Efficacy and Safety of Medication Used to Stimulate Ovulation
Study Details
Study Description
Brief Summary
Individuals undergoing In Vitro Fertilization must undergo controlled ovarian hyperstimulation (COH) to produce enough quality eggs for fertility treatment. Ovarian follicular responsiveness to COH with gonadotropins is extremely variable between patients and even from cycle to cycle for the same patient. Achieving an ideal follicular response is critical to the success of assisted reproduction treatment (ART). Patients have been classified as 'poor', 'normal' or 'high' responders, which dictate the amount of gonadotropins that they receive. It is still important to develop treatments with high efficacy, lower multiple birth rates, and a lower complication rate for each of these groups. In an era of evidence-based medicine and with special emphasis on reducing IVF risks (mainly OHSS and pregnancies with multiples), it is very important to find optimal and safe ovulation induction and triggering regimens for each patient population.
The use of GnRH agonist (GnRHa) triggering among high responders in order to reduce or eliminate OHSS is an example of an important breakthrough in the clinical management of IVF patients. Although GnRHa triggering was shown to be as effective as human chorionic gonadotropin (hCG) at inducing oocyte maturation more than 20 years ago, its use to trigger ovulation was not possible until the introduction of GnRH antagonists for pituitary suppression.
Another prominent trend in ART in recent years has been the introduction of dual triggering, which involves a combination of GnRHa plus hCG for triggering. This regimen creates simultaneous lutenizing hormone (LH) and follicle stimulating hormone (FSH) surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, which stimulates the corpus luteum to excrete sufficient hormonal endometrial support. Since its introduction, dual triggering has been gaining popularity due to outstanding results in retrospective studies among both normal and high responders. Moreover, in spite of the encouraging retrospective reports, prospective randomized controlled trials (RCT) on dual triggering have not been reported to date. The aim of the current proposed study is to compare the efficacy of dual triggering and conventional triggering among the three IVF populations (high, normal and poor responders).
Condition or Disease | Intervention/Treatment | Phase |
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Phase 4 |
Detailed Description
Ovarian follicular responsiveness to controlled ovarian hyperstimulation (COH) with gonadotropins is extremely variable between patients and even from cycle to cycle for the same patient. Achieving an ideal follicular response is critical to the success of assisted reproduction treatment (ART). Since the early years of ART, patients have been classified as 'poor', 'normal' or 'high' responders. Although these terms are widely used in research and in daily clinical practice, their precise definitions are not fully agreed upon. Distinguishing them has been based on various measures of ovarian reserve. The first description of a poor responder occurred in 1983, and the first international consensus criteria for poor responders (the Bologna Criteria) was published in 2011. Poor responders, in general, exhibit an inadequate response to hormonal stimulation and diminished reproductive outcome. In contrast to poor responders, high responders are characterized by an exaggerated ovarian responsiveness, accompanied by a higher risk for ovarian hyperstimulation syndrome (OHSS). In most IVF clinics, "normal responders" comprise the majority of their patients. These patients are characterized by an adequate response to gonadotropins stimulation, a relatively low risk for OHSS, and a low cancellation rate. However, even with their relatively good prognosis, it is still important to develop treatments with high efficacy, lower multiple birth rates, and a lower complication rate. In addition, ovum donors are a unique population of patients with special characteristics and challenges. Egg donation has proven to be an effective treatment option for the treatment of various forms of infertility. However, ovum donors are a young population with a significant OHSS risk. Moreover, studies regarding this population provide an ideal opportunity to determine the effects of various triggering regimens on implantation (endometrial effect) from those attributable to the oocyte cohort alone (follicular effect). In an era of evidence-based medicine and with special emphasis on reducing IVF risks (mainly OHSS and pregnancies with multiples, it is very important to find optimal and safe ovulation induction and triggering regimens for each patient population. The use of GnRH agonist (GnRHa) triggering among high responders in order to reduce or eliminate OHSS is an example of an important breakthrough in the clinical management of IVF patients. Although GnRHa triggering was shown to be as effective as human chorionic gonadotropin (hCG) at inducing oocyte maturation more than 20 years ago, its use to trigger ovulation was not possible until the introduction of GnRH antagonists for pituitary suppression. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. Early results with GnRHa triggering were disappointing, as reported in several RCT"s, where higher pregnancy loss rates and lower ongoing pregnancy rates were observed. Subsequently, outcomes were dramatically improved after the adoption of adjusted regimens to enhance luteal support. A pivotal study by Engmann et al (2008) included high responder patients during their first IVF cycle and patients with a history of high response in a previous cycle. The authors reported no cases of OHSS in those patients who underwent GnRHa triggering together with intensified estrogen and progesterone supplementation, while maintaining comparable reproductive outcome to those receiving HCG triggering. Moreover, increased safety of GnRHa triggering has been reported among ovum donors in several reports. Another well designed RCT, recruited patients with OHSS risk factors (PCOS as well as oligo/amenorrhea) and further differentiated them on the triggering day into "low" vs. "high" OHSS risk according to their actual ovarian response. These researchers emphasized the fact that pre-stimulation classification as a high responder does not optimally correlate with actual response to hormonal stimulation. Therefore, there is a need to distinguish between a) pre-stimulation assessment based on clinical, laboratory and ultrasonographic parameters (such as previous OHSS, anti-müllerian hormone (AMH) and antral follicle count (AFC), respectively) and b) the actual response evaluated by the number and size of recruited follicles and serum estradiol concentration. Another prominent trend in ART in recent years has been the introduction of dual triggering, which involves a combination of GnRHa plus hCG for triggering. This regimen creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, which stimulates the corpus luteum to excrete sufficient hormonal endometrial support. Since its introduction, dual triggering has been gaining popularity due to outstanding results in retrospective studies among both normal and high responders. Griffin et al, 2012 reported that among high responders, their dual-trigger group (GnRHa plus 1,000 IU hCG) had a significantly higher live birth rate (52.9% vs. 30.9%), implantation rate (41.9% vs. 22.1%), and clinical pregnancy rate (58.8% vs. 36.8%) as compared to GnRHa alone, without a higher risk for OHSS. A large retrospective study, which included 376 normal responders patients with 378 completed cycles, resulted in a significantly higher implantation (29.6% vs. 18.4%), clinical pregnancy (50.7% vs. 40.1%), and live-birth (41.3% vs. 30.4%) rates with an hCG (6,500 IU) together with GnRH agonist, as compared to hCG alone. Additionally, dual triggering was found as efficient method to improve final oocyte maturation among patients with a high immature oocyte rate and in patients with a low number of oocytes retrieved per number of pre-ovulatory follicles. To the best of our knowledge, there are no reports on the effect of dual triggering on IVF outcome among poor responders or OHSS occurrence in ovum donors. Moreover, in spite of the encouraging retrospective reports, prospective RCTs on dual triggering have not been reported to date. The aim of the current proposed study is to compare the efficacy of dual triggering and conventional triggering among the three IVF populations (high, normal and poor responders), as well as ovum donors. The current proposal includes three different protocols, which will be implemented in four populations in separate simultaneous RCT's:
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Dual triggering with 1000 units hCG vs. GnRH agonist alone in high responder IVF patients and in ovum donors.
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Dual triggering vs. 5000 units hCG in normal responders
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Dual triggering vs. 10000 units hCG in poor responders
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Study group: High Responders 1000 units hCG |
Drug: Ovulation induction with hCG and Lupron (GnRH agonist)
Patients treated for infertility are categorized as a low-, normal- or high responder according to their estimated ovarian response to hormonal stimulation. This classification dictates the hormonal stimulation regimen that they will receive. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. A combination of GnRHa plus hCG for triggering creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, stimulating the corpus luteum to excrete sufficient hormonal endometrial support.
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No Intervention: Control group: High Responders 1000 units hCG |
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Experimental: Study group: Normal Responders 5000 units hCG |
Drug: Ovulation induction with hCG and Lupron (GnRH agonist)
Patients treated for infertility are categorized as a low-, normal- or high responder according to their estimated ovarian response to hormonal stimulation. This classification dictates the hormonal stimulation regimen that they will receive. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. A combination of GnRHa plus hCG for triggering creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, stimulating the corpus luteum to excrete sufficient hormonal endometrial support.
|
No Intervention: Control group: Normal Responders 5000 units hCG |
|
Experimental: Study group: Low Responders 10000 units hCG |
Drug: Ovulation induction with hCG and Lupron (GnRH agonist)
Patients treated for infertility are categorized as a low-, normal- or high responder according to their estimated ovarian response to hormonal stimulation. This classification dictates the hormonal stimulation regimen that they will receive. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. A combination of GnRHa plus hCG for triggering creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, stimulating the corpus luteum to excrete sufficient hormonal endometrial support.
|
No Intervention: Control group: Low Responders 10000 units hCG |
Outcome Measures
Primary Outcome Measures
- Implantation rate [14 days post IVF procedure]
- Human Chorionic Gonadotropin serum levels [2-4 weeks post IVF procedure]
- Ongoing pregnancy rate [9 months post IVF procedure]
- Miscarriage rate [9 months post procedure]
- Ovarian hyperstimulation syndrome [7 days post IVF procedure]
Mild OHSS: Grade 1: Abdominal distention, Ovaries <6 cm Grade 2: Abdominal distention and nausea, vomiting and diarrhea, Ovaries <6 cm Moderate OHSS: a) Grade 3: Grade II criteria and ultrasound ascites/weight gain, Ovaries 6-12 cm Severe OHSS: Grade 4: Ascites/hydrothorax, Ovaries >12 cm Grade 5: Ascites/hydrothorax and hypovolemia, hemoconcentration, coagulation disorder, oliguria, shock, Ovaries >12 cm
- Fetal heartbeat measured by ultrasound [2-4 weeks post IVF procedure]
Secondary Outcome Measures
- Number of retrieved oocytes [5 days post IVF procedure]
- Number of retrieved Meiosis II oocytes [5 days post IVF procedure]
- Fertilization rate [5 days post IVF procedure]
- Number of Day 3 embryos/eggs retrieved [5 days post IVF procedure]
- Number of blastocysts/eggs retrieved [5 days post IVF procedure]
Eligibility Criteria
Criteria
- Dual triggering vs. GnRH agonist alone in high responders IVF patients
Inclusion Criteria - At least one of the following risk factors:
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AMH > 29 pmol/L
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AFC > 16
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PCOS diagnosed according to Rotterdam criteria: any two of the following three features: 1) oligo- or anovulation; 2) clinical and/or biochemical hyper-androgenemia; and 3) PCO-US with exclusion of other etiologies as mentioned in the National Institute of Child Health and Human Development (NICHD) criteria
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Previous OHSS
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Previous cycle cancellation due to OHSS risk
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Previous coasting
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Participants initially recruited to the normal responders study who exhibit excessive ovarian response markers on triggering day: high amount of middle-large follicles (> 13 follicles ≥ 11mm on triggering day). All previous inclusion criteria are assessed before initiation of the IVF cycle and ovarian stimulation, and all of them represent pre-stimulation risk factors for high ovarian response. The patient's actual response will be assessed on triggering day (after completion of ovarian stimulation). Final assignment of responder category followed by randomization will only be performed on the day of triggering
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informed consent obtained
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Must be 18 years or older
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Ability to speak and read English, or understand French, Mandarin, Cantonese, Arabic, or Filipino.
Exclusion criteria:
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Chronic disease
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Hypogonadotrophic hypogonadism
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Untreated uterine abnormalities
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E2>4000 pg/ml (>14,680 pmol/L) on trigger day. These very high risk patients will undergo GnRHa only trigger and will be excluded from the trial.
- Dual triggering vs. 5000 units hCG in normal responders
Inclusion criteria:
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Age above 18 years and less than 40 years
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Do not fulfill criteria for poor responder or high responder
Exclusion criteria:
- Bologna criteria for poor responders exclusion: two of the following should need to be fulfilled:
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Age > 40 or other risk factor for decreased ovarian reserve (ex. ovarian surgery)
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Single abnormal test for ovarian reserve (AFC < 6 or AMH < 8 pmol/L)
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Previous poor response in previous cycle: cancellation or < 4 retrieved oocytes in response to daily 150 FSH units
- Criteria for high responders' exclusion
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AMH > 29 pmol/L
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AFC > 16
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PCOS diagnosed according to Rotterdam criteria [19, 28]: any two of the following three features: 1) oligo- or anovulation; 2) clinical and/or biochemical hyper-androgenemia; and 3) PCO-US with exclusion of other etiologies as mentioned in the NICHD criteria
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Previous OHSS
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Previous cycle cancellation due to OHSS risk
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Previous coasting
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Excessive ovarian response markers on triggering day such as high amount of middle-large follicles (> 13 follicles ≥ 11mm on triggering day) and E2 concentration (optional E2 > 14500 pmol/L on triggering day). These patients will be allocated to the high responders group.
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Untreated uterine abnormalities
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Chronic disease
- Dual Triggering for Poor Responders
Inclusion criteria: According to Bologna criteria two of the following should be fulfilled:
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Age > 40 or other risk factor for decreased ovarian reserve (ex. ovarian surgery).
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Single abnormal test for ovarian reserve (AFC < 6 or AMH < 8 pmol/L).
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Previous poor response in previous cycle: cancellation or < 4 retrieved oocytes in response to daily 150 FSH units.
Exclusion criteria:
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Chronic disease
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Untreated uterine abnormalities
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Response consistent with normal or high responder, as defined above
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Create Fertility Centre | Toronto | Ontario | Canada | M5G1N8 |
Sponsors and Collaborators
- Create Fertility Center
Investigators
- Principal Investigator: Clifford Librach, MD, University of Toronto
Study Documents (Full-Text)
None provided.More Information
Publications
- Acevedo B, Gomez-Palomares JL, Ricciarelli E, Hernández ER. Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates. Fertil Steril. 2006 Dec;86(6):1682-7. Epub 2006 Oct 30.
- Blazquez A, Guillén JJ, Colomé C, Coll O, Vassena R, Vernaeve V. Empty follicle syndrome prevalence and management in oocyte donors. Hum Reprod. 2014 Oct 10;29(10):2221-7. doi: 10.1093/humrep/deu203. Epub 2014 Aug 1.
- Bodri D, Guillén JJ, Trullenque M, Schwenn K, Esteve C, Coll O. Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasing-hormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study. Fertil Steril. 2010 May 1;93(7):2418-20. doi: 10.1016/j.fertnstert.2009.08.036. Epub 2009 Oct 2.
- Broekmans FJ, Verweij PJ, Eijkemans MJ, Mannaerts BM, Witjes H. Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2014 Aug;29(8):1688-97. doi: 10.1093/humrep/deu090. Epub 2014 Jun 5.
- Datta AK, Eapen A, Birch H, Kurinchi-Selvan A, Lockwood G. Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders. Reprod Biomed Online. 2014 Nov;29(5):552-8. doi: 10.1016/j.rbmo.2014.08.006. Epub 2014 Aug 28.
- Engmann L, DiLuigi A, Schmidt D, Nulsen J, Maier D, Benadiva C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril. 2008 Jan;89(1):84-91. Epub 2007 Apr 26.
- Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J, van Hooren HG. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab. 2002 Feb;87(2):709-15.
- Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011 Jul;26(7):1616-24. doi: 10.1093/humrep/der092. Epub 2011 Apr 19.
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- Griffin D, Benadiva C, Kummer N, Budinetz T, Nulsen J, Engmann L. Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders. Fertil Steril. 2012 Jun;97(6):1316-20. doi: 10.1016/j.fertnstert.2012.03.015. Epub 2012 Apr 3.
- Griffin D, Feinn R, Engmann L, Nulsen J, Budinetz T, Benadiva C. Dual trigger with gonadotropin-releasing hormone agonist and standard dose human chorionic gonadotropin to improve oocyte maturity rates. Fertil Steril. 2014 Aug;102(2):405-9. doi: 10.1016/j.fertnstert.2014.04.028. Epub 2014 May 17.
- Haas J, Zilberberg E, Dar S, Kedem A, Machtinger R, Orvieto R. Co-administration of GnRH-agonist and hCG for final oocyte maturation (double trigger) in patients with low number of oocytes retrieved per number of preovulatory follicles--a preliminary report. J Ovarian Res. 2014 Aug 2;7:77. doi: 10.1186/1757-2215-7-77.
- Huber M, Hadziosmanovic N, Berglund L, Holte J. Using the ovarian sensitivity index to define poor, normal, and high response after controlled ovarian hyperstimulation in the long gonadotropin-releasing hormone-agonist protocol: suggestions for a new principle to solve an old problem. Fertil Steril. 2013 Nov;100(5):1270-6. doi: 10.1016/j.fertnstert.2013.06.049. Epub 2013 Aug 6.
- Humaidan P, Bredkjaer HE, Bungum L, Bungum M, Grøndahl ML, Westergaard L, Andersen CY. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod. 2005 May;20(5):1213-20. Epub 2005 Mar 10.
- Humaidan P, Kol S, Papanikolaou EG; Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011 Jul-Aug;17(4):510-24. doi: 10.1093/humupd/dmr008. Epub 2011 Mar 30. Review.
- Humaidan P, Polyzos NP, Alsbjerg B, Erb K, Mikkelsen AL, Elbaek HO, Papanikolaou EG, Andersen CY. GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients. Hum Reprod. 2013 Sep;28(9):2511-21. doi: 10.1093/humrep/det249. Epub 2013 Jun 9.
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- Lainas TG, Sfontouris IA, Papanikolaou EG, Zorzovilis JZ, Petsas GK, Lainas GT, Kolibianakis EM. Flexible GnRH antagonist versus flare-up GnRH agonist protocol in poor responders treated by IVF: a randomized controlled trial. Hum Reprod. 2008 Jun;23(6):1355-8. doi: 10.1093/humrep/den107. Epub 2008 Apr 10.
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