Dr Ahmed Ismail

Consultant Gynaecologist & Fertility Expert

Ovarian Hyperstimulation

  • We received today from British Fertility Society of The methods of controlling Ovarian Hyper stimulations in Ovarian stimulation during IVF or induced ovulation fertility treatment, Ou Practice at Queensway Clinic has shown a 0% hyper stimulation for all the patients treated by us in UK and Egypt.
    Controlled ovarian hyperstimulation regimens: a review of the available evidence for clinical practice. On behalf of the British Fertility Society P&P Committee.

    L.G. Nardo1, E. Bosch2, C.B. Lambalk3, T.A. Gelbaya4

1Conceive International, Reproductive Health Group, Manchester, UK; 2IVI Madrid, Madrid, Spain; 3Division of Reproductive Medicine, VU University Medical Centre, Amsterdam, The Netherlands; 4Leicester Fertility Centre, University Hospitals of Leicester, Leicester, UK
Correspondence: Luciano Nardo, lnardo@reproductivehealthgroup.co.uk

Since the birth of the first in vitro fertilisation (IVF) baby more than 30 years ago, various protocols of controlled ovarian hyperstimulation (COH) have been developed in an attempt to improve oocyte quality and live birth rate, enhance ovarian response in poor responders and minimise the risk of ovarian hyperstimulation syndrome (OHSS).  Different regimens used different gonadotrophin preparations with or without pituitary down regulation using gonadotrophin releasing hormone (GnRH) agonist or antagonist. Understandably, there is no one protocol that fits all and treatment should be individualised (Nardo et al., 2011) to take into account women’s age, ovarian reserve, endocrine status and any other associated conditions such as endometriosis, polycystic ovary syndrome (PCOS) and ovarian cysts. In addition, the choice of COH protocol should be discussed with couples for cost implications and women’s preference. Some women may opt for the short protocol, as it is more convenient while others may wish to try the ultra long protocol to control pain from endometriosis. The aim of this article is to discuss three main aspects of COH: the choice of gonadotrophins, luteinising hormone (LH) supplementation and the use of gonadotrophin releasing hormone (GnRH) agonist versus GnRH antagonist.  

Choice of gonadotrophins
The first generation gonadotrophins used in the 1970s, was human menopausal gonadotrophin [hMG, a combination of follicle stimulating hormone (FSH) and LH in a 1:1 ratio] produced from the urine of menopausal women. Since the early 1980s, progress in protein purification technology facilitated the production of a variety of urinary gonadotrophins with lower concentrations of contaminating proteins, such as purified FSH (FSH-P) which contains less than one international unit (IU) of LH per 75 IU of FSH and highly purified FSH (FSH-HP) with less than 0.1 IU of LH per 75 IU of FSH. An early systematic review (Daya et al., 1995) reported a higher clinical pregnancy rate per cycle stimulated with FSH-P or FSH-HP when compared with HMG in women undergoing in IVF, but a later review (Agrawal et al., 2000) reported no difference between these urinary gonadotrophin products. However, adequate supply of urinary gonadotrophins could not be guaranteed due to increased demands for postmenopausal urine worldwide. Meanwhile, a rising concern emerged regarding the limited batch-to-batch consistency and possibilities of urine contaminants (Balen et al., 1999). Advancement in recombinant DNA technology allowed for, the large scale production of human recombinant FSH (r-FSH), which is free from LH activity (Keene et al., 1989). The recombinant products offer improved purity, consistency, and large-scale availability.
The comparison of hMG and r-FSH effectiveness in ovarian stimulation for assisted reproductive technology (ART) cycles has been the subject of a number of studies. They have been compared in non down-regulated cycles (Jansen et al., 1998), in down-regulated cycles with a GnRH agonist short protocol (Strehler et al., 2001), but mainly in long GnRH agonist cycles (Ng et al., 2001; Westergaard et al., 2001; European and Israeli Study Group on Highly Purified Menotrophin versus Recombinant Follicle-Stimulating Hormone 2002; Balasch et al., 2003; Goldfarb and Desai, 2003; Kilani et al., 2003; Rashidi et al., 2005; Nyboe Andersen et al., 2006; Hompes et al., 2008). Very few data have been reported when both compounds were compared in GnRH antagonist cycles (Bosch et al., 2008).
Several systematic reviews and one international Health Technology Assessment report compared r-FSH with different urinary gonadotrophins including FSH-P and FSH-HP. Three reviews (Larizgoitia 2000; Al-Inany et al., 2011; National Collaborating Centre for Women’s and Children’s Health 2004) compared r-FSH versus all urinary gonadotrophins (hMG, FSH-P, FSH-HP) and found no evidence of a statistically significant difference between these two groups. Three reviews compared r-FSH with hMG and observed a significantly better live birth rate when hMG was used for ovarian stimulation compared with rFSH, with a relative increase of 5% (van Wely et al., 2003), 18% (Coomarasamy et al., 2008) and 20% (Al-Inany et al., 2008). A recent Cochrane review (van Wely et al., 2012) compared the effectiveness of rFSH with the three main types of urinary gonadotrophins (hMG, FSH-P and FSH-HP) for ovarian stimulation in women undergoing IVF or intracytoplasmic sperm injection (ICSI) treatment cycles. Overall, there was no evidence of a difference in pregnancy outcomes or the incidence of OHSS when r-FSH was compared to all urinary gonadotrophins. There was also no evidence of a difference in cumulative live birth and clinical pregnancy rates following frozen-thawed embryo transfer cycles for r-FSH versus urinary gonadotrophins. Comparing r-FSH with hMG or highly purified hMG (12 of the 42 trials) resulted in a lower live birth rate in the r-FSH group, though differences were small. The authors’ conclusion was that all available gonadotrophins appear equally effective and safe. The choice of gonadotrophin for COH will depend upon the availability of the product, the convenience of its use and the associated costs. Collectively there is no sufficient evidence to recommend the use of one type of gonadotrophins over the other for women undergoing IVF or ICSI.

LH supplementation
According to the two-cell/two-gonadotrophin hypothesis, both LH and FSH are essential for ovarian steroidogenesis in gonadotrophin-deficient anovulatory women (European Recombinant Human LH Study Group, 1998). LH supplementation during the follicular phase is needed for ensuring an appropriate follicular oestradiol (E2) production, complete oocyte maturation and endometrial development. Nevertheless, the requirements of LH for ovarian stimulation in normogonadotrophic women have been widely debated.  Supplementation of LH in FSH stimulated cycles may offer advantages in some patients by enhancing large follicle development and therefore shortening the duration of treatment (Filicori et al., 1999). It is believed that changing gonadotrophins from FSH to LH during ovarian stimulation may be useful to stimulate a more homogeneous cohort of developing follicles (Sullivan et al., 1999; Filicori et al., 2002). However, there are opposing views of no added value of LH supplementation (Balasch et al., 2001). Some authors proposed that there is a LH window during which optimal follicular development occur. Accordingly, there is a threshold LH level, below which E2 production is not adequate, and a ceiling level, above which LH may be detrimental to follicular development (Shoham., 2002).
In the last decade, a number of studies have been performed in order to elucidate if the administration of LH together with FSH provides any benefit in terms of cycle outcome. A Cochrane review (Mochtar et al., 2007) included 14 RCTs that evaluated the effectiveness of a combination of r-LH and r-FSH versus r-FSH alone in COH for IVF or ICSI. Of the 14 included trials, 10 trials involved women using long GnRH agonist protocol (Balasch et al., 2001; Marrs et al., 2003; Ferraretti et al., 2004; Humaidan et al., 2004; De Placido et al., 2005; Lisi et al., 2005; Fábreques et al., 2006; Abdelmassih et al., 2006; Tarlatzis et al., 2006; Nyboe Andersen et al., 2006), one trial used a short GnRH agonist protocol (Barrenetxea et al., 2008) and 3 trials used GnRH antagonist protocol (Sauer et al., 2004; Griesinger et al., 2005; Levi-Setti et al., 2006). Regarding GnRH antagonist protocol, there was no significant differences in pregnancy outcomes, OHSS incidence, r-FSH dose used or number of oocyte retrieved when r-LH was co-administered to r-FSH.  However, the data were far too small to affirm any conclusion. Considering the GnRH agonist studies, the two studies that reported on live birth rate found remarkable opposite results. One study found a beneficial effect in favour of r-LH co-treatment (Ferraretti et al., 2004) and the other was in favour of treatment with r-FSH alone (Tarlatzis et al., 2006). Consequently, the pooled data showed no evidence of a significant difference in live birth rate and significant statistical heterogeneity was found. There was no evidence of a statistical difference in clinical pregnancy rates reported in seven trials (OR 1.15, 95% CI 0.91 to 1.45) or in ongoing pregnancy rates reported in seven trials (OR 1.22, 95% CI 0.95 to 1.56). However, the pooled pregnancy estimates of trials including only poor responders (Ferraretti et al., 2004; De Placido et al., 2005; Barrenetxea et al., 2008) showed significant increase in pregnancy rate, in favour of co-administrating r-LH (OR 1.85, 95% CI 1.10 to 3.11). The authors concluded that poor responders and/or older women may benefit from co-treatment with r-LH.
Of note, none of the large RCTs (Nyboe Anderson et al., 2008, Marrs et al., 2003, Humaidan et al., 2004 and Lisi et al., 2005) included in this Cochrane review reported on live birth rate. Humaidan and colleagues (2004) and Marrs and colleagues (2003) found no difference in clinical pregnancy rate, whereas Lisi and colleagues (2005) found a significant increase in implantation rate (9% for r-FSH vs. 11% and 16% with 37.5 IU and 75.0 IU r-LH groups, respectively), clinical pregnancy rate (19% for r-FSH vs. 23% and 31% with 37.5 IU and 75.0 IU r-LH groups, respectively) and the number of top grade embryos available for transfer in women who received r-LH and r-FSH for COH. In the study by Marrs and colleagues (2003), the implantation rate was markedly higher in women over 35 years of age, who received r-LH compared with those who received r-FSH alone.
It is widely accepted that there is no benefit of LH supplementation in the unselected population. The current evidence review suggests that there is a potential benefit of r-LH administration in patients with poor response to ovarian stimulation and in those older than 35 years.

GnRH agonist versus GnRH antagonist
The use of GnRH analogues optimises COH and lowers cycle cancellation rates as a result of prevention of premature LH surge, improved follicular recruitment and increased number of oocytes retrieved (Hughes et al., 1992, Templeton and Morris, 1998). After an initial short period of gonadotrophin hyper-secretion, continuous administration of GnRH agonist causes desensitisation, resulting in a reversible state of chemical hypophysectomy. GnRH antagonists cause an immediate and rapid, reversible suppression of gonadotrophin secretion, by competitive occupancy of the GnRH receptor (Huirne et al., 2004).  The immediate and dose-dependent suppressive action of antagonists potentially provides a convenient alternative to agonists in ART cycles.
Different treatment regimens utilising GnRH agonists in COH have been developed. In the long protocol, GnRH agonist commences in the follicular or luteal phase of the preceding cycle and continues until pituitary and ovarian suppression is achieved before stimulation with gonadotrophins is started. The short or flare-up protocol combines GnRH agonist therapy starting on cycle day 2, with gonadotrophins initiated a day later. The ultra short protocol consists of daily subcutaneous administration of GnRH agonist during the first 3 days of ovarian stimulation.
A recent Cochrane review (Maheshwari et al., 2011) comparing ultra-short, short and long IVF protocols showed a higher number of oocytes retrieved and higher clinical pregnancy rates with the long protocol, at cost of more ampoules of gonadotrophins. There was no evidence of a difference in the outcomes amongst various long protocols such as luteal versus follicular start. Similarly, no difference in cycle outcome was found in cycles stimulated with long protocols when GnRH agonist is stopped or reduced at the start of gonadotrophin stimulation.
GnRH antagonists have been introduced in clinical practice for COH in IVF/ICSI cycles to prevent premature luteinisation. Because of the acute gonadotrophin suppressive activity of these agents, GnRH antagonists may be administered at any time during the follicular phase of a treatment cycle to prevent a premature LH surge. The principal approach is the multiple dose antagonist protocol with cetrorelix or ganirelix 0.25mg given daily subcutaneously from day 6 of gonadotrophin stimulation onward, including the day of human chorionic gonadotrophin (hCG) administration. With this regimen and dosage these studies reported one premature LH surge in 155 patients (Huirne and Lambalk, 2001). In the flexible protocol, GnRH antagonist is commenced when the leading follicle is ≥ 14 mm in diameter. The flexible protocol has not been shown to be superior in terms of IVF cycle outcome (Kolibianakis et al., 2011).
A Cochrane analysis evaluating the use of long GnRH agonist versus antagonist protocol in COH for IVF/ICSI showed no differences in live birth rates (OR 0.86 95 % CI 0.69-1.08) or ongoing pregnancy rates (OR 0.87 95 % CI 0.77- 1.00) (Al-Inany et al., 2011). Interestingly, another systematic review which included ovulatory patients and studies with either long agonist or antagonist protocol as the only variable demonstrated a significantly lower ongoing pregnancy rate with the use of antagonist protocol (OR 0.82 95% CI 0.70-0.95) (Banga et al., 2011) suggesting that in these patients circa 1 out 5 will not have an ongoing pregnancy. However, a number of factual considerations have to be borne in mind. With an antagonist fewer follicles are seen at the time of hCG injection compared with an agonist. The number of recovered oocytes is significantly lower (Al-Inany et al., 2005; Banga et al., 2011). A likely explanation is that long agonist protocols extend the duration of the 'FSH window' by suppressing the inter-cycle FSH rise. It has been suggested that the larger numbers of oocytes and embryos with agonists allow better selection (Huirne et al., 2007). With an antagonist, the duration of gonadotrophin treatment is shortened by 1-2 days and in comparison to a long GnRH agonist protocol it requires less daily dosage. A recent discrete choice experiment in which patient’s preference for GnRH agonist or antagonist was evaluated showed at a trade-off point of 2% increase of a chance to pregnancy a major switch (82%) to agonist despite the information provided on possible negative characteristics of an agonist treatment. Patients considered pregnancy as the most important attribute (Van Den Wijngaard et al., 2011). Nevertheless, the recent Cochrane meta-analysis by Al Inany and colleagues (2011) showed significantly lower incidence of OHSS after GnRH antagonists than after GnRH agonists (OR 0.43, 95% CI 0.33-0.57). The reduction in OHSS was observed in the high-risk group of patients with PCOS (OR 0.25, 95% CI 0.14-0.45).  

GnRH agonist versus antagonist in poor responders
A recent systematic review addressing interventions for poor responders (Pandian et al., 2010) included an analysis of a variety of GnRH analogue schedules, such as long GnRH agonist versus GnRH agonist-stop upon desensitisation; long agonist versus antagonist; GnRH flare-up versus GnRH antagonist; low dose GnRH flare-up versus natural cycle; multiple dose antagonist versus mini-dose long agonist; flare-up agonist versus modified long agonist and long agonist versus modified long agonist. Compared to the conventional long GnRH agonist protocol the GnRH agonist-stop upon desensitisation (Garcia-Velasco et al., 2000) and the GnRH antagonist (Marci et al., 2005) yielded more oocytes. Pooled data of 3 studies comparing the flare-up protocol versus the antagonist regimen showed no overall difference in oocyte yield, pregnancy rates and cancellation rates (Pandian et al., 2010).  This review clearly demonstrates the painful absence of well designed and powered studies in poor responders. The conclusion of the review was that there is insufficient evidence to support the routine use of any particular intervention for pituitary down regulation in the management of poor responders in IVF cycles (Pandian et al., 2010).

GnRH agonist versus antagonist in women with endometriosis
There are indications that fertilisation rates, implantation rates and pregnancy rates with IVF are lower in patients with endometriosis compared to IVF patients with tubal factor possibly as result of poorer oocyte quality (Barnhart et al., 2002). The question is whether reduction of active endometriosis prior to IVF will lead to improved outcomes. Treatment options for patients with endometriosis include surgical removal and/or ovarian suppression. A meta-analysis of three small randomized studies (Sallam et al., 2006) in which prolonged three to six months pre-treatment with a GnRH agonist was compared to controls showed a strong improvement of clinical pregnancy rates (OR 4.28 95% CI (2.00-9.15). Prolonged GnRH pre-treatment prior to IVF in endometriosis patients seems to be of benefit. Further trials are required to reach more robust conclusions.

Sex steroid pre-treatment followed by GnRH agonist or antagonist
Biljan and colleagues (1998) convincingly showed that pre-treatment with an oral contraceptive pill (OCP) could effectively prevent ovarian cyst formation that often occurs when GnRH agonist is started mid-luteally in the long protocol. It also appeared that OCP pre-treatment shortens the time to achieve pituitary desensitisation and reduced the gonadotropin use without compromising oocyte yield and pregnancy outcome (Biljan et al., 1998). According to a meta-analysis pre-treatment with progesterone alone followed by GnRH agonist desensitization resulted in a higher clinical pregnancy rate (OR 1.95 95% CI 1.2-3.17). However, the live birth and ongoing pregnancy rates were not statistically different (Smulders et al., 2010).
The initiation of FSH administration in a GnRH antagonist regimen is cycle dependent. It is mostly started on day 2 or 3 of the menstrual cycle, which makes the treatment planning and scheduling difficult (Huirne and Lambalk, 2001) and increases the clinical site workload. An advantage of steroid hormonal pre-treatment is that a withdrawal bleeding can be induced to adjust the treatment cycle to both the patient and centre time plan (Huirne et al., 2006). However, recently pooled data from six randomized controlled trials comparing pre-treatment with OCP in GnRH antagonist cycles with no pre-treatment, showed fewer ongoing pregnancies (relative risk: 0.80, 95% CI: 0.66-0.97), longer duration of ovarian stimulation and higher total amount of gonadotrophins (MD 207.08, 95% CI 167.77 to 246.39; P < 0.00001) after OCP pre-treatment (Griesinger et al., 2010). The number of oocytes retrieved was higher in the OCP pre-treated group (MD 2.01, 95% CI 1.76- 2.25; P < 0.00001) (Smulders et al., 2010). These data point to a possible adverse effect of OCP pre-treatment in combination with a GnRH antagonist. The reason for the observed reduction in pregnancy rate with OCP pre-treatment is still unclear. Additional research is needed to determine a reliable and efficacious way of scheduling GnRH antagonist ovarian stimulation cycles by pre-treatment with sex steroids. Of note, a recent study comparing OCP pre-treatment antagonist protocol with long agonist protocol failed to show any difference in pregnancy rates (Garcia-Velasco et al., 2011).

Before planning a new IVF or ICSI treatment cycle a thorough assessment of the women’s hormone profile and ovarian reserve is essential before decisions are made on the appropriate protocol used for COH. There is no sufficient evidence to recommend the use of one type of gonadotrophins over the other. There is no benefit of LH supplementation in cycles stimulated with FSH only in the unselected population. There is some evidence to suggest a potential benefit for LH supplementation in patients with poor response to ovarian stimulation and in those older than 35 years. The long GnRH agonist protocol is the most widely used and the preferred protocol for normal responder women undergoing COH for IVF or ICSI. The GnRH antagonist protocol is best used for known or suspected high responders including women with PCOS, as it reduces the risk of OHSS. There is lack of robust evidence to suggest that the GnRH agonist protocol is better than the antagonist protocol in poor responders.

Abdelmassih V, Salgueiro R, Abdelmassih C, Carizza C. 2006.  Less miscarriage rate using LH (rLH) in nGnRH agonists long protocols. Hum Reprod 21 (Suppl 1): i7.
Agrawal R, Holmes J, Jacobs HS. 2000. Follicle-stimulating hormone or human menopausal gonadotropin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis. Fertil Steril 73:338–343.
Al-Inany H, Aboulghar M A, Mansour R T, Serour G I. 2005. Optimizing GnRH antagonist administration: meta-analysis of fixed versus flexible protocol. Reprod Biomed Online 10: 567-570.
Al-Inany HG, Abou-Setta AM, Aboulghar MA, Mansour RT, Serour GI. 2008. Efficacy and safety of human menopausal gonadotrophins versus recombinant FSH: a meta analysis. Reprod Biomed Online 16:81–88.
Al-Inany H G, Youssef  M A, Aboulghar  M, Broekmans  F, Sterrenburg  M, Smit  J, Abou-Setta A M. 2011. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 19 (1): CD008046.
Balasch J, Vidal E, Penarrubia J, Casamitjana R, Carmona F, Creus M, Fabregues F and Vanrell JA. 2001. Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH. Hum Reprod 16: 1636–1643.
Balasch J, Penarrubia J, Fabregues F, Vidal E, Casamitjana R, Manau D, Carmona F, Creus M, Vanrell JA. 2003. Ovarian responses to recombinant FSH or HMG in normogonadotrophic women following pituitary desensitization by a depot GnRH agonist for assisted reproduction. Reprod Biomed Online 7: 35–42.
Balen AH, Hayden CJ, Rutherford AJ. 1999. What are the clinical benefits of recombinant gonadotrophins? Clinical efficacy of recombinant gonadotrophins. Hum Reprod 14:1411–1417.
Banga F R, Lambalk C B, Huirne J A, van Wely M, van der Veen F. 2011.  Comparison of oral contraceptive pill pre-treated GnRH antagonist versus long agonist protocols in IVF, a systematic review and meta-analysis. Hum Reprod 26 (Suppl 1): i1 - i353.
Barnhart K, Dunsmoor-Su R, Coutifaris  C.  2002. Effect of endometriosis on in vitro fertilization. Fertil  Steril  77: 1148-1155.
Barrenetxea G, Agirregoikoa JA, Jimeenez MR, de Larruzea AL, Ganzabal T, Carbonero K. 2008. Ovarian response and pregnancy outcome in poorresponder women: A randomized controlled trial on the effect of luteinizing hormone supplementation on in vitro fertilization cycles. Fertil Steril 89:546-53.
Biljan M M, Mahutte N G, Dean N, Hemmings R, Bissonnette F, Tan S L. 1998. Effects of pre-treatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates. Fertil Steril 70: 1063-1069.
Bosch E, Vidal C, Labarta E, Remohi J, Pellicer A. 2008. Highly purified HMG versus recombinant FSH in ovarian hyperstimulation with GnRH antagonist - a randomised study. Hum reprod 23: 2346–51.
Bosch E, Labarta E, Crespo J, Simón C, Remohí J, Pellicer A. 2011. Impact of luteinizing hormone administration on gonadotropin-releasing hormone antagonist cycles: An age-adjusted analysis. Fertil Steril 95:1031-6.
Coomarasamy A, Masoud A, Cheema D, van der Veen, Bossuyt PMM, van Wely M. 2008. Urinary hMG versus recombinant FSH for controlled ovarian hyperstimulation following an agonist long down-regulation protocol in IVF or ICSI treatment: a systematic review and meta-analysis. Hum Reprod 23:310–5.
Daya S, Gunby J, Hughes EG, Collins JA, Sagle MA. 1995. Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis. Fertil Steril 64:347-54.
De Placido G, Alviggi C, Perino A, Strina I, Lisi F, Fasolino A, De Palo R, Ranieri A, Colacurci N, Mollo A. 2005. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum Reprod 20: 390–396.
European and Israeli Study Group on Highly Purified Menotrophin versus Recombinant Follicle-Stimulating Hormone. 2002. Efficacy and safety of highly purified menotrophins versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized comparative trial. Fertil Steril 78: 520–8.
European Recombinant Human, L.H. Study Group. 1998. Recombinant human luteinizing hormone (LH) to support recombinant human follicle stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dose-finding study. J Clin Endocrinol Metab 83: 1507–1514.
Fábreques F, Creus M, Penarrubia J, Manau D, Vanrell JA, Balasch J. 2006. Effect of recombinant human luteinizing hormone supplementation on ovarian stimulation and the implantation rate in down-regulated women of advanced reproductive age. Fertil Steril 85: 925–931.
Ferraretti AP, Gianaroli L, Magli MC, D’Angelo A, Farfalli V, Montanaro N. 2004. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril 82:1521–1526.
Filicori M, Cognigni GE, Taraborrelli S, Spettoli D, Ciampaglia W, de Fatis CT. 1999. Low-dose human chorionic gonadotrophin therapy can improve sensitivity to exogenous follicle-stimulating hormone in patients with secondary amenorrhea. Fertil Steril 72: 1118–1120.
Filicori M, Cognigni GE, Samara A, Melappioni S, Perri T, Cantelli B, Parmegiani L, Pelusi G, DeAloysio D. 2002. The use of LH activity to drive folliculogenesis: exploring uncharted territories in ovulation induction. Hum Reprod Update 8:543–557.
Garcia-Velasco, J.A., Isaza, V., Requena, A., Martínez-Salazar, F.J., Landazábal, A.,Remohí, J., Pellicer, A., Simón, C.  2000. High doses of gonadotrophins combined with stopversus non-stop protocol of GnRH analogue administration in low responder IVFpatients: a prospective, randomized, controlled trial. Hum Reprod 15: 2292-2296.
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 protocolvs the long protocol: a randomized, controlled trial. Fertil Steril 96: 590-593.
Goldfarb JM, Desai N. 2003. Follitropin-alpha versus human menopausal gonadotrophin in an in vitro fertilization program. Fertil Steril 80:1094–1099.
Griesinger G, Schultze-Mosgau A, Dafopoulos K, Schroeder A, Schroer A, von Otte S, Hornung D, Diedrich K, Felberbaum R. 2005. Recombinant luteinizing hormone supplementation to recombinant follicle-stimulating hormone induced ovarian hyperstimulation in the GnRH-antagonist multiple-dose protocol. Hum Reprod 20: 1200–1206.
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.
Hompes PGA, Broekmans FJ, Hoozemans DA, Schats R. 2008. Effectiveness of highly purified menopausal gonadotrophin vs. recombinant follicle-stimulating hormone in first-cycle in vitro fertilization-intracytoplasmatic sperm injection patients. Fertil Steril. 89:1685–93.
Hughes, E.G., Fedorkow, D.M., Daya, S. Sagle, M.A., Van de Koppel, P., Collins, J.A. 1992. The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials. Fertil Steril 58:  888–896.
Huirne, J.A., Lambalk, C.B.. 2001. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 358: 1793-1803.
Huirne, J.A., Lambalk, C.B., van Loenen, A.C., Schats, R., Hompes, P.G., Fauser, B.C., Macklon, N.S 2004. Contemporary pharmacological manipulation in assisted reproduction. Drugs 64: 297-322.
Huirne J A, Hugues J N, Pirard C, Fischl F, Sage J C, Pouly J L, Obruca A, Braat  DM, van Loenen A C, Lambalk C B. 2006. Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated withr-hFSH: a randomized, multicentre, phase IIIb study. Hum Reprod 21: 1408-1415.
Huirne J A, Homburg R, Lambalk CB. 2007. Are GnRH antagonists comparable to agonists for use in IVF? Hum Reprod 22: 2805-2813.
Humaidan P, Bungum M, Bungum L and Yding Andersen C. 2004. Effects of recombinant LH supplementation in women undergoing assisted reproduction with GnRH agonist down-regulation and stimulation with recombinant FSH: an opening study. Reprod Biomed Online 8: 635–643.
Jansen CA, van Os HC, Out HJ, Coelingh Bennink HJ.  1998. A prospective randomized clinical trial comparing recombinant follicle stimulating hormone (Puregon) and human menopausal gonadotrophins (Humegon) in non-down-regulated in-vitro fertilization patients. Hum Reprod 13: 2995–2999.
Keene JL, Matzuk MM, Boime I. 1989. Expression of recombinant human choriogonadotropin in Chinese hamster ovary glycosylation mutants. Mol Endocrinol 3: 2011–2017.
Kilani Z, Dakkak A, Ghunaim S, Cognigni GE, Tabarelli C, Parmegiani L, Filicori M. 2003.  A prospective, randomized, controlled trial comparing highly purified hMG with recombinant FSH in women undergoing ICSI: ovarian response and clinical outcomes. Hum Reprod 18:1194–1199.
Kolibianakis, E.M., Venetis, C.A., Kalogeropoulou, L., Papanikolaou, E., Tarlatzis, B.C. 2011. Fixed versus flexible gonadotropin-releasing hormone antagonist administration in in vitro fertilization: a randomized controlled trial. Fertil Steril  95: 558-562.
Larizgoitia I, Estrada M D, Garcia-Altes A. 2000. Recombinant FSH as adjuvant in assisted reproduction: some data on the efficacy and efficiency of recombinant FSH urinary FSH. Catalan Agency for Health Technology Assessment and Research (CAHTA): 1–16.
Levi-Setti PE, Cavagna M, Bulletti C. 2006. Recombinant gonadotrophins associated with GnRH antagonist (cetrorelix) in ovarian stimulation for ICSI: comparison of rFSH alone and in combination with rLH. Eur J Obstet Gynecol Reprod Biol 126: 212–16.
Lisi F, Rinaldi L, Fishel S, Caserta D, Lisi R and Campbell A. 2005. Evaluation of two doses of recombinant luteinising hormone supplementation in an unselected group of women undergoing follicular stimulation for in vitro fertilization. Fertil Steril 83: 309–315.
Maheshwari A, Gibreel A, Siristatidis CS, Bhattacharya S. 2011. Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction. Cochrane Database Syst Rev 10 (8): CD006919.
Marci R, Caserta D, Dolo V, Tatone C, Pavan A, Moscarini M. 2005. GnRH antagonist in IVF poor-responder patients: results of a randomized trial. Reprod  Biomed Online 11: 189-193.
Marrs R, Meldrum D, Muasher S, Schoolcraft W, Werlin L, Kelly E. 2003. Randomized trial to compare the effect of recombinant human FSH (follitropin alfa) with or without recombinant human LH in women undergoing assisted reproduction treatment. Reprod Biomed Online 8: 175–182.
Mochtar MH, Van der Veen F, Ziech M, van Wely M, Musters A. 2007. Recombinant luteinizing hormone (rLH) for controlled ovarian hyperstimulation in assisted reproductive cycles. Cochrane Database Syst Rev 18 (2): CD005070.
Nardo LG, Fleming R, Howles CM, Bosch E, Hamamah S, Ubaldi FM, Hugues JN, Balen AH, Nelson SM. 2011. Conventional ovarian stimulation no longer exists: welcome to the age of individualized ovarian stimulation. Reprod Biomed Online 23: 141-148.
National Collaborating Centre for Women’s and Children’s Health. 2004. Fertility: assessment and management for people with fertility problems. Clinical guideline. London, UK: RCOG Press.
Ng EH, Lau EY, Yeung WS, Ho PC. 2001. HMG is as good as recombinant human FSH in terms of oocyte and embryo quality: a prospective randomized trial. Hum Reprod 16: 319–325.
Nyboe Andersen  N, Devroey P, Arce JC. 2006. Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing IVF: a randomized assessor-blind controlled trial. Hum Reprod 21: 3217–27.
Pandian Z, McTavish  A R, Aucott L, Hamilton M P R, Bhattacharya S. 2010. Interventions for ’poor responders’ to controlled ovarian hyper stimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev 20 (1): CD004379.
Rashidi BH, Sarvi F, Tehrani ES, Zayeri F, Movahedin M, Khanafshar N. 2005. The effect of HMG and recombinant human FSH on oocyte quality: a randomized single-blind clinical trial. Eur J Obstet Gynecol Reprod Biol 120:190–194.
Sallam H N, Garcia-Velasco  J A, Dias S, Arici A, Abou-Setta A M. 2006.  Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 25 (1): CD004635.
Sauer MV, Thornton MH 2nd, Schoolcraft W, Frishman GN. 2004. Comparative efficacy and safety of cetrorelix with or without mid-cycle recombinant LH and leuprolide acetate for inhibition of premature LH surges in assisted reproduction. Reprod Biomed Online 9: 487–93.
Shoham Z. 2002. The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation. Fertil Steril 77:1170–1177.
Smulders B, van Oirschot SM, Farquhar C, Rombauts L, Kremer  J A M. 2010. Oral contraceptive pill, progestogen or estrogen pre-treatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques. Cochrane Database Syst Rev 20 (1): CD006109.
Strehler E, Abt M, El-Danasouri I, De Santo M, Sterzik K. 2001. Impact of recombinant follicle-stimulating hormone and humanmenopausal gonadotropins on in vitro fertilization outcome. Fertil Steril 75: 332–336.
Sullivan MW, Stewart-Akers A, Krasnow JS, Berga SL, Zeleznik AJ. 1999. Ovarian responses in women to recombinant follicle-stimulating hormone and luteinizing hormone (LH): a role for LH in the final stages of follicular maturation. J Clin Endocrinol Metab 84: 228–232.
Tarlatzis B, Tavmergen E, Szamatowicz M, Barash A, Amit A, Levitas E and Shoham Z. 2006. The use of recombinant human LH (lutropin alfa) in the late stimulation phase of assisted reproduction cycles: a double-blind, randomized, prospective study. Hum Reprod 21: 90–94.
Templeton, A., Morris, J.K. 1998. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. New Eng J  Med  339: 573-577.
Van Den Wijngaard, L., Van Wely, M., Van Voorst, S., Van Mello,, N.M., Koks, C.A., Van Der Veen, F., Mol, B.W., Mochtar, M.H.. (2011). Patient’s preference for GnRH-agonists or GnRH-antagonists in IVF or ICSI- a discrete choice experiment. Hum Reprod 26 (Suppl 1): i1 - i353. 
van Wely M, Westergaard LG, Bossuyt PM, van der Veen F. 2003. Effectiveness of human menopausal gonadotropin versus recombinant follicle-stimulating hormone for controlled ovarian hyperstimulation in assisted reproductive cycles: a meta-analysis. Fertil Steril 80:1086–1093.
van Wely M, Kwan I, Burt AL, Thomas J, Vail A, Van der Veen F, Al-Inany HG. 2012. Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. Hum Reprod Update 18: 111.
Westergaard LG, Erb K, Laursen SB, Rex S and Rasmussen PE. 2001. Human menopausal gonadotropin versus recombinant follicle-stimulating hormone in normogonadotrophic women down-regulated with a gonadotropinreleasing hormone agonist who were undergoing in vitro fertilization and intracytoplasmic sperm injection: a prospective randomized study. Fertil Steril 76: 543–549.

  • For more information or an appointment at Queensway Gynaecology Clinic call:

    Landline: 0207-935 55 40 / 0207-935 66 00

    English: 077 409 444 73 / 077 457 481 88 / 077 450 461 44
    Russian: 078 351 255 50 / 078 351 255 51 / 077 962 309 99 / 077 450 461 44
    Lithuanian: 077 962 309 99 / 078 351 255 50
    Arabic: 077 409 444 73 / 077 457 481 88

    Email: info (at) queensclinic.co.uk



Bupa axappphealthcare cigna Aetna