- Email: [email protected]
The use of aromatase inhibitors in in vitro fertilization
The use of aromatase inhibitors in in vitro fertilization Juan A. Garcia-Velasco, M.D. IVI-Madrid, Rey Juan Carlos University, Madrid, Spain
The use of aromatase inhibitors (AIs) in IVF patients remains controversial. AIs can be considered for ovulation induction for IVF in women who are normal and poor responders, are at risk of ovarian hyperstimulation syndrome or thrombosis, who have endometriosis, and/or are undergoing fertility preservation procedures as a result of estrogen-dependent cancers, primarily breast and endometrial cancers. Although the biologic plausibility of the capacity Use your smartphone of AIs in IVF patients is promising, results should be interpreted with caution, because the efto scan this QR code ficacy of AIs needs to be proven in randomized trials. (Fertil SterilÒ 2012;98:1356–8. Ó2012 and connect to the by American Society for Reproductive Medicine.) Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/garcia-velascoj-aromatase-inhibitors-ivf/
T
he use of aromatase inhibitors (AIs) as an adjuvant treatment in IVF has been assessed in the past decade (1–4). AIs can be considered for ovulation induction for IVF in normal and poor responders, women at risk of ovarian hyperstimulation syndrome (OHSS) or thrombosis, who have endometriosis, and/or who are undergoing fertility preservation procedures as a result of estrogendependant cancers, primarily breast and endometrial cancers. Studies are heterogeneous, and the evidence is scarce, mainly owing to unfounded safety fears or the risk of teratogenesis, which has limited the generation of well designed studies based on preliminary retrospective series or pilot trials. AI use for IVF in hormone-dependent cancers and the risk for teratogenicity will not be discussed here, because they are addressed elsewhere in this section of Views and Reviews. AIs inhibit aromatization of androgens to estrogens, mainly in the ovarian granulosa cells, inducing a re-
duction in circulating estrogen levels, which has several implications for IVF: Pituitary escape from estrogen feedback, leading to elevated gonadotropins and improved follicular recruitment A transient accumulation of these intraovarian androgens, creating an androgenic microenvironment in the maturing follicle that may enhance follicular sensitivity to FSH with a relatively short duration, because letrozole has a short has life (45 h). This may be of interest in poor responders, because it has been shown that along with ovarian aging a significant androgen reduction is observed, and androgen pretreatment may improve ovarian performance and follicle development. A strong reduction in the secretion of estrogens from the granulosa cells. The reduction of circulat-
Received August 9, 2012; revised September 23, 2012; accepted September 24, 2012; published online October 11, 2012. J.A.G.-V. has nothing to disclose. Reprint requests: Juan A. Garcia-Velasco, M.D., Reproductive Endocrinology and Infertility, IVI-Madrid, Av del Talgo 68, Madrid 28023, Spain (E-mail: [email protected]). Fertility and Sterility® Vol. 98, No. 6, December 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.09.042 1356
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
ing steroid levels is an attractive option to minimize the risk of thrombosis in hyperestrogenic states and/or the risk of complications if OHSS develops, as well as to provide additional safety in women who have hormone-dependent cancers undergoing controlled ovarian hyperstimulation (COH) for fertility preservation. Inhibition of aromatase could potentially improve endometrial receptivity, particularly in patients with endometriosis in whom aromatase is aberrantly expressed. According to basic and clinical studies, there are three different areas in which the use of aromatase inhibitors may prove beneficial for IVF patients: improving cycle outcome in low-responder patients, reducing the risk of OHSS, and reducing the risk that high estrogen levels can pose to women with a high response to COH.
LOW RESPONDERS The rationale for using AIs in poor responders to COH is based on their capacity to transiently accumulate androgens in the ovarian micromilieu, VOL. 98 NO. 6 / DECEMBER 2012
Fertility and Sterility® which may increase ovarian sensitivity to FSH, because it is known that androgens play a crucial role in early follicular development and granulosa cell proliferation (5–7). Both of the third-generation AIs, anastrazole and letrozole, which are highly potent reversible inhibitors, have been used as adjuvant treatments in an attempt to create a hyperandrogenic intraovarian state in women who previously had a poor response to COH. The biologic plausibility of the theory of androgenization is attractive, but is it clinically relevant? We evaluated the impact of letrozole as an adjuvant treatment in 147 women with a previous IVF cycle cancelled due to low response (8). Letrozole (2.5 mg) was administered to 71 patients during the first 5 days of the stimulation, whereas the control subjects received a similar dose of FSH/hMG. Interestingly, letrozole-treated patients showed significantly higher levels of follicular fluid T and A (80.3 pg/mL vs. 43.8 pg/mL and 57.9 mg/mL vs. 37.4 mg/mL, respectively). Clinically speaking, patients who received letrozole had a higher number of oocytes retrieved (6.1 vs. 4.3) and a higher implantation rate (25% vs. 9.4%). This initial observation could not be confirmed in a proper randomized trial, because around the same time the manufacturer of letrozole, based on an inadequately designed study (9), suggested not using AIs in assisted reproduction. Reassuring data from later publications could not completely resolve this issue (10). However, additional publications became available. The concept that AIs could contribute to the follicular response was validated in normal responders, both with letrozole (11) and anastrazole (12), even though embryo quality in this particular population was not improved. A large, prospective trial compared the impact of letrozole co-treatment in past or potential poor responders with a microdose GnRH agonist flare protocol, finding similar results in stimulation parameters and a higher pregnancy rate with the microflare protocol (13). In this study, the definition of poor responders in the patients may not have been exactly the same as in other studies, as patients had a mean number of 9 antral follicles and produced between 12 and 13 oocytes. Although other potential confounders could have contributed to the different results such as different protocols, doses, or even GnRH analogues a larger sample size would have been necessary to verify these findings. Nevertheless, further trials suggested that letrozole co-treatment could be an effective protocol that could be used in poor ovarian responders, reducing cancellations and costs, although live birth rates remained low (14–18).
RISK OF OHSS It is obvious that today the most effective way to avoid OHSS is the use of agonist triggering rather than hCG in women under the antagonist protocol, because the corpora lutea have a short life after agonist triggering. However, thousands of cycles are still being performed worldwide under the long agonist protocol (19), where agonist triggering is not an option. Thus, reducing the production of high amounts of E2 by the granulosa cells may help to minimize the risk of developing OHSS as well as the risk of thrombosis. The effect of letrozole has been investigated as an option to inhibit E2 production VOL. 98 NO. 6 / DECEMBER 2012
and modulate LH levels during the luteal phase. Fatemi et al. (20) investigated this concept in a pilot study that included three oocyte donors who were given letrozole (5 mg) and three others who received placebo. Serum E2 concentrations on days 4, 7, and 10 after hCG administration for final oocyte maturation were significantly lower compared with placebo. However, no differences were observed in progesterone and LH profiles during the same period. Garcia-Velasco et al. (21) performed a randomized trial to explore the same concept. Thirty volunteers were randomized to receive letrozole (2.5 mg) or placebo after hCG triggering. As expected, serum E2 concentrations dropped dramatically in those receiving AIs (279 pg/mL vs. 1,589 pg/mL) on day 4 after hCG, and similarly on days 7 and 10. Although P did not change, LH serum concentrations were lower in the control group on days 7 and 10 after hCG, when serum E2 was higher. The quick reduction in serum E2 levels allowed a faster recovery of the LH concentrations, an interesting concept not only for egg donors who are undergoing embryo transfer, but also for patients undergoing COH for fertility preservation and women at risk of OHSS who freeze all their embryos or who cancel hCG administration to reduce the potential risk that high E2 levels pose. In both studies (20, 21), VEGF levels or any other vascular permeability factors were not studied. We should bear in mind that E2 reduction does not necessarily mean that the risk of severe OHSS is lessened, so extrapolating lower E2 levels to a lower risk of OHSS is not necessarily true. However, this reduction in E2 levels contributes to reduced risk of thrombosis.
ENDOMETRIOSIS Another potential benefit of AIs for patients undergoing IVF might be to inhibit aromatase, the key enzyme in the biosynthesis of E2, not only in the granulosa cells but also ‘‘in situ’’ in endometriotic tissue and the eutopic endometrium of women with endometriosis, because aromatase is expressed in these tissues (22). A pilot study was recently published to study the concept of dual suppression. A 3-month GnRH agonist course combined with anastrazole (1 mg daily) was used in infertile women with endometriomas undergoing IVF (23). A significant reduction in endometrioma volume (29%) and serum CA-125 concentration (61%) was observed. Although the pregnancy rate was 45%, a high pregnancy loss was noted; the live birth rate was 15%, which may be due to poor embryo quality, as in other endometriosis patients (24). No further validation of this concept has been made available. In line with this concept, women with endometriosis show aberrant endometrial aromatase expression, which is associated with poor reproductive outcomes (25). Long-term GnRH agonist therapy has been assayed in an attempt to improve IVF outcome in these women (26, 27), because it suppresses endometrial aromatase expression (28). Because AIs are capable of suppressing the P450 aromatase enzyme in situ, they might hypothetically improve endometrial receptivity. Very recently, Miller et al. (29) examined the effect of letrozole on infertile women with endometriosis undergoing IVF who lacked normal integrin expression, 1357
VIEWS AND REVIEWS a marker of endometrial receptivity. They confirmed that the use of aromatase inhibitors might improve the IVF success rates in a subset of women with endometriosis and implantation failure. The use of AIs in IVF patients is still controversial. However, the biologic plausibility of their capacity to improve follicular recruitment by escaping from estrogen feedback, to transiently increase androgen concentrations to improve follicle development, inhibit aromatase to potentially improve endometrial receptivity, or decrease estrogen levels and consequently the risk of thrombosis is promising. Even if the available evidence seems favorable, the results should still be interpreted with caution, because the efficacy should be proven in randomized trials. For this purpose, and based on available safety data (10), a reassuring statement from medical societies and/or the pharmaceutical industry would be needed. Still, further research is needed on FSH receptor modulation during ovarian stimulation, dose-finding studies should be performed, the impact on endometrial receptivity in women with and without endometriosis should be further analyzed, and the ideal timing for coadjuvant treatment needs to be defined.
11.
12.
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Requena A, Herrero J, Landeras J, Navarro E, Neyro JL, Salvador C, et al. Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum Reprod Update 2008;14:571–82. Bosdou J, Venetis C, Kolibinakis E, Toulis K, Goulis D, Zepiridis L, et al. The use of androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analsysis. Hum Reprod Update 2012;18:127–45. Papanikolau E, Polyzos N, Humaidan P, Pados G, Bosch E, Tournaye H, et al. Aromatase inhibitors in stimulated IVF cycles. Reprod Biol Endocrinol 2011; 9:85–8. Lee V, Ledger W. Aromatase inhibitors for ovulation induction and ovarian stimulation. Clin Endocrinol (Oxf) 2011;74:537–46. Hillier S, De Zwart F. Evidence that granulosa cell aromatase induction/activation by follicle-stimulating hormone is an androgen receptor-regulated process in-vitro. Endocrinology 1981;4:1303–5. Weil S, Vendola K, Zhou J, Adesanya O, Wang J, Okafor J, et al. Androgen receptor gene expression in the primate ovary: cellular localization, regulation and functional correlations. J Clin Endocrinol Metab 1998;7:2479–85. Garcia-Velasco JA, Rodriguez S, Agudo D, Pacheco A, Schneider J, Pellicer A. FSH receptor in vitro modulation by testosterone and hCG in human luteinized granulosa cells. Eur J Obstet Gynecol Reprod Biol. ePub ahead of print, September 7, 2012. doi:10.1016/j.ejogrb.2012.08.020. Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril 2005;84:82–7. Biljan M, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005; 84(Suppl I):S95. Tulandi T, Martin J, Al-Fadhi R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5.
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Verpoest W, Kolibianakis E, Papanikolau E, Smitz J, van Steirteghem A, Devroey P. Aromatase inhibitors in ovarian stimulation for IVF/ICSI: a pilot study. Reprod Biomed Online 2006;13:166–72. Lossl K, Andersen CY, Loft A, Freiesleben N, Bangsboll S, Andersen AN. Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial. Hum Reprod 2008;23:1820–9. Schoolcraft W, Surrey E, Minjarez D, Stevens J, Gardner D. Management of poor responders: can outcomes be improved with a novel gonadotropinreleasing hormone antagonist/letrozole protocol? Fertil Steril 2008;89:151–6. Yarali H, Esinler I, Polat M, Bozdag G, Tiras B. Antagonist/letrozole protocol in poor ovarian responders for intracytoplasmic sperm injection: a comparative study with the microdose flare-up protocol. Fertil Steril 2009;92:231–5. Ozmen B, Sonmezer M, Atabekoglu C, Olmus H. Use of aromatase inhibitors in poor-responder patients receiving GnRH antagonist protocols. Reprod Biomed Online 2009;19:478–85. Jovanovic V, Kort D, Guarnaccia M, Sauer M, Lobo R. Does the addition of clomiphene citrate or letrozole to gonadotropin treatment enhance the oocyte yield in poor responders undergoing IVF? J Assist Reprod Genet 2011; 28:1067–72. Lee V, Chan C, Ng E, Yeung W, Ho P. Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial. Reprod Biomed Online 2011;23:380–8. Goswami S, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, et al. A randomized, single blinded controlled trial of letrozole as a low cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004;19:2031–5. Tur-Kaspa I, Fauser B. The use of TnRH agonist in IVF protocols. Available at: http://www.ivf-worldwide.com/survey/survey-the-use-of-gnrh-agonist-inivf-protocols-results.html. Accessed September 1, 2012. Fatemi H, Popovic-Todorovic B, Donoso P, Papanikolau E, Smitz J, Devroey P. Luteal phase oestradiol suppression by letrozole: a pilot study in oocyte donors. Reprod Biomed Online 2008;17:307–11. M, Mayoral M, Ruiz M, Toribio M, et al. LeGarcia-Velasco JA, Quea G, Piro trozole administration during the luteal phase after ovarian stimulation impacts corpus luteum function: a randomized, placebo-controlled trial. Fertil Steril 2009;92:222–5. Casper RF, Mitwally M. Aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab 2006;91:760–71. Lossl K, Loft A, Freiesleben N, Bangsboll S, Andersen CY, Pedersen A, et al. Combined down-regulation by aromatase inhibitor and GnRH-agonist in IVF patients with endometriomas—a pilot study. Eur J Obstet Gynecol Reprod Biol 2009;144:48–53. Ruiz-Florez F, Garcia-Velasco JA. Is there a benefit for surgery in endometriomas-associated infertility? Curr Opin Obstet Gynecol 2012;24: 136–40. Brosens J, Verhoeven H, Campo R, Gianaroli L, Gordts S, Hazekamp J, et al. High endometrial aromatase P450 mRNA expression is associated with poor IVF outcome. Hum Reprod 2004;19:352–6. Surrey E, Silverberg K, Surrey M, Schoolcraft W. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization–embryo transfer in patients with endometriosis. Fertil Steril 2002;78:699–704. Salam H, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary downregulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 2006:CD004635. Ishikara H, Kitawaki J, Kado N, Koshiba H, Fushiki S, Honjo H. Gonadotropinreleasing hormone agonist and danazol normalize aromatase cyctochrome P450 expression in eutopic endometrium from women with endometriosis, adenomyosis, or leiomyomas. Fertil Steril 2003;79(Suppl I):735–42. Miller P, Parnell B, Bushnell G, Tallman N, Forstein D, Lee Higdon H III, et al. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum Reprod 2012;27:881–8.
VOL. 98 NO. 6 / DECEMBER 2012
The use of aromatase inhibitors (AIs) in IVF patients remains controversial. AIs can be considered for ovulation induction for IVF in women who are normal and poor responders, are at risk of ovarian hyperstimulation syndrome or thrombosis, who have endometriosis, and/or are undergoing fertility preservation procedures as a result of estrogen-dependent cancers, primarily breast and endometrial cancers. Although the biologic plausibility of the capacity Use your smartphone of AIs in IVF patients is promising, results should be interpreted with caution, because the efto scan this QR code ficacy of AIs needs to be proven in randomized trials. (Fertil SterilÒ 2012;98:1356–8. Ó2012 and connect to the by American Society for Reproductive Medicine.) Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/garcia-velascoj-aromatase-inhibitors-ivf/
T
he use of aromatase inhibitors (AIs) as an adjuvant treatment in IVF has been assessed in the past decade (1–4). AIs can be considered for ovulation induction for IVF in normal and poor responders, women at risk of ovarian hyperstimulation syndrome (OHSS) or thrombosis, who have endometriosis, and/or who are undergoing fertility preservation procedures as a result of estrogendependant cancers, primarily breast and endometrial cancers. Studies are heterogeneous, and the evidence is scarce, mainly owing to unfounded safety fears or the risk of teratogenesis, which has limited the generation of well designed studies based on preliminary retrospective series or pilot trials. AI use for IVF in hormone-dependent cancers and the risk for teratogenicity will not be discussed here, because they are addressed elsewhere in this section of Views and Reviews. AIs inhibit aromatization of androgens to estrogens, mainly in the ovarian granulosa cells, inducing a re-
duction in circulating estrogen levels, which has several implications for IVF: Pituitary escape from estrogen feedback, leading to elevated gonadotropins and improved follicular recruitment A transient accumulation of these intraovarian androgens, creating an androgenic microenvironment in the maturing follicle that may enhance follicular sensitivity to FSH with a relatively short duration, because letrozole has a short has life (45 h). This may be of interest in poor responders, because it has been shown that along with ovarian aging a significant androgen reduction is observed, and androgen pretreatment may improve ovarian performance and follicle development. A strong reduction in the secretion of estrogens from the granulosa cells. The reduction of circulat-
Received August 9, 2012; revised September 23, 2012; accepted September 24, 2012; published online October 11, 2012. J.A.G.-V. has nothing to disclose. Reprint requests: Juan A. Garcia-Velasco, M.D., Reproductive Endocrinology and Infertility, IVI-Madrid, Av del Talgo 68, Madrid 28023, Spain (E-mail: [email protected]). Fertility and Sterility® Vol. 98, No. 6, December 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.09.042 1356
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
ing steroid levels is an attractive option to minimize the risk of thrombosis in hyperestrogenic states and/or the risk of complications if OHSS develops, as well as to provide additional safety in women who have hormone-dependent cancers undergoing controlled ovarian hyperstimulation (COH) for fertility preservation. Inhibition of aromatase could potentially improve endometrial receptivity, particularly in patients with endometriosis in whom aromatase is aberrantly expressed. According to basic and clinical studies, there are three different areas in which the use of aromatase inhibitors may prove beneficial for IVF patients: improving cycle outcome in low-responder patients, reducing the risk of OHSS, and reducing the risk that high estrogen levels can pose to women with a high response to COH.
LOW RESPONDERS The rationale for using AIs in poor responders to COH is based on their capacity to transiently accumulate androgens in the ovarian micromilieu, VOL. 98 NO. 6 / DECEMBER 2012
Fertility and Sterility® which may increase ovarian sensitivity to FSH, because it is known that androgens play a crucial role in early follicular development and granulosa cell proliferation (5–7). Both of the third-generation AIs, anastrazole and letrozole, which are highly potent reversible inhibitors, have been used as adjuvant treatments in an attempt to create a hyperandrogenic intraovarian state in women who previously had a poor response to COH. The biologic plausibility of the theory of androgenization is attractive, but is it clinically relevant? We evaluated the impact of letrozole as an adjuvant treatment in 147 women with a previous IVF cycle cancelled due to low response (8). Letrozole (2.5 mg) was administered to 71 patients during the first 5 days of the stimulation, whereas the control subjects received a similar dose of FSH/hMG. Interestingly, letrozole-treated patients showed significantly higher levels of follicular fluid T and A (80.3 pg/mL vs. 43.8 pg/mL and 57.9 mg/mL vs. 37.4 mg/mL, respectively). Clinically speaking, patients who received letrozole had a higher number of oocytes retrieved (6.1 vs. 4.3) and a higher implantation rate (25% vs. 9.4%). This initial observation could not be confirmed in a proper randomized trial, because around the same time the manufacturer of letrozole, based on an inadequately designed study (9), suggested not using AIs in assisted reproduction. Reassuring data from later publications could not completely resolve this issue (10). However, additional publications became available. The concept that AIs could contribute to the follicular response was validated in normal responders, both with letrozole (11) and anastrazole (12), even though embryo quality in this particular population was not improved. A large, prospective trial compared the impact of letrozole co-treatment in past or potential poor responders with a microdose GnRH agonist flare protocol, finding similar results in stimulation parameters and a higher pregnancy rate with the microflare protocol (13). In this study, the definition of poor responders in the patients may not have been exactly the same as in other studies, as patients had a mean number of 9 antral follicles and produced between 12 and 13 oocytes. Although other potential confounders could have contributed to the different results such as different protocols, doses, or even GnRH analogues a larger sample size would have been necessary to verify these findings. Nevertheless, further trials suggested that letrozole co-treatment could be an effective protocol that could be used in poor ovarian responders, reducing cancellations and costs, although live birth rates remained low (14–18).
RISK OF OHSS It is obvious that today the most effective way to avoid OHSS is the use of agonist triggering rather than hCG in women under the antagonist protocol, because the corpora lutea have a short life after agonist triggering. However, thousands of cycles are still being performed worldwide under the long agonist protocol (19), where agonist triggering is not an option. Thus, reducing the production of high amounts of E2 by the granulosa cells may help to minimize the risk of developing OHSS as well as the risk of thrombosis. The effect of letrozole has been investigated as an option to inhibit E2 production VOL. 98 NO. 6 / DECEMBER 2012
and modulate LH levels during the luteal phase. Fatemi et al. (20) investigated this concept in a pilot study that included three oocyte donors who were given letrozole (5 mg) and three others who received placebo. Serum E2 concentrations on days 4, 7, and 10 after hCG administration for final oocyte maturation were significantly lower compared with placebo. However, no differences were observed in progesterone and LH profiles during the same period. Garcia-Velasco et al. (21) performed a randomized trial to explore the same concept. Thirty volunteers were randomized to receive letrozole (2.5 mg) or placebo after hCG triggering. As expected, serum E2 concentrations dropped dramatically in those receiving AIs (279 pg/mL vs. 1,589 pg/mL) on day 4 after hCG, and similarly on days 7 and 10. Although P did not change, LH serum concentrations were lower in the control group on days 7 and 10 after hCG, when serum E2 was higher. The quick reduction in serum E2 levels allowed a faster recovery of the LH concentrations, an interesting concept not only for egg donors who are undergoing embryo transfer, but also for patients undergoing COH for fertility preservation and women at risk of OHSS who freeze all their embryos or who cancel hCG administration to reduce the potential risk that high E2 levels pose. In both studies (20, 21), VEGF levels or any other vascular permeability factors were not studied. We should bear in mind that E2 reduction does not necessarily mean that the risk of severe OHSS is lessened, so extrapolating lower E2 levels to a lower risk of OHSS is not necessarily true. However, this reduction in E2 levels contributes to reduced risk of thrombosis.
ENDOMETRIOSIS Another potential benefit of AIs for patients undergoing IVF might be to inhibit aromatase, the key enzyme in the biosynthesis of E2, not only in the granulosa cells but also ‘‘in situ’’ in endometriotic tissue and the eutopic endometrium of women with endometriosis, because aromatase is expressed in these tissues (22). A pilot study was recently published to study the concept of dual suppression. A 3-month GnRH agonist course combined with anastrazole (1 mg daily) was used in infertile women with endometriomas undergoing IVF (23). A significant reduction in endometrioma volume (29%) and serum CA-125 concentration (61%) was observed. Although the pregnancy rate was 45%, a high pregnancy loss was noted; the live birth rate was 15%, which may be due to poor embryo quality, as in other endometriosis patients (24). No further validation of this concept has been made available. In line with this concept, women with endometriosis show aberrant endometrial aromatase expression, which is associated with poor reproductive outcomes (25). Long-term GnRH agonist therapy has been assayed in an attempt to improve IVF outcome in these women (26, 27), because it suppresses endometrial aromatase expression (28). Because AIs are capable of suppressing the P450 aromatase enzyme in situ, they might hypothetically improve endometrial receptivity. Very recently, Miller et al. (29) examined the effect of letrozole on infertile women with endometriosis undergoing IVF who lacked normal integrin expression, 1357
VIEWS AND REVIEWS a marker of endometrial receptivity. They confirmed that the use of aromatase inhibitors might improve the IVF success rates in a subset of women with endometriosis and implantation failure. The use of AIs in IVF patients is still controversial. However, the biologic plausibility of their capacity to improve follicular recruitment by escaping from estrogen feedback, to transiently increase androgen concentrations to improve follicle development, inhibit aromatase to potentially improve endometrial receptivity, or decrease estrogen levels and consequently the risk of thrombosis is promising. Even if the available evidence seems favorable, the results should still be interpreted with caution, because the efficacy should be proven in randomized trials. For this purpose, and based on available safety data (10), a reassuring statement from medical societies and/or the pharmaceutical industry would be needed. Still, further research is needed on FSH receptor modulation during ovarian stimulation, dose-finding studies should be performed, the impact on endometrial receptivity in women with and without endometriosis should be further analyzed, and the ideal timing for coadjuvant treatment needs to be defined.
11.
12.
13.
14.
15.
16.
17.
18.
19.
REFERENCES 1.
2.
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4. 5.
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Requena A, Herrero J, Landeras J, Navarro E, Neyro JL, Salvador C, et al. Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum Reprod Update 2008;14:571–82. Bosdou J, Venetis C, Kolibinakis E, Toulis K, Goulis D, Zepiridis L, et al. The use of androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analsysis. Hum Reprod Update 2012;18:127–45. Papanikolau E, Polyzos N, Humaidan P, Pados G, Bosch E, Tournaye H, et al. Aromatase inhibitors in stimulated IVF cycles. Reprod Biol Endocrinol 2011; 9:85–8. Lee V, Ledger W. Aromatase inhibitors for ovulation induction and ovarian stimulation. Clin Endocrinol (Oxf) 2011;74:537–46. Hillier S, De Zwart F. Evidence that granulosa cell aromatase induction/activation by follicle-stimulating hormone is an androgen receptor-regulated process in-vitro. Endocrinology 1981;4:1303–5. Weil S, Vendola K, Zhou J, Adesanya O, Wang J, Okafor J, et al. Androgen receptor gene expression in the primate ovary: cellular localization, regulation and functional correlations. J Clin Endocrinol Metab 1998;7:2479–85. Garcia-Velasco JA, Rodriguez S, Agudo D, Pacheco A, Schneider J, Pellicer A. FSH receptor in vitro modulation by testosterone and hCG in human luteinized granulosa cells. Eur J Obstet Gynecol Reprod Biol. ePub ahead of print, September 7, 2012. doi:10.1016/j.ejogrb.2012.08.020. Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, et al. The aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril 2005;84:82–7. Biljan M, Hemmings R, Brassard N. The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins. Fertil Steril 2005; 84(Suppl I):S95. Tulandi T, Martin J, Al-Fadhi R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5.
1358
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