- Email: [email protected]
To pill or not to pill in GnRH antagonist cycles: that is the question!
Reproductive BioMedicine Online (2015) 30, 39–42
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
MINI-REVIEW
To pill or not to pill in GnRH antagonist cycles: that is the question! Juan A Garcia-Velasco a,*, Human M Fatemi b a
IVI-Madrid, Av Talgo, 68 28035 Madrid, Spain; b Nova IVI Fertility-Abu Dhabi, PO Box 60202, Abu Dhabi, UAE
* Corresponding author.
E-mail address: [email protected] (JA Garcia-Velasco). Juan A. Garcia-Velasco is Director of IVI-Madrid and Full Professor of Obstetrics and Gynecology at Rey Juan Carlos University in Madrid, Spain. After his Fellowship in Reproductive Endocrinology at Yale, his main interest has been ovulation induction in difficult patients, mainly endometriosis and hyper and poor responders. He has published extensively in main journals and edited several books on these topics.
Worldwide, gonadotrophin-releasing hormone (GnRH) antagonists are gaining ground, and the number of patients being treated for IVF with a GnRH antagonist is increasing. Cycle planning in GnRH antagonist IVF cycles has been a challenge. During the past 2 years, debate has been ongoing about the possible disadvantages of oral contraceptive pill (OCP) pre-treatment in GnRH antagonist IVF cycles. A recent meta-analysis clearly showed a significant decrease in ongoing pregnancy rates between patients who received OCP pre-treatment and those who did not. In this review, the published meta-analysis are is evaluated. It is argued that caution must be exercised in drawing conclusions too quckly on whether or not OCP pre-treatment might have a negative effect on outcome in GnRH antagonist IVF cycles.
Abstract
© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: estrogens, GnRH antagonist, OCP, scheduling
To pill or not to pill? During the past 2 decades, gonadotrophin-releasing hormone (GnRH) antagonist protocols have gained more popularity for ovarian stimulation. Their administration is linked to several advantages over the long agonist protocol, including shorter overall treatment duration, absence of perimenopausal symptoms caused by pituitary desensitization, no risk of ovarian cyst formation and a lower consumption of gonadotrophins (Devroey et al., 2009).
Moreover, similar live birth rates can be achieved with the use of GnRH antagonist protocols, while significantly reducing the risk of ovarian hyperstimulation syndrome, compared with the long GnRH agonist protocol (Al-Inany et al., 2011). An issue debated for the past 2 years is the possibility of cycle planning with the oral contraceptive pill (OCP) in GnRH antagonist cycles. Looking back in time, cycle planning has been a challenge. Although we might say, ‘why planning?’, there are several reasons to consider cycle planning. In fact, we do plan most of our lives: our daily agenda with patients
http://dx.doi.org/10.1016/j.rbmo.2014.09.010 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
40 or surgeries, our holidays, our family, and many other areas of our life. Therefore, it would make sense to plan the activity during the week for gynaecologists and embryologists, as well as for patients. Moreover, it is important to avoid a high volume of work on certain days of the week to ensure that all patients receive the same quality of treatment and attention, and that the IVF staff can focus on each individual patient in the same manner. Moreover, incubator overusage and door openings could be minimized, thus reducing the negative effect on embryo development caused by carbon dioxide and temperature variations. Efforts have been made to plan the day and the time of egg retrieval, as ovum retrieval is not dependent on spontaneous LH but on the capacity of human chorionic gonadotrophin (HCG) to bind and activate the LH receptor (Zorn et al., 1987). Different options have been suggested to plan an IVF cycle. For many years, oral contraceptive pills and synthetic progestogens have been used to schedule IVF cycles (Frydman et al., 1986; Gerli et al., 1989; Wardle et al., 1986; Zorn et al., 1987). Combined OCP consist of oestrogen and progestogen, which inhibit the women’s own production of FSH and LH through a negative feedback (Cohen and Katz, 1979; Gaspard et al., 1984). The combined OCP suppresses gonadal function, and ovulation can be prevented in the absence of a LH-surge. Moreover, only progestogen does also have a contraceptive effect (Erkkola, 2007). Progestogen inhibits the GnRH pulsatility of the pituitary gland, reducing gonadotrophin surges and, according to dose, inhibiting ovulation (Anderson et al., 1990; Erkkola, 2007; Le Nestour et al., 1993). Hence, oestrogen is co-administered in the combined OCP to regulate the bleeding patterns, although it is also capable of reducing FSH levels (De Ziegler et al., 1998; Le Nestour et al., 1993). Lately, the use of natural oestrogens has also been advocated (Blockeel, 2012; De Ziegler et al., 1998; Guivarc’h-Levêque et al., 2011). Among the different suggested options, oral contraceptive pills in particular are one of the most popular options among clinicians for cycle planning in IVF. This is less of an issue in the long GnRH agonist protocol; however, with GnRH antagonist protocol, significantly lower ongoing pregnancy rate per randomized woman has been found to be present in patients being pre-treated with an OCP compared with patients without an OCP pre-treatment (Griesinger et al., 2010). Controversy has arisen over the last few years, as contradictory data have been published on whether the use of OCPs in the previous cycle might have a deleterious effect on subsequent IVF cycle outcome. Although no differences were found in ongoing pregnancy rate in more than 1500 patients retrospectively analysed, whether they received the pill or not (Bellver et al., 2007), recent publications and metaanalyses suggest the contrary. It is known that, after OCP administration, altered endocrinology and follicular growth takes place, as described by Cédrin-Durnerin et al. (2007), a few years ago. When they compared the recovery of endogenous FSH with the natural cycle, they observed that, after FSH suppression induced by the oestrogens in the OCP (Tsai and Yen, 1971), it took most patients 5 days to restore levels to normal values; consequently, they suggested an endocrine wash-out period of 5 days. An attempt to start ovarian stimulation earlier than this may result in a poorer and slower response owing to a strong
JA Garcia-Velasco, HM Fatemi early suppression, with a higher consumption of gonadotrophins; delaying the start of ovarian stimulation by more than 5 days would be comparable to a late start, making it difficult to recruit several follicles as dominance may have been initiated already. Even when starting after the suggested washout period, several investigators have described a significantly higher consumption of gonadotrophins compared with women who had not been pre-treated with OCPs (Barmat et al., 2005; Griesinger et al., 2008; Huirne et al., 2006). More precisely, it was estimated that women pre-treated with OCP would need 542 IU and stimulation required 1.4 more days (Griesinger et al., 2010). Whether this is clinically relevant or not, compared with planning the activity in the clinic, may be at least debatable. A meta-analysis of published trials (Griesinger et al., 2010) has suggested that pre-treatment with OCP might reduce chances of ongoing pregnancy rate (relative risk: 0.80, 95% confidence interval : 0.66 to 0.97; rate difference: –5%, 95% CI –10% to –1%). Although meta-analyses are the most powerful tools to interpret current evidence to guide our practice, we have to be extremely careful with what type of studies are included in these analyses, as well as to be able to interpret the final message. Today, many of the published metaanalyses lack robust evidence from properly conducted randomized controlled trials, which could lead to the acceptance of treatment modalities of ambiguous value (Simón and Bellver, 2014). In this particular meta-analysis (Griesinger et al., 2010), of the 34 studies reviewed, only six were included as per inclusion criteria, the rest were excluded for several reasons. These six studies included both normo and poor responders, which are clearly different patient populations, one-half of the studies included 30 patients or less per arm (with the limitations and bias that this may carry along when looking at pregnancy rates), different types of OCPs were used, different duration of the administration (14–28 days) and, most relevant, varying pill-free intervals of 2–5 days (Table 1). Therefore, we have to interpret carefully the conclusions of this study, as most of the included studies are not free from bias. Hence, we cannot neglect the conclusions, and rather than obviate it, we should investigate what is the hypothesis behind, if any. The mean duration from the intake of the last oral contraceptive tablet until the start of withdrawal bleeding has been described to be 3.5 + 1.0 days (Duijkers et al., 2004). This means that, in the studies included in the meta-analysis by Griesinger et al. (2010), many patients initiated the ovarian stimulation without having a withdrawal bleed (pill-free intervals 2–5 days). Furthermore, endometrial biopsies obtained from patients with and without OCP pre-treatment, with an assessment of the known crucial genes expressed during the window of implantation, did not show any significant differences between groups, concluding that OCP pre-treatment does not affect the expression of known genes related with embryo implantation (Bermejo et al., 2014). The other theoretical effect of the pill pre-treatment is related to the low endogenous LH that is observed when OCP is being administered, which may impair oocyte competence. Adding LH activity to the gonadotrophins administered might easily restore this effect, although evidence is lacking.
Steroid cycle scheduling Table 1
41
Heterogeneity among studies included in the meta-analysisa of OCP effect on assisted reproductive techniques.
Huirne et al., 2006 Kolibianakis et al., 2006 Rombauts et al., 2006 Cédrin-Durnerin et al., 2007 Kim et al., 2009 Tavmergen et al., 2009
Patients
Sample size/arm
Type of gestogen
Duration
Pill free
FSH dose
Day of embryo transfer
Normo Normo Normo Normo Poor responder Normo
32 and 31 211 and 214 110 and 111 21 and 21 41 and 41 221 and 221
Levonorgestrel Desogestrel Desogestrel Desogestrel Levonorgestrel Desogestrel
14–28 15 14–28 15–21 21 14–21
2 or 3 5 2 5 5 5 (variable)
150–300 200 200 150–300 22 200
2 or 3 3 or 5 2 or 3 ? 3 3 or 5
a
Griesinger et al., 2010.
In order to shed light on this discussion, we designed a prospective, randomized trial in which patients received OCP before their IVF cycle under the antagonist protocol and compared their outcomes to patients that received the goldstandard protocol, classical long protocol, in which also profound LH suppression has been described (Garcia-Velasco et al., 2011). When patients received the pill only for 12–16 days, and had a wash-out period of 5 days, no difference could be found in live birth rates between the groups. In a further randomized controlled trial, cycle outcome was compared in women who planned they cycles with the pill versus cycle planning with only oestrogens, as previously described (Blockeel, 2012; Guivarc’h-Levêque et al., 2011). Again, no differences could be found in live birth rates (Hauzman et al., 2013). Therefore, we could conclude that the benefits of cycle scheduling with the pill (equal distribution of work load in large busy units and staff distribution, avoiding weekend retrievals in small units, synchronization of follicular cohort, avoiding excessive incubator openings) must be weighed against the drawbacks (i.e. higher FSH consumption and longer duration of the stimulation). When given for a minimum number of days, and if ovarian stimluation is started after a washout period that resembles the natural cycle, OCP pretreatment might not have a negative effect on endometrial receptivity and IVF outcome might be comparable to women undergoing classical long protocol or who were pre-treated only with oestrogens. Clear consensus is lacking on whether pre-treatment with combined oral contraceptives in ovarian stimulation protocols has a negative effect on pregnancy rates and live birth. Therefore, future, well-designed and adequately powered randomized controlled trials are required to evaluate the most appropriate OCP pre-treatment in GnRH antagonist cycles and subsequent ideal gonadotropin treatment.
References Al-Inany, H.G., Youssef, M.A., Aboulghar, M., Broekmans, F., Sterrenburg, M., Smit, J., Abou-Setta, A.M., 2011. GnRH antagonists are safer than agonists: an update of a Cochrane review. Hum. Reprod. Update 17, 435. Anderson, R.E., Stein, A.L., Paulson, R.J., Stanczyk, F.Z., Vijod, A.G., Lobo, R.A., 1990. Effects of norethindrone on gonadotropin and ovarian steroid secretion when used for cycle programming during in vitro fertilization. Fertil. Steril. 54, 96–101. Barmat, L.I., Chantilis, S.J., Hurst, B.S., Dickey, R.P., 2005. A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating
hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization. Fertil. Steril. 83, 321–330. Bellver, J., Albert, C., Labarta, E., Pellicer, A., 2007. Early pregnancy loss in women stimulated with gonadotropin-releasing hormone antagonist protocols according to oral contraceptive pill pretreatment. Fertil. Steril. 87, 1098–1101. Bermejo, A., Iglesias, C., Ruiz-Alonso, M., Blesa, D., Simón, C., Pellicer, A., Garcia-Velasco, J., 2014. The impact of using the combined oral contraceptive pill for cycle scheduling on gene expression related to endometrial receptivity. Hum. Reprod. 29, 1271– 1278. Blockeel, C., 2012. Estradiol valerate pretreatment in GnRHantagonist cycles. Reprod. Biomed. Online 25, 223–224. Cédrin-Durnerin, I., Bständig, B., Parneix, I., Bied-Damon, V., Avril, C., Decanter, C., Hugues, J.N., 2007. Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol. Hum. Reprod. 22, 109–116. Cohen, B.L., Katz, M., 1979. Pituitary and ovarian function in women receiving hormonal contraception. Contraception 20, 475– 487. De Ziegler, D., Jääskeläinen, A.S., Brioschi, P.A., Fanchin, R., Bulletti, C., 1998. Synchronization of endogenous and exogenous FSH stimuli in controlled ovarian hyperstimulation (COH). Hum. Reprod. 13, 561–564. Devroey, P., Aboulghar, M., Garcia-Velasco, J., Griesinger, G., Humaidan, P., Kolibianakis, E., Ledger, W., Tomás, C., Fauser, B.C., 2009. Improving the patient’s experience of IVF/ICSI: a proposal for an ovarian stimulation protocol with GnRH antagonist co-treatment. Hum. Reprod. 24, 764–767. Duijkers, I.J., Klipping, C., Verhoeven, C.H., Dieben, T.O., 2004. Ovarian function with the contraceptive vaginal ring or an oral contraceptive: a randomized study. Hum. Reprod. 19, 2668– 2673. Erkkola, R., 2007. Recent advances in hormonal contraception. Curr. Opin. Obstet. Gynecol. 19, 547–553. Frydman, R., Forman, R., Rainhorn, J.D., Belaisch-Allart, J., Hazout, A., Testart, J., 1986. A new approach to follicular stimulation for in vitro fertilization: programed oocyte retrieval. Fertil. Steril. 46, 657–662. Garcia-Velasco, J.A., Bermejo, A., Ruiz, F., Martinez-Salazar, J., Requena, A., Pellicer, A., 2011. Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial. Fertil. Steril. 96, 590– 593. Gaspard, U.J., Dubois, M., Gillain, D., Franchimont, P., Duvivier, J., 1984. Ovarian function is effectively inhibited by a low-dose triphasic oral contraceptive containing ethinylestradiol and levonorgestrel. Contraception 29, 305–318. Gerli, S., Remohi, J., Partrizio, P., Borrero, C., Balmaceda, J.P., Silber, S.J., Asch, R.H., 1989. Programming of ovarian
42 stimulation with norethindrone acetate in IVF/GIFT cycles. Hum. Reprod. 4, 746–748. Griesinger, G., Venetis, C.A., Marx, T., Diedrich, K., Tarlatzis, B.C., Kolibianakis, E.M., 2008. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta-analysis. Fertil. Steril. 90, 1055–1063. Griesinger, G., Kolibianakis, E.M., Venetis, C., Diedrich, K., Tarlatzis, B., 2010. Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis. Fertil. Steril. 94, 2382–2384. Guivarc’h-Levêque, A., Homer, L., Arvis, P., Broux, P.L., Moy, L., Priou, G., Vialard, J., Colleu, D., Dewailly, D., 2011. Programming in vitro fertilization retrievals during working days after a gonadotropin-releasing hormone antagonist protocol with estrogen pretreatment: does the length of exposure to estradiol impact on controlled ovarian hyperstimulation outcomes? Fertil. Steril. 96, 872–876. Hauzman, E.E., Zapata, A., Bermejo, A., Iglesias, C., Pellicer, A., Garcia-Velasco, J.A., 2013. Cycle scheduling for in vitro fertilization with oral contraceptive pills versus oral estradiol valerate: a randomized, controlled trial. Reprod. Biol. Endocrinol. 28, 96. Huirne, J.A., Hugues, J.N., Pirard, C., Fischl, F., Sage, J.C., Pouly, J.L., Obruca, A., Braat, D.M., van Loenen, A.C., Lambalk, C.B., 2006. Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study. Hum. Reprod. 21, 1408–1415. Kim, C.H., Jeon, G.H., Cheon, Y.P., Jeon, I., Kim, S.H., Chae, H.D., Kang, B.-M., 2009. Comparison of GnRH antagonist protocol with or without oral contraceptive pill pretreatment and GnRH agonist low-dose long protocol in low responders undergoing IVF/ intracytoplasmic sperm injection. Fertil. Steril. 92, 1758–1760. Kolibianakis, E.M., Papanikolaou, E.G., Camus, M., Tournaye, H., Van Steirteghem, A.C., Devroey, P., 2006. Effect of oral contraceptive pill pretreatment on ongoing pregnancy rates in patients
JA Garcia-Velasco, HM Fatemi stimulated with GnRH antagonists and recombinant FSH for IVF. A randomized controlled trial. Hum. Reprod. 21, 352–357. Le Nestour, E.1., Marraoui, J., Lahlou, N., Roger, M., de Ziegler, D., Bouchard, P., 1993. Role of estradiol in the rise in folliclestimulating hormone levels during the luteal-follicular transition. J. Clin. Endocrinol. Metab. 77, 439–442. Rombauts, L., Healy, D., Norman, R.J., 2006. Comparative randomized trial to assess the impact of oral contraceptive pretreatment on follicular growth and hormone profiles in GnRH antagonist-treated patients. Hum. Reprod. 21, 95–103. Simón, C.1., Bellver, J., 2014. Scratching beneath ‘The Scratching Case’: systematic reviews and meta-analyses, the back door for evidence-based medicine. Hum. Reprod. 29, 1618–1621. Tavmergen, E., von Mauw, E., Witjes, H., Mannaerts, B., 2009. Outcome of a trial to identify predictive factors for ovarian response in a GnRH antagonist protocol with or without oral contraceptive scheduling. Abstracts of the 25th Annual Meeting of ESHRE, Amsterdam, the Netherlands, 28 June–1 July. Hum. Reprod. 24 (Suppl. 1), i85. [O-211]. Tsai, C.C., Yen, S.S., 1971. The effect of ethinyl estradiol administration during early follicular phase of the cycle on the gonadotropin levels and ovarian function. J. Clin. Endocrinol. Metab. 33, 917–923. Wardle, P.G., Foster, P.A., Mitchell, J.D., McLaughlin, E.A., Williams, J.A., Corrigan, E., Ray, B.D., McDermott, A., Hull, M.G., 1986. Norethisterone treatment to control timing of the IVF cycle. Hum. Reprod. 1, 455–457. Zorn, J.R., Boyer, P., Guichard, A., 1987. Never on a Sunday: programming for IVF-ET and GIFT. Lancet 14, 385–386.
Declaration: The authors report no commercial or financial conflicts of interest.
Received 10 July 2014; refereed 14 August 2014; accepted 11 September 2014.
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
MINI-REVIEW
To pill or not to pill in GnRH antagonist cycles: that is the question! Juan A Garcia-Velasco a,*, Human M Fatemi b a
IVI-Madrid, Av Talgo, 68 28035 Madrid, Spain; b Nova IVI Fertility-Abu Dhabi, PO Box 60202, Abu Dhabi, UAE
* Corresponding author.
E-mail address: [email protected] (JA Garcia-Velasco). Juan A. Garcia-Velasco is Director of IVI-Madrid and Full Professor of Obstetrics and Gynecology at Rey Juan Carlos University in Madrid, Spain. After his Fellowship in Reproductive Endocrinology at Yale, his main interest has been ovulation induction in difficult patients, mainly endometriosis and hyper and poor responders. He has published extensively in main journals and edited several books on these topics.
Worldwide, gonadotrophin-releasing hormone (GnRH) antagonists are gaining ground, and the number of patients being treated for IVF with a GnRH antagonist is increasing. Cycle planning in GnRH antagonist IVF cycles has been a challenge. During the past 2 years, debate has been ongoing about the possible disadvantages of oral contraceptive pill (OCP) pre-treatment in GnRH antagonist IVF cycles. A recent meta-analysis clearly showed a significant decrease in ongoing pregnancy rates between patients who received OCP pre-treatment and those who did not. In this review, the published meta-analysis are is evaluated. It is argued that caution must be exercised in drawing conclusions too quckly on whether or not OCP pre-treatment might have a negative effect on outcome in GnRH antagonist IVF cycles.
Abstract
© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: estrogens, GnRH antagonist, OCP, scheduling
To pill or not to pill? During the past 2 decades, gonadotrophin-releasing hormone (GnRH) antagonist protocols have gained more popularity for ovarian stimulation. Their administration is linked to several advantages over the long agonist protocol, including shorter overall treatment duration, absence of perimenopausal symptoms caused by pituitary desensitization, no risk of ovarian cyst formation and a lower consumption of gonadotrophins (Devroey et al., 2009).
Moreover, similar live birth rates can be achieved with the use of GnRH antagonist protocols, while significantly reducing the risk of ovarian hyperstimulation syndrome, compared with the long GnRH agonist protocol (Al-Inany et al., 2011). An issue debated for the past 2 years is the possibility of cycle planning with the oral contraceptive pill (OCP) in GnRH antagonist cycles. Looking back in time, cycle planning has been a challenge. Although we might say, ‘why planning?’, there are several reasons to consider cycle planning. In fact, we do plan most of our lives: our daily agenda with patients
http://dx.doi.org/10.1016/j.rbmo.2014.09.010 1472-6483/© 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
40 or surgeries, our holidays, our family, and many other areas of our life. Therefore, it would make sense to plan the activity during the week for gynaecologists and embryologists, as well as for patients. Moreover, it is important to avoid a high volume of work on certain days of the week to ensure that all patients receive the same quality of treatment and attention, and that the IVF staff can focus on each individual patient in the same manner. Moreover, incubator overusage and door openings could be minimized, thus reducing the negative effect on embryo development caused by carbon dioxide and temperature variations. Efforts have been made to plan the day and the time of egg retrieval, as ovum retrieval is not dependent on spontaneous LH but on the capacity of human chorionic gonadotrophin (HCG) to bind and activate the LH receptor (Zorn et al., 1987). Different options have been suggested to plan an IVF cycle. For many years, oral contraceptive pills and synthetic progestogens have been used to schedule IVF cycles (Frydman et al., 1986; Gerli et al., 1989; Wardle et al., 1986; Zorn et al., 1987). Combined OCP consist of oestrogen and progestogen, which inhibit the women’s own production of FSH and LH through a negative feedback (Cohen and Katz, 1979; Gaspard et al., 1984). The combined OCP suppresses gonadal function, and ovulation can be prevented in the absence of a LH-surge. Moreover, only progestogen does also have a contraceptive effect (Erkkola, 2007). Progestogen inhibits the GnRH pulsatility of the pituitary gland, reducing gonadotrophin surges and, according to dose, inhibiting ovulation (Anderson et al., 1990; Erkkola, 2007; Le Nestour et al., 1993). Hence, oestrogen is co-administered in the combined OCP to regulate the bleeding patterns, although it is also capable of reducing FSH levels (De Ziegler et al., 1998; Le Nestour et al., 1993). Lately, the use of natural oestrogens has also been advocated (Blockeel, 2012; De Ziegler et al., 1998; Guivarc’h-Levêque et al., 2011). Among the different suggested options, oral contraceptive pills in particular are one of the most popular options among clinicians for cycle planning in IVF. This is less of an issue in the long GnRH agonist protocol; however, with GnRH antagonist protocol, significantly lower ongoing pregnancy rate per randomized woman has been found to be present in patients being pre-treated with an OCP compared with patients without an OCP pre-treatment (Griesinger et al., 2010). Controversy has arisen over the last few years, as contradictory data have been published on whether the use of OCPs in the previous cycle might have a deleterious effect on subsequent IVF cycle outcome. Although no differences were found in ongoing pregnancy rate in more than 1500 patients retrospectively analysed, whether they received the pill or not (Bellver et al., 2007), recent publications and metaanalyses suggest the contrary. It is known that, after OCP administration, altered endocrinology and follicular growth takes place, as described by Cédrin-Durnerin et al. (2007), a few years ago. When they compared the recovery of endogenous FSH with the natural cycle, they observed that, after FSH suppression induced by the oestrogens in the OCP (Tsai and Yen, 1971), it took most patients 5 days to restore levels to normal values; consequently, they suggested an endocrine wash-out period of 5 days. An attempt to start ovarian stimulation earlier than this may result in a poorer and slower response owing to a strong
JA Garcia-Velasco, HM Fatemi early suppression, with a higher consumption of gonadotrophins; delaying the start of ovarian stimulation by more than 5 days would be comparable to a late start, making it difficult to recruit several follicles as dominance may have been initiated already. Even when starting after the suggested washout period, several investigators have described a significantly higher consumption of gonadotrophins compared with women who had not been pre-treated with OCPs (Barmat et al., 2005; Griesinger et al., 2008; Huirne et al., 2006). More precisely, it was estimated that women pre-treated with OCP would need 542 IU and stimulation required 1.4 more days (Griesinger et al., 2010). Whether this is clinically relevant or not, compared with planning the activity in the clinic, may be at least debatable. A meta-analysis of published trials (Griesinger et al., 2010) has suggested that pre-treatment with OCP might reduce chances of ongoing pregnancy rate (relative risk: 0.80, 95% confidence interval : 0.66 to 0.97; rate difference: –5%, 95% CI –10% to –1%). Although meta-analyses are the most powerful tools to interpret current evidence to guide our practice, we have to be extremely careful with what type of studies are included in these analyses, as well as to be able to interpret the final message. Today, many of the published metaanalyses lack robust evidence from properly conducted randomized controlled trials, which could lead to the acceptance of treatment modalities of ambiguous value (Simón and Bellver, 2014). In this particular meta-analysis (Griesinger et al., 2010), of the 34 studies reviewed, only six were included as per inclusion criteria, the rest were excluded for several reasons. These six studies included both normo and poor responders, which are clearly different patient populations, one-half of the studies included 30 patients or less per arm (with the limitations and bias that this may carry along when looking at pregnancy rates), different types of OCPs were used, different duration of the administration (14–28 days) and, most relevant, varying pill-free intervals of 2–5 days (Table 1). Therefore, we have to interpret carefully the conclusions of this study, as most of the included studies are not free from bias. Hence, we cannot neglect the conclusions, and rather than obviate it, we should investigate what is the hypothesis behind, if any. The mean duration from the intake of the last oral contraceptive tablet until the start of withdrawal bleeding has been described to be 3.5 + 1.0 days (Duijkers et al., 2004). This means that, in the studies included in the meta-analysis by Griesinger et al. (2010), many patients initiated the ovarian stimulation without having a withdrawal bleed (pill-free intervals 2–5 days). Furthermore, endometrial biopsies obtained from patients with and without OCP pre-treatment, with an assessment of the known crucial genes expressed during the window of implantation, did not show any significant differences between groups, concluding that OCP pre-treatment does not affect the expression of known genes related with embryo implantation (Bermejo et al., 2014). The other theoretical effect of the pill pre-treatment is related to the low endogenous LH that is observed when OCP is being administered, which may impair oocyte competence. Adding LH activity to the gonadotrophins administered might easily restore this effect, although evidence is lacking.
Steroid cycle scheduling Table 1
41
Heterogeneity among studies included in the meta-analysisa of OCP effect on assisted reproductive techniques.
Huirne et al., 2006 Kolibianakis et al., 2006 Rombauts et al., 2006 Cédrin-Durnerin et al., 2007 Kim et al., 2009 Tavmergen et al., 2009
Patients
Sample size/arm
Type of gestogen
Duration
Pill free
FSH dose
Day of embryo transfer
Normo Normo Normo Normo Poor responder Normo
32 and 31 211 and 214 110 and 111 21 and 21 41 and 41 221 and 221
Levonorgestrel Desogestrel Desogestrel Desogestrel Levonorgestrel Desogestrel
14–28 15 14–28 15–21 21 14–21
2 or 3 5 2 5 5 5 (variable)
150–300 200 200 150–300 22 200
2 or 3 3 or 5 2 or 3 ? 3 3 or 5
a
Griesinger et al., 2010.
In order to shed light on this discussion, we designed a prospective, randomized trial in which patients received OCP before their IVF cycle under the antagonist protocol and compared their outcomes to patients that received the goldstandard protocol, classical long protocol, in which also profound LH suppression has been described (Garcia-Velasco et al., 2011). When patients received the pill only for 12–16 days, and had a wash-out period of 5 days, no difference could be found in live birth rates between the groups. In a further randomized controlled trial, cycle outcome was compared in women who planned they cycles with the pill versus cycle planning with only oestrogens, as previously described (Blockeel, 2012; Guivarc’h-Levêque et al., 2011). Again, no differences could be found in live birth rates (Hauzman et al., 2013). Therefore, we could conclude that the benefits of cycle scheduling with the pill (equal distribution of work load in large busy units and staff distribution, avoiding weekend retrievals in small units, synchronization of follicular cohort, avoiding excessive incubator openings) must be weighed against the drawbacks (i.e. higher FSH consumption and longer duration of the stimulation). When given for a minimum number of days, and if ovarian stimluation is started after a washout period that resembles the natural cycle, OCP pretreatment might not have a negative effect on endometrial receptivity and IVF outcome might be comparable to women undergoing classical long protocol or who were pre-treated only with oestrogens. Clear consensus is lacking on whether pre-treatment with combined oral contraceptives in ovarian stimulation protocols has a negative effect on pregnancy rates and live birth. Therefore, future, well-designed and adequately powered randomized controlled trials are required to evaluate the most appropriate OCP pre-treatment in GnRH antagonist cycles and subsequent ideal gonadotropin treatment.
References Al-Inany, H.G., Youssef, M.A., Aboulghar, M., Broekmans, F., Sterrenburg, M., Smit, J., Abou-Setta, A.M., 2011. GnRH antagonists are safer than agonists: an update of a Cochrane review. Hum. Reprod. Update 17, 435. Anderson, R.E., Stein, A.L., Paulson, R.J., Stanczyk, F.Z., Vijod, A.G., Lobo, R.A., 1990. Effects of norethindrone on gonadotropin and ovarian steroid secretion when used for cycle programming during in vitro fertilization. Fertil. Steril. 54, 96–101. Barmat, L.I., Chantilis, S.J., Hurst, B.S., Dickey, R.P., 2005. A randomized prospective trial comparing gonadotropin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating
hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives before in vitro fertilization. Fertil. Steril. 83, 321–330. Bellver, J., Albert, C., Labarta, E., Pellicer, A., 2007. Early pregnancy loss in women stimulated with gonadotropin-releasing hormone antagonist protocols according to oral contraceptive pill pretreatment. Fertil. Steril. 87, 1098–1101. Bermejo, A., Iglesias, C., Ruiz-Alonso, M., Blesa, D., Simón, C., Pellicer, A., Garcia-Velasco, J., 2014. The impact of using the combined oral contraceptive pill for cycle scheduling on gene expression related to endometrial receptivity. Hum. Reprod. 29, 1271– 1278. Blockeel, C., 2012. Estradiol valerate pretreatment in GnRHantagonist cycles. Reprod. Biomed. Online 25, 223–224. Cédrin-Durnerin, I., Bständig, B., Parneix, I., Bied-Damon, V., Avril, C., Decanter, C., Hugues, J.N., 2007. Effects of oral contraceptive, synthetic progestogen or natural estrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol. Hum. Reprod. 22, 109–116. Cohen, B.L., Katz, M., 1979. Pituitary and ovarian function in women receiving hormonal contraception. Contraception 20, 475– 487. De Ziegler, D., Jääskeläinen, A.S., Brioschi, P.A., Fanchin, R., Bulletti, C., 1998. Synchronization of endogenous and exogenous FSH stimuli in controlled ovarian hyperstimulation (COH). Hum. Reprod. 13, 561–564. Devroey, P., Aboulghar, M., Garcia-Velasco, J., Griesinger, G., Humaidan, P., Kolibianakis, E., Ledger, W., Tomás, C., Fauser, B.C., 2009. Improving the patient’s experience of IVF/ICSI: a proposal for an ovarian stimulation protocol with GnRH antagonist co-treatment. Hum. Reprod. 24, 764–767. Duijkers, I.J., Klipping, C., Verhoeven, C.H., Dieben, T.O., 2004. Ovarian function with the contraceptive vaginal ring or an oral contraceptive: a randomized study. Hum. Reprod. 19, 2668– 2673. Erkkola, R., 2007. Recent advances in hormonal contraception. Curr. Opin. Obstet. Gynecol. 19, 547–553. Frydman, R., Forman, R., Rainhorn, J.D., Belaisch-Allart, J., Hazout, A., Testart, J., 1986. A new approach to follicular stimulation for in vitro fertilization: programed oocyte retrieval. Fertil. Steril. 46, 657–662. Garcia-Velasco, J.A., Bermejo, A., Ruiz, F., Martinez-Salazar, J., Requena, A., Pellicer, A., 2011. Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial. Fertil. Steril. 96, 590– 593. Gaspard, U.J., Dubois, M., Gillain, D., Franchimont, P., Duvivier, J., 1984. Ovarian function is effectively inhibited by a low-dose triphasic oral contraceptive containing ethinylestradiol and levonorgestrel. Contraception 29, 305–318. Gerli, S., Remohi, J., Partrizio, P., Borrero, C., Balmaceda, J.P., Silber, S.J., Asch, R.H., 1989. Programming of ovarian
42 stimulation with norethindrone acetate in IVF/GIFT cycles. Hum. Reprod. 4, 746–748. Griesinger, G., Venetis, C.A., Marx, T., Diedrich, K., Tarlatzis, B.C., Kolibianakis, E.M., 2008. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta-analysis. Fertil. Steril. 90, 1055–1063. Griesinger, G., Kolibianakis, E.M., Venetis, C., Diedrich, K., Tarlatzis, B., 2010. Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis. Fertil. Steril. 94, 2382–2384. Guivarc’h-Levêque, A., Homer, L., Arvis, P., Broux, P.L., Moy, L., Priou, G., Vialard, J., Colleu, D., Dewailly, D., 2011. Programming in vitro fertilization retrievals during working days after a gonadotropin-releasing hormone antagonist protocol with estrogen pretreatment: does the length of exposure to estradiol impact on controlled ovarian hyperstimulation outcomes? Fertil. Steril. 96, 872–876. Hauzman, E.E., Zapata, A., Bermejo, A., Iglesias, C., Pellicer, A., Garcia-Velasco, J.A., 2013. Cycle scheduling for in vitro fertilization with oral contraceptive pills versus oral estradiol valerate: a randomized, controlled trial. Reprod. Biol. Endocrinol. 28, 96. Huirne, J.A., Hugues, J.N., Pirard, C., Fischl, F., Sage, J.C., Pouly, J.L., Obruca, A., Braat, D.M., van Loenen, A.C., Lambalk, C.B., 2006. Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study. Hum. Reprod. 21, 1408–1415. Kim, C.H., Jeon, G.H., Cheon, Y.P., Jeon, I., Kim, S.H., Chae, H.D., Kang, B.-M., 2009. Comparison of GnRH antagonist protocol with or without oral contraceptive pill pretreatment and GnRH agonist low-dose long protocol in low responders undergoing IVF/ intracytoplasmic sperm injection. Fertil. Steril. 92, 1758–1760. Kolibianakis, E.M., Papanikolaou, E.G., Camus, M., Tournaye, H., Van Steirteghem, A.C., Devroey, P., 2006. Effect of oral contraceptive pill pretreatment on ongoing pregnancy rates in patients
JA Garcia-Velasco, HM Fatemi stimulated with GnRH antagonists and recombinant FSH for IVF. A randomized controlled trial. Hum. Reprod. 21, 352–357. Le Nestour, E.1., Marraoui, J., Lahlou, N., Roger, M., de Ziegler, D., Bouchard, P., 1993. Role of estradiol in the rise in folliclestimulating hormone levels during the luteal-follicular transition. J. Clin. Endocrinol. Metab. 77, 439–442. Rombauts, L., Healy, D., Norman, R.J., 2006. Comparative randomized trial to assess the impact of oral contraceptive pretreatment on follicular growth and hormone profiles in GnRH antagonist-treated patients. Hum. Reprod. 21, 95–103. Simón, C.1., Bellver, J., 2014. Scratching beneath ‘The Scratching Case’: systematic reviews and meta-analyses, the back door for evidence-based medicine. Hum. Reprod. 29, 1618–1621. Tavmergen, E., von Mauw, E., Witjes, H., Mannaerts, B., 2009. Outcome of a trial to identify predictive factors for ovarian response in a GnRH antagonist protocol with or without oral contraceptive scheduling. Abstracts of the 25th Annual Meeting of ESHRE, Amsterdam, the Netherlands, 28 June–1 July. Hum. Reprod. 24 (Suppl. 1), i85. [O-211]. Tsai, C.C., Yen, S.S., 1971. The effect of ethinyl estradiol administration during early follicular phase of the cycle on the gonadotropin levels and ovarian function. J. Clin. Endocrinol. Metab. 33, 917–923. Wardle, P.G., Foster, P.A., Mitchell, J.D., McLaughlin, E.A., Williams, J.A., Corrigan, E., Ray, B.D., McDermott, A., Hull, M.G., 1986. Norethisterone treatment to control timing of the IVF cycle. Hum. Reprod. 1, 455–457. Zorn, J.R., Boyer, P., Guichard, A., 1987. Never on a Sunday: programming for IVF-ET and GIFT. Lancet 14, 385–386.
Declaration: The authors report no commercial or financial conflicts of interest.
Received 10 July 2014; refereed 14 August 2014; accepted 11 September 2014.