy of medroxyprogesterone [58] Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, treatment in infertile women with endometriosis: a prospective, Crosignani PG.Comparison of a levonorgestrel-releasing intra- randomized, placebo-controlled study. Fertil Steril 2000; 74: 24-30. uterine device versus expectant management after conservative [41] Bergqvist A, Theorell T. Changes in quality of life after hormonal surgery for symptomatic endometriosis: a pilot study. Fertil Steril treatment of endometriosis. Acta Obstet Gynecol Scand 2001; 80: 2003; 80(2): 305-9. 628-37. [59] Ewies AAA. Mirena: the other side of the story. BJOG 2007; 114: [42] Cundy T, Evans M, Roberts H, Wattie D, Ames R, Reid IR. Bone 1307-8. density in women receiving depot medroxyprogesterone acetate for [60] Vercellini P, Vigano P, Somigliana E. The role of the contraception. BMJ 1991; 303(6793): 13-6. Erratum in: BMJ 1991; levonorgestrel-releasing intrauterine device in the management of 303(6796): 220. symptomatic endometriosis. Curr Opin Obstet Gynecol 2005; 17: [43] Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. 359-65. Injectable hormone contraception and : results from a [61] Schlaff W, Dugoff L, Danewood M, Rock J. for prospective study. Epidemiology 2002; 13(5): 581-7. Erratum in: treatment of endometriosis. Obstet Gynecol. 1990; 75: 646-8. Epidemiology 2002; 13(6): 749 [62] Overton CE, Lindsay PC, Johal B, Collins SA, Siddle NC, Shaw [44] Clark MK, Sowers MR, Nichols S, Levy B. Bone mineral density RW, Barlow DH. A randomized, double-blind, placebo-controlled changes over two years in first-time users of depot study of luteal phase dydrogesterone (Duphaston) in women with medroxyprogesterone acetate. Fertil Steril 2004; 82(6): 1580-6. minimal to mild endometriosis. Fertil Steril 1994; 62(4): 701-7. [45] Shaarawy M, El-Mallah SY, Seoudi S, Hassan M, Mohsen IA. [63] Cosson M, Querleu D, Donnez J, Madelenat P, Konincks P, Effect of long-term use of depot medroxyprogesterone acetate as Audebert A, Manhes H. Dienogest is as effective as triptorelin in hormonal contraceptive on bone mineral density and biochemical the treatment of endometriosis after laparoscopic surgery: results of markers of bone remodeling. Contraception 2006; 74(4): 297-302. a prospective, multicenter, randomized study. Fertil Steril 2002; [46] Cundy T, Cornish J, Roberts H, Reid IR. Menopausal bone loss in 77(4):684-692. long-term users of depot medroxyprogesterone acetate [64] Timonen J, Johansson C. Endometriosis treated with lynestrenol. contraception. Am J Obstet Gynecol 2002; 186(5): 978-83. Ann Chir Gynaecol Fenn 1968; 57: 144 -7. [47] Cundy T, Cornish J, Evans MC, Roberts H, Reid IR.. Recovery of [65] D.L. Olive, Medical therapy of endometriosis, Semin Reprod Med bone density in women who stop using medroxyprogesterone 2003; 21: 209-222. acetate. BMJ 1994; 308(6923): 247-8. [66] Ekstrom P, Juchnicka E, Laudanski T, Akerlund M. Effect of an [48] Orr-Walker BJ, Evans MC, Ames RW, Clearwater JM, Cundy oral contraceptive in primary dysmenorrhea - changes in uterine T, Reid IR.The effect of past use of the injectable contraceptive activity and reactivity to agonists. Contraception 1989; 40: 39-47. depot medroxyprogesterone acetate on bone mineral density in [67] Ekstrom P, Akerlund M, Forsling M, Kindahl H, Laudanski T, normal post-menopausal women. Clin Endocrinol (Oxf). 1998; Mrugacz G. Stimulation of vasopressin release in women with 49(5): 615-8. primary dysmenorrhea and after oral contraceptive treatment - [49] Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcutaneous effect on uterine contractility. Br J Obstet Gynaecol 1992; 99: depot medroxyprogesterone acetate versus leuprolide acetate in the 680-4. treatment of endometriosis-associated pain. Hum Reprod 2006; [68] Milsom I, Andersch B. Effect of various oral contraceptive 21(1): 248-56. combinations on dysmenorrhea. Gynecol Obstet Invest 1984; [50] Vercellini P, De Giorgi O, Oldavi S, Cortesi I, Panazza S, 17(6): 284-92. Crosignani P. Depot medroxyprogesterone acetate versus an oral [69] Larsson G, Milsom I, Lindstedt G, Rybo G. The influence of a low- contraceptive combined with very-low-dose danazol for long-term dose combined oral contraceptive on menstrual blood loss and iron treatment of pelvic pain associated with endometriosis. Am J status. Contraception 1992; 46(4): 327-34. Obstet Gynecol 1996; 175: 396-401. [70] Robinson JC, Plichta S, Weisman CS, Nathanson CA, Ensminger [51] Schlaff W, Carson S, Luciano A, Ross D, Bergqvist A. M.Dysmenorrhea and use of oral contraceptives in adolescent Subcutaneous injection of depot medroxyprogesterone acetate women attending a family planning clinic. Am J Obstet Gynecol compared with leuprolide acetate in the treatment of endometriosis 1992; 166(2): 578-83. associated pain. Fertil Steril 2006; 85: 314-25. [71] Ulstein M, Svendsen E, Steier A, Bratt H, Fylling P, Lie S, [52] Crosignani P, Luciano A, Roy A, Bergqvist A. Subcutaneous depot Schiefloe A, Aaserud J. Clinical experience with a triphasic oral medroxyprogesterone acetate versus leuprolide acetate in the contraceptive. Acta Obstet Gynecol Scand 1984; 63(3): 233-6. Endometriosis: The Role of Pharmacotherapy Current Women’s Health Reviews, 2012, Vol. 8, No. 2 147

[72] Weber-Diehl F, Unger R, Lachnit U. Triphasic combination of [93] Barbieri RL. Hormone treatment of endometriosis: the estrogen ethinyl estradiol and gestodene. Long-term clinical trial. threshold hypothesis. Am J Obstet Gynecol 1992; 166: 740-5. Contraception 1992; 46: 19-27. [94] Schindler AE. Gonadotropin-releasing hormone agonists for [73] Davis AR, Westhoff C, O'Connell K, Gallagher N. Oral prevention of postoperative adhesions: an overview. Gynecol contraceptives for dysmenorrhea in adolescent girls: a randomized Endocrinol 2004; 19: 51-5 trial. Obstet Gynecol 2005; 106(1): 97-104. [95] Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, [74] Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. Endometriosis: preoperative and postoperative Crosignani PG. A gonadotropin-releasing hormone agonist versus a medical treatment. Obstet Gynecol Clin North Am 2003; 30(1): low-dose oral contraceptive for pelvic pain associated with 163-80. endometriosis. Fertil Steril 1993; 60(1): 75-9. [96] Yap C, Furness S, Farquhar C. Pre and post operative medical [75] Parazzini F, Di Cintio E, Chatenoud L, et al. Estroprogestin vs. therapy for endometriosis surgery. Cochrane Database Syst Rev gonadotropin agonists plus estroprogestin in the treatment of 2004; 3: CD003678. endometriosis-related pelvic pain: a randomized trial. Eur J Obstet [97] Reissmann T, Schally AV, Bouchard P, Riethmiiller H, Engel J. Gynecol Reprod Biol 2000; 88(1): 11-4. The LHRH antagonist : a review. Hum Reprod Update [76] Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low- 2000; 6(4): 322-31 dose for dysmenorrhea associated with [98] Huirne JA, Lambalk CB. Gonadotropin-releasing-hormone- endometriosis: a placebo-controlled, double-blind, randomized receptor antagonists. Lancet 2001; 358(9295): 1793-803. trial. Fertil Steril 2008; 90(5): 1583-8. [99] Küpker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich [77] Vercellini P, Somigliana E, Daguati R, Vigano P, Meroni F, K. Use of GnRH antagonists in the treatment of endometriosis. Crosignani PG. Postoperative oral contraceptive exposure and risk Reprod Biomed Online 2002; 5(1): 12-6. of endometrioma recurrence. Am J Obstet Gynecol 2008; 198(5): [100] Batzer FR. GnRH analogs: options for endometriosis associated 504e1-5. pain treatment. J Minim Invasive Gynecol 2006; 13: 539-45. [78] Modugno F, Ness RB, Allen GO, Schildkraut JM, Davis FG, [101] Pabuccu R, Onalan G, Kaya C. GnRH agonist and antagonist Goodman MT. Oral contraceptive use, reproductive history, and protocols for stage I-II endometriosis and endometrioma in in vitro risk of epithelial in women with and without fertilization/intracytoplasmic sperm injection cycles. Fertil Steril endometriosis. Am J Obstet Gynecol 2004; 191(3): 733-40. 2007; 88: 832-9. [79] Loudon NB, Foxwell M, Potts DM, Guild AL, Short RV. [102] Seli E, Berkkanoglu M, Arici A. Pathogenesis of endometriosis. Acceptability of an oral contraceptive that reduces the frequency Obstet Gynecol Clin N Am 2003; 30: 41-61. of menstruation: the tri-cycle pill regimen. BMJ 1977; 2(6085): [103] Bulun SE, Zeitoun KM, Takayama K, Sasano H. Molecular basis 487-90. for treating endometriosis with aromatase inhibitors. Hum Reprod [80] Sulak PJ, Cressman BE, Waldrop E, Holleman S, Kuehl Update 2000; 6(5): 413-8. TJExtending the duration of active oral contraceptive pills to [104] Felberbaum RE, Kupker W, Diedrich K. Will GnRH antagonists manage hormone withdrawal symptoms. Obstet Gynecol 1997; assist in the treatment of benign gynaecological ? Reprod 89(2): 179-83. Biomed Online 2002; 5 (Suppl. 1): 68-72. [81] Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the [105] Goss PE, Strasser K. Aromatase inhibitors in the treatment and standard 21-day/7-day oral contraceptive regimen to delay menses prevention of breast cancer. J Clin Oncol 2001; 19: 881-94. and reduce hormone withdrawal symptoms. Am J Obstet Gynecol [106] Buzdar A, Howell A. Advances in aromatase inhibition: clinical 2002; 186(6): 1142-9. efficacy and in the treatment of breast cancer. Clin [82] Coffee AL, Sulak PJ, Kuehl TJ. Long-term assessment of Cancer Res 2001; 7: 2620 -35. symptomatology and satisfaction of an extended oral contraceptive [107] Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An regimen. Contraception 2007; 75(6): 444-9. overview of the pharmacology and of the newer [83] Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, generation aromatase inhibitors anastrozole, letrozole, and Crosignani PG.Continuous use of an oral contraceptive for exemestane. Cancer 2002; 95: 2006 -16. endometriosis-associated recurrent dysmenorrhoea that does not [108] Amsterdam LL, Gentry W, Jobanputra S, Wolf M, Rubin SD, respond to a cyclic pill regimen. Fertil Steril 2003; 80(3): 560-3. Bulun SE. Anastrazole and oral oral contraceptives: a novel [84] Guillebaud J. Reducing withdrawal bleeds. Lancet 2000; treatment for endometriosis. Fertil Steril 2005; 84(2): 300-4. 355(9221): 2168-9. [109] Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. [85] Davis L, Kennedy SS, Moore J, Prentice A. Modern combined oral Treatment of endometriosis and chronic pelvic pain with letrozole contraceptives for pain associated with endometriosis. Cochrane and norethindrone acetate: a pilot study. Fertil Steril 2004; 81(2): Database Syst Rev 2007; (3):CD001019. 290-6. [86] Osuga Y. Novel therapeutic strategies for endometriosis: a [110] Viganò P, Mangioni S, Odorizzi MP, Chiodini A, Rocca S, Chiodo pathophysiological perspective. Gynecol Obstet Invest 2008; 66 I. Use of estrogen antagonists and aromatase inhibitors in (Suppl 1): 3-9. endometriosis. Curr Opin Investig Drugs 2003; 4 (10):1209-12. [87] Tesone M, Bilotas M, Barañao RI, Meresman G. The role of GnRH [111] Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of analogs in endometriosis-associated apoptosis and angiogenesis. postsurgical administration of goserelin plus anastrozole compared Gynecol Obstet Invest 2008; 66 (Suppl 1): 10-8. to goserelin alone in patients with severe endometriosis: a [88] Waller KG, Shaw RW. Gonadotropin-releasing hormone analogs prospective randomized trial. Hum Reprod 2004; 19(1): 160-7. for the treatment of endometriosis: long-term follow-up. Fertil [112] Ho HN, Wu MY, Yang YS. Peritoneal cell immunity and Steril 1993; 59: 511-5 endometriosis. Am J Reprod Immunol 1997; 38: 400-12. [89] Prentice A, Deary A, Goldbeck-Wood S, Farquhar CM, Smith S. [113] Sharpe-Timms KL. Basic research in endometriosis. Obstet Gonadotrophin-releasing hormone analogs for pain associated with Gynecol Clin Nor Am 1997; 24: 269-90. endometriosis (Review). Cochrane Database Syst Rev 2007; (2): [114] Kupker W, Schultze-Mosgau A, Diedrich K. Paracrine changes in CD000346. the peritoneal environment of women with endometriosis. Hum [90] Pickersgill A. GnRH agonists and add-back therapy: is there a Reprod Update 1998; 4: 719-23. perfect combination? Br J Obstet Gynaecol 1998; 105: 475-85 [115] Lebovic DI, Mueller M, Taylor RN. Immunobiology of [91] Bedaiwy M, Casper R. Treatment with leuprolide acetate and endometriosis. Fertil Steril 2001; 75: 1-10. hormonal add-back for up to 10 years in stage IV endometriosis [116] Olive DL, Lindheim SR, Pritts EA: New medical treatments for patients with chronic pelvic pain. Fertil Steril 2006; 86: 220-2 endometriosis. Best Prac and Res Clin Obstet Gynecol 2004; 18: [92] Laufer, MR. Current Approaches to Optimizing the Treatment of 319-328. Endometriosis in Adolescents. Gynecol Obstet Invest 2008; 66 [117] Nothnick WB. Treating endometriosis as an . (Suppl.1): 19-27. Fertil Steril 2001; 76: 223-31. 148 Current Women’s Health Reviews, 2012, Vol. 8, No. 2 Sardeli et al.

[118] Chishima F, Hayakawa S, Sugita K, Kinukawa N, Aleemuzzaman [137] Somigliana E, Viganò P, Rossi G, Carinelli S, Vignali M, Panina- S, Nemoto N, Yamamoto T, Honda M. Increased expression of Bordignon P. Endometrial ability to implant in ectopic sites can be cyclooxygenase-2 in local lesions of endometriosis patients. Am J prevented by interleukin-12 in a murine model of endometriosis. Reprod Immunol 2002; 48(1): 50-6. Hum Reprod 1999; 14: 2944-50. [119] Matsuzaki S, Canis M, Pouly JL, Wattiez A, Okamura K, Mage G. [138] Badawy SZ, Etman A, Cuenca V, Montante A, Kaufman L. Effect Cyclooxygenase-2 expression in deep endometriosis and matched of interferon alpha-2b on endometrioma cells in vitro. Obstet eutopic endometrium. Fertil Steril 2004; 82(5): 1309-15. Gynecol 2001; 98: 417-20. [120] Lev-Ari S, Lichtenberg D, Arber N. Compositions for treatment of [139] Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective cancer and inflammation. Recent Pat Anticancer Drug Discov progesterone receptor modulators and progesterone antagonists: 2008; 3 (1): 55-62. mechanisms of action and clinical applications. Hum Reprod [121] Efstathiou JA, Sampson DA, Levine Z, Rohan RM, Zurakowski Update 2005; 11(3): 293-307. D, Folkman J, D'Amato RJ, Rupnick MA. anti- [140] Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger inflammatory drugs differentially suppress endometriosis in a W. Selective progesterone development and use murine model. Fertil Steril 2005; 83(1): 171-81. in the treatment of leiomyomata and endometriosis. Endocr Rev [122] Hull ML, Prentice A, Wang DY, Butt RP, Phillips SC, Smith SK, 2005; 26: 423-38. Charnock-Jones DS. Nimesulide, a COX-2 inhibitor, does not [141] Olive DL, Lindheim SR, Pritts EA. New medical treatments for reduce lesion size or number in a nude mouse model of endometriosis. Best Pract Res Clin Obstet Gynaecol 2004; 18: 319- endometriosis. Hum Reprod 2005; 20 (2): 350-8. 28. [123] Cobellis L, Razzi S, De Simone S, Sartini A, Fava A, Danero S, [142] Ferrero S, Abbamonte LH, Anserini P, Remorgida V, Ragni N. Gioffrè W, Mazzini M, Petraglia F. The treatment with a COX-2 Future perspectives in the medical treatment of endometriosis. specific inhibitor is effective in the management of pain related to Obstet Gynecol Surv 2005; 60: 817-26. endometriosis. Eur J Obstet Gynecol Reprod Biol 2004; 116(1): [143] Chwalisz K, Mattia-Goldberg C, Lee M, et al. Treatment of 100-2. endometriosis with the novel selective progesterone receptor [124] Barrier BF, Bates GW, Leland MM, Leach DA, Robinson RD, modulator (SPRM) Asoprisnil. Fertil Steril 2004; 82: S83-4. Propst AM. Efficacy of antitumor necrosis factor therapy in the [144] Williams AR, Critchley HO, Osei J, et al. The effects of the treatment of spontaneous endometriosis in baboons. Fertil Steril selective progesterone receptor modulator asoprisnil on the 2004; 81 (Suppl. 1): 775-9. morphology of uterine tissues after 3 months treatment in patients [125] Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy with symptomatic uterine leiomyomata. Hum Reprod. 2007; 22(6): S. Anti-TNF-alpha treatment for deep endometriosis-associated 1696-704. pain: a randomized placebo-controlled trial. Hum Reprod 2008; 23: [145] Healy DL, Rogers PA, Hii L, Wingfield M. Angiogenesis: a new 2017-23. theory for endometriosis. Hum Reprod Update 1998; 4: 736-40. [126] Balasch J, Creus M, Fábregues F, Carmona F, Martínez-Román S, [146] McLaren J. Vascular endothelial growth factor and endometriotic Manau D, Vanrell JA. Pentoxifylline versus placebo in the angiogenesis. Hum Reprod Update 2000; 6: 45-55. treatment of infertility associated with minimal or mild [147] Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M. endometriosis: a pilot randomized clinical trial. Hum Reprod. 1997; Vascular endothelial growth factor (VEGF) in endometriosis. Hum 12(9): 2046-50. Reprod 1998; 13: 1686-90. [127] Alborzi S, Momtahan M, Parsanezhad ME, Dehbashi S, Zolghadri [148] McLaren J, Prentice A, Charnock-Jones DS, Smith SK. Vascular J, Alborzi S. A prospective, randomized study comparing endothelial growth factor (VEGF) concentrations are elevated in laparoscopic ovarian cystectomy versus fenestration and peritoneal fluid of women with endometriosis. Hum Reprod 1996; coagulation in patients with endometriomas. Fertil Steril 2004; 11: 220-3. 82(6): 1633-7. [149] Tan XJ, Lang JH, Liu DY, Shen K, Leng JH, Zhu L. Expression of [128] Kamencic H, Thiel JA. Pentoxifylline after conservative surgery vascular endothelial growth factor and thrombospondin-1 mRNA for endometriosis: a randomized, controlled trial. J Minim Invasive in patients with endometriosis. Fertil Steril 2002; 78: 148-53. Gynecol 2008; 15 (1): 62-6. [150] Tabruyn SP, Griffioen AW. Molecular pathways of angiogenesis [129] Creus M, Fábregues F, Carmona F, del Pino M, Manau D, Balasch inhibition. Biochem Biophys Res Commun 2007; 355(1): 1-5. J. Combined laparoscopic surgery and pentoxifylline therapy for [151] Becker CM, Sampson DA, Rupnick MA, Rohan RM, Efstathiou treatment of endometriosis-associated infertility: a preliminary JA, Short SM, Taylor GA, Folkman J, D'Amato RJ. Endostatin trial. Hum Reprod 2008; 23(8): 1910-6. inhibits the growth of endometriotic lesions but does not affect [130] Lv D, Song H, Li Y, Clarke J, Shi G. Pentoxifylline versus medical fertility. Fertil Steril 2005; 84 (Suppl. 2): 1144-55. therapies for subfertile women with endometriosis. Cochrane [152] Smith C and O'Malley BW. Coregulator functions: a key to Database Syst Rev 2009; (3):CD007677. understanding tissue specificity of selective receptor modulators. [131] Biron CA. Role of early cytokines, including alpha and beta Endocr Rev 2004; 25: 45-71. interferons (IFN-alpha/beta), in innate and adaptive immune [153] Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective responses to viral infections. Semin Immunol 1998; 10: 383-90. progesterone receptor modulators and progesterone antagonists: [132] Goodman MG, Reitz AB, Chen R, Bobardt MD, Goodman JH, mechanisms of action and clinical applications. Hum Reprod Pope BL. Selective modulation of elements of the immune system Update 2005; 11(3): 293-307. by low molecular weight nucleosides. J Pharmacol Exp Ther 1995; [154] Murphy AA, Zhou MH, Malkapuram S, Santanam N, Parthasarathy 274: 1552-7. S, Sidell N. RU486-induced growth inhibition of human [133] Holcombe RF, Milovanovic T, Stewart RM, Brodhag TM. endometrial cells. Fertil Steril 2000; 74: 1014-9. Investigating the role of immunomodulation for colon cancer [155] Jiang J, Wu RF, Wang ZH, Sun HC, Xu Z, Xiu HM. Effect of prevention: results of an in vivo dose escalation trial of levamisole mifepristone on estrogen and progesterone receptors in human with immunologic endpoints. Cancer Detect Prev 2001; 25: 183-91. endometrial and endometriotic cells in vitro. Fertil Steril 2002; 77: [134] Namazi MR. Levamisole: a safe and economical weapon against 995-1000. pediculosis. Int J Dermatol 2001; 40: 292-347. [156] Grow DR, Williams RF, Hsiu JG, Hodgen GD. Antiprogestin [135] Ingelmo JM, Quereda F, Acien P. Intraperitoneal and subcutaneous and/or gonadotropin-releasing hormone agonist for endometriosis treatment of experimental endometriosis with recombinant human treatment and bone maintenance: a 1-year primate study. J Clin interferon-alpha-2b in a murine model. Fertil Steril 1999; 71: 907- Endocrinol Metab 1996; 81: 1933-9. 11. [157] Kettel LM, Murphy AA, Mortola JF, Liu JH, Ulmann A, Yen SS. [136] Keenan JA, Williams-Boyce PK, Massey PJ, Chen TT, Caudle Endocrine responses to long-term administration of the MR, Bukovsky A Regression of endometrial explants in a rat antiprogesterone RU486 in patients with pelvic endometriosis. model of endometriosis treated with the immune modulators Fertil Steril 1991; 56: 402-7. loxoribine and levamisole. Fertil Steril 1999; 72: 135-41. Endometriosis: The Role of Pharmacotherapy Current Women’s Health Reviews, 2012, Vol. 8, No. 2 149

[158] Kettel LM, Murphy AA, Morales AJ, Yen SS. Clinical efficacy of [161] French L. Dysmenorrhea. Am Fam Physician. 2005; 71(2): 285-91. the antiprogesterone RU486 in the treatment of endometriosis and [162] Guerrera MP, Volpe SL, Mao JJ. Therapeutic uses of magnesium. uterine fibroids. Hum Reprod 1994; 9(suppl 1): 116-20. Am Fam Physician 2009; 80(2): 157-62. [159] Kettel LM, Murphy AA, Morales AJ, Ulmann A, Baulieu EE, Yen [163] Flower A, Liu JP, Chen S, Lewith G, Little P. Chinese herbal SS. Treatment of endometriosis with the antiprogesterone medicine for endometriosis. Cochrane Database Syst Rev 2009; mifepristone (RU486). Fertil Steril 1996; 65: 23-8. (3): CD006568. [160] Kettel LM, Murphy AA, Morales AJ, Yen SS. Preliminary report [164] Wienhard J, Tinneberg HR. Alternative treatment possibilities of on the treatment of endometriosis with low-dose mifepristone (RU complaints due to endometriosis [Article in German] Zentralbl 486). Am J Obstet Gynecol 1998; 178: 1151-6. Gynakol 2003; 125(7-8): 286-9.

Received: February 15, 2011 Revised: October 31, 2011 Accepted: December 30, 2011