- Email: [email protected]
‘Controlled’ ovarian stimulation: who's kidding who?
International Congress Series 1279 (2005) 35 – 38
www.ics-elsevier.com
dControlledT ovarian stimulation: who’s kidding who? Nick Macklon* Centre for Reproduction, Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, Netherlands
Abstract. In modern fertility practice, much time and energy is devoted to controlling ovarian stimulation. Is this effort well directed? Does monitoring and dose adjustment prevent complications and improve outcomes? Or does it just provide clinicians with a false sense of security and power to influence ovarian function? Monitoring ovarian stimulation can identify excess response, and enable the clinician to prevent complications of hyperstimulation by terminating the cycle. However, subtle interventions such as dose adjustment to monitored response have little impact on outcomes. Poor responders are frequently subjected to increased doses of gonadotropins in the hope of improving chances of undergoing oocyte pick up and achieving pregnancy. However, the evidence supporting this approach is scarce. In the context of ovarian stimulation for IUI, interventions aimed at limiting response have little impact on the risk of multiple pregnancies. Why is the ovarian response so difficult to control? While recent studies suggest that batch variation in the bioactivity of gonadotropin preparations may be partially to blame, it is becoming increasingly evident that patientrelated factors, rather than doctor-controlled factors are the primary determinants of outcome from ovarian stimulation. D 2005 Elsevier B.V. All rights reserved. Keywords: Controlled ovarian stimulation; Monitoring; Response
1. Introduction In 1879 Mark Twain advised his audience of future parents: bSufficient unto the day is one baby. As long as you are in your right mind don’t you ever pray for twins. Twins amount to a permanent riot; and there ain’t any real difference between triplets and an insurrectionQ. * Tel.: +31 104635093; fax: +31 104367306. E-mail address: [email protected]. 0531-5131/ D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.12.053
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N. Macklon / International Congress Series 1279 (2005) 35–38
These sentiments increasingly inform the practice of modern fertility specialists, who spend many hours carefully and expertly monitoring ovarian response to stimulation in order to prevent multiple pregnancies and ovarian hyperstimulation syndrome (OHSS). Of equal concern to the clinician and his or her patient is that a response to stimulation be dachievedT which is adequate to offer a good chance of conception from the treatment cycle. Almost 50 years after the introduction of gonadotropins into clinical practice, and countless hours of monitoring and carefully considered dose adjustment, OHSS, multiple pregnancy and poor response remain the principle challenges in ovarian stimulation. In this brief article, the ability of the clinician to control the response to ovarian response will be critically assessed, and strategies for improving outcomes from ovarian stimulation, which are less dependent on dcontrolT, are proposed. 2. Ovarian stimulation in intrauterine insemination Ovarian hyperstimulation before timed intercourse or IUI is designed to induce the development of 2–3 pre-ovulatory follicles releasing oocytes for subsequent fertilization in vivo. Although this goal can often be achieved, the individual ovarian response is highly variable. When more than three large follicles are observed (which may occur in up to 40% of cycles) the chances of multiple pregnancy are substantial [1]. These cycles should therefore be cancelled, or conversion to IVF may be considered. Unfortunately, even a conscientious application of this approach will not prevent multiple pregnancies. A realistic assessment of our ability to monitor and control ovarian hyperstimulation for IUI demands a critical appraisal of the use of ovarian stimulation for this end. Recent large clinical studies have delineated the impact of IUI and ovarian hyperstimulation alone or in combination on the chance of conceiving. While the pregnancy rate in the largest randomized controlled trial was around 10% per cycle with gonadotrophin/IUI treatment [2], (higher order) multiple pregnancies represent around 30% of these [2,3]. Calculated odds ratios suggest 1.5- to 2.8-fold increased pregnancy chances in unexplained subfertility, independently for ovarian hyperstimulation and IUI [2,4,5]. A health economics evaluation based on the randomized allocation to IUI or IVF, recommended IUI in the natural cycle as the therapy of first choice [6] and recently the Fertility Treatment Guidelines published by the National Institute for Clinical Excellence in the UK made similar recommendations [6]. 3. Ovarian stimulation in IVF In contrast to ovulation induction in anovulatory women, and ovarian stimulation for IUI, the therapeutic margins in the context of IVF are considerably greater. However, despite improvements in ultrasound technology and the growth in the number of ways in which ovarian response is monitored during IVF, rates of ovarian hyperstimulation syndrome at one extreme, and poor response at the other, remain depressingly similar to those 10 or even 20 years ago [7]. Addition of other forms of monitoring ovarian response such as estradiol measurements have been shown to be of little additional value in improving pregnancy rates or predicting OHSS [8]. With respect to poor responders to
N. Macklon / International Congress Series 1279 (2005) 35–38
37
ovarian stimulation, the impact on pregnancy rates of adjusting gonadotropin dose during monitored cycles has been shown to be negligible [9,10]. Indeed, the focus on ovarian response as a surrogate marker of success, combined with the need to dachieve an oocyte pick upT as consolation endpoint, is responsible for many unnecessary invasive procedures. If we are to improve outcomes and reduce risks associated with ovarian stimulation, we must recognize the individual and cycle-to-cycle variability in ovarian response, the limited correlation between monitoring an outcome, and the restricted impact adjustment of gonadotropin dose has on treatment outcomes. It is time to shift the focus from the ultrasound monitor to the patient herself. 4. Response to ovarian stimulation: from management to prediction It is now clear that individual variation is the primary determinant of response to ovarian stimulation. The challenge is to understand the characteristics that determine this response. Much work has been done in identifying factors obtained at initial screening which are predictive of ovarian response to ovulation induction with clomiphene and gonadotropins and subsequent pregnancy [11]. Models have been developed which enable the response dose to FSH for ovulation induction to be determined on the basis of initial screening parameters. Application of such models promise greater individualization of treatment, lower risks of multiple pregnancy and OHSS, and shorter more successful treatment cycles. Recently, predictive factors for response to recombinant FSH in IVF have been identified, and a nomogram for initial reFSH proposed. This nomogram includes the number of antral follicles, ovarian volume, age and smoking habits [12]. A subsequent prospective randomized trial comparing an individualized dose of recFSH with a standard starting dose of 150 IU/day suggested that this approach could improve outcomes [13]. Currently, other studies are in progress prospectively testing alternative models, which allow individual dose requirements to be calculated prior to commencing treatment. Development and application of these nomograms in practice may benefit from fill- by mass preparations, which enable more reliable dose administration. This approach recognizes the difficulty of managing ovarian response, and offers a promising route to improving outcomes from ovarian stimulation. References [1] N. Gleicher, et al., Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins, N. Engl. J. Med. 343 (2000) 2 – 7. [2] D.S. Guzick, et al., Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network, N. Engl. J. Med. 340 (1999) 177 – 183. [3] R. Tur, et al., Risk factors for high-order multiple implantation after ovarian stimulation with gonadotrophins: evidence from a large series of 1878 consecutive pregnancies in a single centre, Hum. Reprod. 16 (2001) 2124 – 2129. [4] E.G. Hughes, The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis, Hum. Reprod. 12 (1997) 1865 – 1872. [5] A.J. Goverde, et al., Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis, Lancet 355 (2000) 13 – 18. [6] NICE, Fertility assessment and treatment for people with fertility problems: Clinical Guidelines, (2004). http://www.nice.org.uk.2004.
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N. Macklon / International Congress Series 1279 (2005) 35–38
[7] B. Fauser, P. Devroey, N. Macklon, The price of ovarian hyperstimulation for assisted reproduction, Lancet (2005) (in press). [8] A. Lass, UK Timing of hCG Group, Monitoring of in-vitro fertilization-embryo transfer cycles by ultrasound and hormonal levels: a prospective, multicenter randomized study, Fertil. Steril. 80 (2003) 80 – 85. [9] M.H. van Hooff, et al., Doubling the human menopausal gonadotrophin dose in the course of an in-vitro fertilization treatment cycle in low responders: a randomized study, Hum. Reprod. 8 (1993) 369 – 373. [10] B.C. Tarlatzis, et al., Clinical management of low ovarian response to stimulation for IVF: a systematic review, Hum. Reprod. Updat. 9 (2003) 61 – 76. [11] B.C.J.M. Fauser, N.S. Macklon, Medical approaches to ovarian stimulation for infertility, in: J. Strauss, R. Barbieri (Eds.), Yen and Jaffe’s reproductive endocrinology, Elsevier Science, Philadephia, 2004, pp. 965 – 1012. [12] B. Popovic-Todorovic, et al., A prospective study of predictive factors of ovarian response in dstandardT IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dose normogram, Hum. Reprod. 18 (2003) 781 – 787. [13] B. Popovic-Todorovic, et al., Prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a dstandardT dose of 150 IU in dstandardT patients undergoing IVF/ICSI treatment, Hum. Reprod. 18 (2003) 2275 – 2282.
www.ics-elsevier.com
dControlledT ovarian stimulation: who’s kidding who? Nick Macklon* Centre for Reproduction, Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, Netherlands
Abstract. In modern fertility practice, much time and energy is devoted to controlling ovarian stimulation. Is this effort well directed? Does monitoring and dose adjustment prevent complications and improve outcomes? Or does it just provide clinicians with a false sense of security and power to influence ovarian function? Monitoring ovarian stimulation can identify excess response, and enable the clinician to prevent complications of hyperstimulation by terminating the cycle. However, subtle interventions such as dose adjustment to monitored response have little impact on outcomes. Poor responders are frequently subjected to increased doses of gonadotropins in the hope of improving chances of undergoing oocyte pick up and achieving pregnancy. However, the evidence supporting this approach is scarce. In the context of ovarian stimulation for IUI, interventions aimed at limiting response have little impact on the risk of multiple pregnancies. Why is the ovarian response so difficult to control? While recent studies suggest that batch variation in the bioactivity of gonadotropin preparations may be partially to blame, it is becoming increasingly evident that patientrelated factors, rather than doctor-controlled factors are the primary determinants of outcome from ovarian stimulation. D 2005 Elsevier B.V. All rights reserved. Keywords: Controlled ovarian stimulation; Monitoring; Response
1. Introduction In 1879 Mark Twain advised his audience of future parents: bSufficient unto the day is one baby. As long as you are in your right mind don’t you ever pray for twins. Twins amount to a permanent riot; and there ain’t any real difference between triplets and an insurrectionQ. * Tel.: +31 104635093; fax: +31 104367306. E-mail address: [email protected]. 0531-5131/ D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.12.053
36
N. Macklon / International Congress Series 1279 (2005) 35–38
These sentiments increasingly inform the practice of modern fertility specialists, who spend many hours carefully and expertly monitoring ovarian response to stimulation in order to prevent multiple pregnancies and ovarian hyperstimulation syndrome (OHSS). Of equal concern to the clinician and his or her patient is that a response to stimulation be dachievedT which is adequate to offer a good chance of conception from the treatment cycle. Almost 50 years after the introduction of gonadotropins into clinical practice, and countless hours of monitoring and carefully considered dose adjustment, OHSS, multiple pregnancy and poor response remain the principle challenges in ovarian stimulation. In this brief article, the ability of the clinician to control the response to ovarian response will be critically assessed, and strategies for improving outcomes from ovarian stimulation, which are less dependent on dcontrolT, are proposed. 2. Ovarian stimulation in intrauterine insemination Ovarian hyperstimulation before timed intercourse or IUI is designed to induce the development of 2–3 pre-ovulatory follicles releasing oocytes for subsequent fertilization in vivo. Although this goal can often be achieved, the individual ovarian response is highly variable. When more than three large follicles are observed (which may occur in up to 40% of cycles) the chances of multiple pregnancy are substantial [1]. These cycles should therefore be cancelled, or conversion to IVF may be considered. Unfortunately, even a conscientious application of this approach will not prevent multiple pregnancies. A realistic assessment of our ability to monitor and control ovarian hyperstimulation for IUI demands a critical appraisal of the use of ovarian stimulation for this end. Recent large clinical studies have delineated the impact of IUI and ovarian hyperstimulation alone or in combination on the chance of conceiving. While the pregnancy rate in the largest randomized controlled trial was around 10% per cycle with gonadotrophin/IUI treatment [2], (higher order) multiple pregnancies represent around 30% of these [2,3]. Calculated odds ratios suggest 1.5- to 2.8-fold increased pregnancy chances in unexplained subfertility, independently for ovarian hyperstimulation and IUI [2,4,5]. A health economics evaluation based on the randomized allocation to IUI or IVF, recommended IUI in the natural cycle as the therapy of first choice [6] and recently the Fertility Treatment Guidelines published by the National Institute for Clinical Excellence in the UK made similar recommendations [6]. 3. Ovarian stimulation in IVF In contrast to ovulation induction in anovulatory women, and ovarian stimulation for IUI, the therapeutic margins in the context of IVF are considerably greater. However, despite improvements in ultrasound technology and the growth in the number of ways in which ovarian response is monitored during IVF, rates of ovarian hyperstimulation syndrome at one extreme, and poor response at the other, remain depressingly similar to those 10 or even 20 years ago [7]. Addition of other forms of monitoring ovarian response such as estradiol measurements have been shown to be of little additional value in improving pregnancy rates or predicting OHSS [8]. With respect to poor responders to
N. Macklon / International Congress Series 1279 (2005) 35–38
37
ovarian stimulation, the impact on pregnancy rates of adjusting gonadotropin dose during monitored cycles has been shown to be negligible [9,10]. Indeed, the focus on ovarian response as a surrogate marker of success, combined with the need to dachieve an oocyte pick upT as consolation endpoint, is responsible for many unnecessary invasive procedures. If we are to improve outcomes and reduce risks associated with ovarian stimulation, we must recognize the individual and cycle-to-cycle variability in ovarian response, the limited correlation between monitoring an outcome, and the restricted impact adjustment of gonadotropin dose has on treatment outcomes. It is time to shift the focus from the ultrasound monitor to the patient herself. 4. Response to ovarian stimulation: from management to prediction It is now clear that individual variation is the primary determinant of response to ovarian stimulation. The challenge is to understand the characteristics that determine this response. Much work has been done in identifying factors obtained at initial screening which are predictive of ovarian response to ovulation induction with clomiphene and gonadotropins and subsequent pregnancy [11]. Models have been developed which enable the response dose to FSH for ovulation induction to be determined on the basis of initial screening parameters. Application of such models promise greater individualization of treatment, lower risks of multiple pregnancy and OHSS, and shorter more successful treatment cycles. Recently, predictive factors for response to recombinant FSH in IVF have been identified, and a nomogram for initial reFSH proposed. This nomogram includes the number of antral follicles, ovarian volume, age and smoking habits [12]. A subsequent prospective randomized trial comparing an individualized dose of recFSH with a standard starting dose of 150 IU/day suggested that this approach could improve outcomes [13]. Currently, other studies are in progress prospectively testing alternative models, which allow individual dose requirements to be calculated prior to commencing treatment. Development and application of these nomograms in practice may benefit from fill- by mass preparations, which enable more reliable dose administration. This approach recognizes the difficulty of managing ovarian response, and offers a promising route to improving outcomes from ovarian stimulation. References [1] N. Gleicher, et al., Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins, N. Engl. J. Med. 343 (2000) 2 – 7. [2] D.S. Guzick, et al., Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network, N. Engl. J. Med. 340 (1999) 177 – 183. [3] R. Tur, et al., Risk factors for high-order multiple implantation after ovarian stimulation with gonadotrophins: evidence from a large series of 1878 consecutive pregnancies in a single centre, Hum. Reprod. 16 (2001) 2124 – 2129. [4] E.G. Hughes, The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis, Hum. Reprod. 12 (1997) 1865 – 1872. [5] A.J. Goverde, et al., Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis, Lancet 355 (2000) 13 – 18. [6] NICE, Fertility assessment and treatment for people with fertility problems: Clinical Guidelines, (2004). http://www.nice.org.uk.2004.
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N. Macklon / International Congress Series 1279 (2005) 35–38
[7] B. Fauser, P. Devroey, N. Macklon, The price of ovarian hyperstimulation for assisted reproduction, Lancet (2005) (in press). [8] A. Lass, UK Timing of hCG Group, Monitoring of in-vitro fertilization-embryo transfer cycles by ultrasound and hormonal levels: a prospective, multicenter randomized study, Fertil. Steril. 80 (2003) 80 – 85. [9] M.H. van Hooff, et al., Doubling the human menopausal gonadotrophin dose in the course of an in-vitro fertilization treatment cycle in low responders: a randomized study, Hum. Reprod. 8 (1993) 369 – 373. [10] B.C. Tarlatzis, et al., Clinical management of low ovarian response to stimulation for IVF: a systematic review, Hum. Reprod. Updat. 9 (2003) 61 – 76. [11] B.C.J.M. Fauser, N.S. Macklon, Medical approaches to ovarian stimulation for infertility, in: J. Strauss, R. Barbieri (Eds.), Yen and Jaffe’s reproductive endocrinology, Elsevier Science, Philadephia, 2004, pp. 965 – 1012. [12] B. Popovic-Todorovic, et al., A prospective study of predictive factors of ovarian response in dstandardT IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dose normogram, Hum. Reprod. 18 (2003) 781 – 787. [13] B. Popovic-Todorovic, et al., Prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a dstandardT dose of 150 IU in dstandardT patients undergoing IVF/ICSI treatment, Hum. Reprod. 18 (2003) 2275 – 2282.