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Aromatase inhibitors for female infertility: a systematic review of the literature

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Aromatase inhibitors for female infertility: a systematic review of the literature
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  Review Aromatase inhibitors for female infertility:a systematic review of the literature Dr Nikolaos P Polyzos graduated from University of Ioannina in Greece. Since 2004 he hasbeen the Head Researcher at the Section of Obstetrics and Gynaecology, Panhellenic Association for Continual Medical Research (PACMeR). He is the author of severalpublications on aromatase inhibitors in ovulation induction and treatment of advancedbreast cancer published in high impact journals. Dr Nikolaos Polyzos Nikolaos P. Polyzos 1,4 , Spyridon Tzioras 2 , Ahmed M. Badawy 3 , Antonis Valachis 1 , Charalabos Dritsas 1 , Davide Mauri 11 PACMeR (PanHellenic Association for Continual Medical Research), Section of Obstetrics and Gynaecology andPublic Health, Athens 10438, Greece;  2 Royal Free Hospital, Department of Obstetrics and Gynecology,London NW3 2QG, UK;  3 Mansoura University, Department of Obstetrics and Gynecology, Mansoura 35111, Egypt 4 Correspondence: e-mail: n.polyzos@gmail.com  Abstract Ovulation induction remains a milestone in the treatment of women with anovulatory infertility. Clomiphene citrate(CC) is considered the first line treatment for induction of ovulation in women with polycystic ovary syndrome(PCOS), while it may be used for ovulation induction in unexplained infertility. Aromatase inhibitors (AI) have beenintroduced as a new treatment option that could challenge CC for ovulation induction. A systematic review of theliterature was conducted in order to highlight the efficacy and safety of AI in female infertility. Current data fromrandomized and non-randomized trials suggest that AI may have a role in ovulation induction regimens in PCOSpatients, as well as for ovarian stimulation, since they achieve comparable clinical pregnancy rates to CC. Further-more, when combined with gonadotrophins, AI improve the ovarian response of poor responders and reduce thegonadotrophin dose required. However, the current review is based on small trials with a limited number of patients.If solid data from future large adequately powered randomized trials support current evidence regarding efficacy andsafety, AI might offer a new treatment choice for infertile women. Keywords : anastrozole, aromatase inhibitors, infertility, letrozole, ovarian stimulation, systematic review Introduction Induction of ovulation remains a milestone in the treatmentof women with anovulatory infertility (WHO group II).Historically, clomiphene citrate (CC) has been consideredthe standard care first line treatment for ovulation induc-tion in women with polycystic ovary syndrome (PCOS)[Thessaloniki European Society for Human Reproductionand Embryology (ESHRE)/American Society for Repro-ductive Medicine (ASRM)-Sponsored PCOS ConsensusWorkshop Group, 2008], whereas it may be used in womenwith unexplained infertility (Zayed and Abu-Heija, 1999).When treatment with CC fails to induce ovulation(clomiphene resistance), and in most cases of unexplainedinfertility, exogenous gonadotrophins are a treatmentchoice prior to artificial reproduction technologies (Zayedand Abu-Heija, 1999). However, despite treatment withgonadotrophins being highly effective, it is related to highercosts and considerably higher risks, such as multiple preg-nancies and ovarian hyperstimulation syndrome, comparedwith treatment with oral ovulation induction regimens(Thessaloniki ESHRE/ASRM-Sponsored PCOS Consen-sus Workshop Group, 2008).Aromatase inhibitors (AI), drugs of choice for advancedbreast cancer (Mauri  et al.,  2006), have been introducedas a new treatment option that could challenge CC for ovu-lation induction in anovulatory women. Inhibition of thearomatase system results in a decrease in aromarizationof androgens into oestrogens and releases the hypotha-lamic–pituitary axis from oestrogenic negative feedback.However, this effect is reduced later in the follicular phase RBMOnline  - Vol 19. No 4. 2009 456–471 Reproductive BioMedicine Online; www.rbmonline.com/Article/4073 on web 24 August 2009   2009 Published by Reproductive Healthcare Ltd, Duck End Farm, Dry Drayton, Cambridge CB23 8DB, UK 456  because selective non-steroidal AI have a relatively shorthalf-life, 45 h, compared with CC, 5 days to 3 weeks(Casper and Mitwally, 2006). Since they are not associatedwith down-regulation of the hypothalamic–pituitary oestro-gen receptors during the late follicular phase, adverse effectson peripheral organs such as endometrium and cervix areconsiderably less, and might be associated with good preg-nancy rates with a lower incidence of multiple pregnanciesthan CC (Casper and Mitwally, 2006). Additionally, in anovarian stimulation protocol, AI combined with gonado-trophins may be more cost-effective compared with gonad-otrophins alone, due to the reduction of gonadotrophindose required to achieve ovulation (Bedaiwy  et al.,  2006).To examine the potential role of these agents in femaleinfertility, a systematic review of the literature wasperformed. Role of AI in different types of infertility Ovulation induction in anovulatory womenwith PCOS CC induces ovulation in almost 75–80% of selected womenwith PCOS-related infertility (Messinis, 2005). After six tonine cycles of treatment with CC cumulative pregnancy ratesreach 70–75% (Imani  et al.,  2002). Life table analysis of themost reliable studies indicated a conception rate up to 22%per cycle in women ovulating on CC (ThessalonikiESHRE/ASRM-Sponsored PCOS Consensus WorkshopGroup, 2008). Nonetheless, CC is associated with a deleteri-ous effect on the endometrium that may affect implantationrates. Whereas it is suggested that endometrial thickness isnot related to conception rates in cycles stimulated with CC(Kolibianakis  et al.,  2004), it has been positively associatedwith pregnancy outcome in women undergoing intrauterineinsemination (IUI) (Esmailzadeh and Faramarzi, 2007).AI, due to their short half-life compared with CC and thereduced anti-oestrogenic effects during the late follicularphase, may not affect the endometrium and the cervix(Casper and Mitwally, 2006), and consequently lead tohigher or at least comparable pregnancy rates comparedwith CC.Cumulatively, nine trials have been published comparingAI versus CC in patients with PCOS-related infertility( Table 1 ). A pooled analysis of four early randomized trialshas shown a significantly higher live pregnancy and deliveryrate in women treated with letrozole or anastrozole com-pared with CC (Polyzos  et al.,  2008a). Nonetheless, resultswere based on a small number of heterogeneous trials witha limited number of patients.Letrozole versus CC has been tested in several trials inwomen with PCOS. However, even after the availabilityof large randomized trials the picture is still ambiguous.Whereas a large randomized trial published in 2007, com-paring letrozole versus CC, failed to detect any differenceamong compared arms (Badawy  et al.,  2007a), the mostrecent large randomized trial provided promising results(Ganesh  et al.,  2009). According to the authors, letrozoleresulted in significantly higher pregnancy rates comparedwith the combination of CC and rFSH.Evidence for the use of anastrozole is limited. Only twocontrolled trials have been published up to date, none of which managed to support its use instead of CC (Sipe et al.,  2006; Badawy  et al.,  2007b).Ongoing trials are being conducted and their resultswill clarify whether these agents may have a role in ovula-tion induction in this group of women (Amer, http://clinicaltrials.gov/ct2/show/NCT00478504; Eisenberg  et al. http://clinicaltrials.gov/ct2/show/NCT00719186; Tredway,http://clinicaltrials.gov/ct2/show/NCT00213148; all acce- ssed11 August 2009). Ovulation induction/ovarian stimulation inunexplained infertility Ovarian stimulation may be used as a first line treatment inyoung women with unexplained infertility (Zayed and Abu-Heija, 1999). CC seems to achieve higher pregnancy ratescompared with placebo in this subgroup of women (Hughes et al.,  2000), whereas a recent trial supported that it mayachieve comparable live birth rates with gonadotrophins(Dankert  et al.,  2007).AI might offer an alternative to CC as a first line regimen inwomen with unexplained infertility, either alone or com-bined with gonadotrophins. However, it is likely to be lesseffective compared with treatment in women with PCOS.Due to their reduced anti-oestrogenic effects in the late fol-licular phase, AI result in fewer mature follicles (mono-ovu-lation) compared with CC. Thus, while they might be anexcellent choice in women with anovulatory infertility, theymay not be the optimal choice in women with unexplainedinfertility.Several trials have tested the effect of AI in couples withunexplained infertility. Six trials compared anastrozole orletrozole versus traditional treatment with CC, while fourtrials involved the comparison of letrozole or anastrozoleversus CC in a ovulation induction protocol combined withgonadotrophins ( Table 2 ). Clinical pregnancy rate did notdiffer among compared arms in most of the trials, while ameta-analysis of seven randomized trials resulted in compa-rable pregnancy rates among AI and CC (Polyzos  et al., 2009a). The most recent and largest trial (Badawy  et al., 2008a) supported the results of this meta-analysis, since nosignificantdifferencewasobservedbetween5 mgofletrozoleversus 100 mg of CC in terms of clinical pregnancy rate inwomen with unexplained infertility.  AI versus gonadotrophins Gonadotrophins are the second-line treatment for patientswho fail to conceive with CC. However, treatment withgonadotrophins is linked to a higher rate of multiple preg-nancies, especially in women with anovulatory infertility, Review - Aromatase inhibitors for female infertility -  NP Polyzos et al. RBMOnline  457  Table 1.  Aromatase inhibitors versus clomiphene citrate in polycystic ovary syndrome (PCOS) related infertility. Author/year Journal Type of trial Arms Patients(cycles)Age(years)BMI Pregnancy(n)Miscarriage(n)Multi  gestOvulationcycle(%)Endometrial thickness(mm)Mature follicles(n)Letrozole trials Atay  et al. (2006) J IntMed Res RCT Letrozole 2.5 mg 51 (51) 27.1 26.1 11 NA 0 42 (82.4) 8.4 1.2Clomiphene 100 mg 55 (55) 26.2 25.8 5 NA 1 35 (63.6) 5.2 2.4Bayar  et al. (2006a) Fertil Steril  RCT Letrozole 2.5 mg 38 (99) 32.2 <25 9 1 0 65 (65.7) 8 * 1 a Clomiphene 100 mg 36 (95) 30.6 <25 7 0 0 71 (74.4) 8 * 1 a Sohrabvand et al.  (2006) HumReprod  RCT Letrozole2.5 mg + metformin29 (53) 28.2 30 10 0 0 48 (90.6) 8.2 1.9Clomiphene100 mg + metformin30 (67) 29.6 30.2 5 2 0 54 (80.6) 5.5 1.8Badawy et al. (2007a) Fertil Steril  RCT Letrozole 5 mg 218(540)27.1 28.1 82 4 0 365(67.5)8.1 2.3Clomiphene 100 mg 220(523)29.3 27.1 94 4 3 371(70.9)9.2 3.1Begum et al. (2008) Fertil Steril  RCT Letrozole 7.5 mg 32(NA)25.5 22.7 13 2 0 20 b 10.4 20 c Clomiphene 100 mg 32(NA)26.1 23.6 6 0 0 12 b 9 12 c R  e  v i    e  w-A r  om a  t   a  s  e i   n h  i    b  i    t   or  s f    or f    e m a l    e i   n f    e r  t  i   l   i    t    y -  NP P  o l     yz  o s  e  t   a l    . RB M Onl   i   n e    4    5    8     Baruah et al. (2009) ArchGynecol Obstet QuasirandomLetrozole 2.5–5 mg 25 (58) 29.7 23.6 11 NA 0 NA 6.9 1.63Clomiphene 100 mg 25 (56) 30.2 24.5 7 NA 0 NA 5.9 1.62Ganesh et al. (2009) J AssistReprod Genet RCT Letrozole 5 mg 372(372)30.3 24.5 87 12 NA 295(79.3)NA NAClomiphene100 mg + rFSH 75 or100 IU/day669(669)30.4 24.8 96 16 NA 381 (57) NA NArFSH 75 or 100 IU/day 346(346)30.8 24.1 62 9 NA 311 (90) NA NA Anastrozole trials Sipe  et al. (2006) Fertil Steril  RCT Anastrazole1 mg + FSH12 (12) 30 d 30 d 3 0 0 NA NA NAClomiphene100 mg + FSH8 (8) 32 d 28 d 2 0 1 NA NA NABadawy et al. (2007b) Fertil Steril  Prospective Anastrozole 1 mg 115(243)23.8 31.1 25 4 0 165(67.9)10.1 1.9Clomiphene 100 mg 101(226)25.3 29.1 18 3 1 150(68.6)8.2 2.1 Abbreviations:  BMI, body mass index; multi gest, multiple gestation; RCT, randomized controlled trial; NA, non-applicable.Unless otherwise stated, all values represent mean values. * Values represent median. a Values represent median, significantly higher number of follicles in CC-treated patients. b Values represent number of patients that achieved ovulation. c Values represent number of follicles >18 mm. d Values refer to patients with PCOS and patients with other causes of infertility. R  e  v i    e  w-A r  om a  t   a  s  e i   n h  i    b  i    t   or  s f    or f    e m a l    e i   n f    e r  t  i   l   i    t    y -  NP P  o l     yz  o s  e  t   a l    . RB M Onl   i   n e    4    5    9     Table 2.  Aromatase inhibitors versus clomiphene citrate for ovulation induction in women with unexplained infertility. Author/  yearJournal Type of trial Arms GonadotrophinsPatients(cycles)Age(years)BMI Pre g nancy(n) d Miscarriage(n)Endometrial thickness(mm)Mature folliclesMulti  gestEctopicAromatase inhibitors versus clomiphene without gonadotrophins Sammour et al. (2001) Fertil Steril  RCT Letrozole2.5 mgNo 25(NA)30.7 NA 16.7% a , d NA 8.6 1 NA NAClomiphene100 mgNo 24(NA)32.8 NA 5.6% a , d NA 6.9 2 NA NAAl-Fozan et al. (2004) Fertil Steril  RCT Letrozole7.5 mgNo 74(115)30.7 NA 11 0 7.1 1.3 0 2Clomiphene100 mgNo 80(123)31.5 NA 11 4 8.2 1.1 1 0Bayar(2006b) Fertil Steril  Quasi-randomLetrozole2.5 mgNo 21(52)31 * NA 5 0 8 * 1 * 0 0Clomiphene100 mgNo 25(67)31 * NA 8 1 8 * 1 * 0 0Fatemi et al. (2003) Reprod Biomed Online RCT Letrozole2.5 mgNo 7 (NA) 28.9 * 18–29 2 NA NA NA 0 0Clomiphene100 mgNo 8 (NA) 28.2 * 18–29 3 NA NA NA 0 0Badawy et al. (2008a) Fertil Steril  RCT Letrozole5 mgNo 205(400)29.1 26.6 76 11 9.3 1.6 0 NAClomiphene100 mgNo 207(404)28.3 28.1 74 12 9.2 3.1 2 NA R  e  v i    e  w-A r  om a  t   a  s  e i   n h  i    b  i    t   or  s f    or f    e m a l    e i   n f    e r  t  i   l   i    t    y -  NP P  o l     yz  o s  e  t   a l    . RB M Onl   i   n e    4    6    0   
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