Mausumi Das1 and Hananel E. G. Holzer1
(1)
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Reproductive Centre, McGill University Hospital, 687 Pine Av., West Montreal, QC, H3A 1A1, Canada
Mausumi Das (Corresponding author)
Email: mausumi24@hotmail.com
Hananel E. G. Holzer
Email: hananel.holzer@muhc.mcgill.ca
Abstract
Advances in recombinant DNA technologies have led to the development of longer-acting preparations with prolonged follicle-stimulating bioactivity. Corifollitropin alfa is a synthetic recombinant follicle-stimulating hormone (r-FSH) molecule containing a hybrid beta subunit, which provides prolonged follicle-stimulating activity while maintaining its pharmacodynamic activity. In controlled ovarian stimulation, long-acting gonadotropins have the ability to initiate and sustain multifollicular growth for 7 days. Current evidence suggests that the use of a medium dose of long-acting FSH is a safe treatment option and equally effective compared to daily FSH. This simplified treatment approach may provide a more patient-friendly approach to controlled ovarian stimulation. Further research is needed to determine whether long-acting FSH is safe and efficacious in patients at risk of ovarian hyperstimulation or poor responders. Studies are also needed to assess patient satisfaction and overall patient experience with the long-acting FSH preparations. Novel drug delivery systems developments will ultimately lead to greater ease of administration, more simplified and convenient dosing regimens and superior safety and efficacy, ultimately leading to greater patient satisfaction and improved patient experience.
Keywords
Long-acting gonadotropinsCorifollitropin alfaFollicle-stimulating hormoneLong actingControlled ovarian hyperstimulationIn vitro fertilizationAssisted reproduction
Introduction
Since the advent of in vitro fertilization (IVF), gonadotropins have been used to stimulate multiple follicle development [1]. This overcomes the physiologic selection of a single dominant follicle by increasing the duration during which serum follicle-stimulating hormone (FSH) levels remain above the threshold required for follicular recruitment and maturation [2, 3]. The presence of several mature oocytes for IVF and intracytoplasmic sperm injection (ICSI) procedures improves the chances of obtaining good-quality embryos and thereby, a successful pregnancy [4].
Several advances have taken place in the use of gonadotropins, beginning from the initial attempts at their extraction from animals, human cadavers and human urine to the production of recombinant products from Chinese hamster ovary (CHO) cells. These developments, especially the introduction of recombinant gonadotropins, have led to improved ovarian stimulation protocols by improving their efficacy and ease of administration.
At present, treatment regimens for IVF usually involve daily injections of FSH, either urinary FSH or recombinant FSH (r-FSH) with or without luteinizing hormone (LH) injections. Premature ovulation due to an LH surge is usually prevented by gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists.
Due to the relatively short half-life and rapid metabolic clearance of current FSH preparations, daily injections are required to maintain steady levels of FSH above the threshold during ovarian stimulation for follicular development [5]. Daily injections may increase discomfort and stress. It has been shown that as many as 40 % of non-pregnant couples withdraw after just one cycle of IVF due to emotional distress [6]. This has led to the search for more patient-friendly treatment protocols, which have the advantage of fewer errors during administration and improved patient compliance. Fewer injections may decrease the emotional stress associated with IVF. Simpler and more convenient treatment options may therefore, improve the overall patient experience.
Several studies have explored whether intermittent administration of r-FSH injections, by increasing the loading dose, could produce outcomes similar to that of daily FSH injections [7]. Alternatively, the development of FSH preparations with a longer half-life and a slower absorption to peak serum levels may be more helpful in obtaining a longer injection-free period than increasing the loading dose of current FSH preparations [8]. Besides improved patient compliance, long-acting compounds may result in more stable serum levels compared with repeated dosing using short-acting preparations.
In this chapter, we have discussed the latest advances in recombinant DNA technologies that have led to the development of longer-acting preparations with FSH bioactivity, including the production of Corifollitropin alfa, a new hybrid molecule with prolonged follicle-stimulating activity.
Gonadotropin Structure and Function
Follicle-stimulating hormone belongs to the glycoprotein hormone family, which also includes LH, human chorionic gonadotropin (hCG) and thyroid-stimulating hormone (TSH). The glycoprotein hormones are cysteine-rich dimeric proteins made up of two non-identical, non-covalently linked α- and β-subunits. The α-subunit is common to all family members, whereas the β-subunit is unique to each hormone and confers its biological and immunological specificity. Each of the two subunits of FSH has oligosaccharides that contain sites for the addition of terminal sialic acid residues [9]. FSH heterogeneity is due to the content of these sialic acid residues. Individual FSH isoforms differ in their extent of post-translational modification. Post-translational modification of the primary protein structure results in differential glycosylation, which in turn produces molecules with different isoelectric properties and bioactivity [9]. An increased sialic acid content produces more acidic isoforms with longer half-lives in vivo. Heavily sialylated FSH therefore, circulates for longer periods of time compared with more basic forms. FSH heterogeneity influences the amount of time that FSH is able to circulate, thereby regulating its in vivo bioactivity. The less acidic isoform was found to have a faster clearance from the circulation in rats as compared with the acidic isoform. The carbohydrate moieties on the FSH molecule play a role in regulating correct protein assembly and secretion of the gonadotropins and signal transduction [10].
Apart from hCG, the human glycoprotein hormones have relatively short terminal half-lives in vivo [11]. Although there is substantial amino acid sequence homology between hCG and LH, hCG has a much longer plasma half-life compared with LH [12]. The main difference between them is the presence of an additional 31 amino acids that form the C-terminal peptide (CTP) of the hCG β-subunit. Deletion of the CTP resulted in decreased in vivo activity of the hCG molecule compared with the wild type in a rat ovulation assay [13].
Development of Long-Acting FSH Compounds
Several techniques of developing longer-acting FSH molecules with increased half-life have been described. It has been suggested that altering the structure of the FSH molecule by additional glycosylation would increase the plasma half-life of FSH by reducing the glomerular filtration. However, there is a maximum plasma half-life beyond which further increases cannot be achieved by additional glycosylation [14].
Longer-acting FSH molecules have also been developed by introducing additional sequences containing glycosylation sites at the N-terminus of the FSH α-subunit [15] or by creating a contiguous, single-chain, covalently bound fusion protein containing the common α- and FSH β-subunits separated by the hCG β-CTP [16].
Using gene transfer techniques, Boime and co-workers [17] constructed a chimeric gene containing the sequence encoding the CTP of the hCG β-subunit fused to the translated sequence of the human FSH β-subunit [17]. The FSH β-CTP chimera was then transfected with the common glycoprotein α-subunit and expressed in Chinese hamster ovary (CHO) cells. This chimeric recombinant molecule was found to have similar in vitro receptor binding and steroidogenic activity compared with wild-type FSH but significantly increased in vivo activity and plasma half-life [17]. A single injection of this chimeric molecule could stimulate follicular maturation in rats enough to induce ovulation induction 52 h later. In contrast, a single injection of the same dose of wild-type FSH was not able to achieve the same effect. The production of a new CHO cell line, expressing the FSH hybrid molecule, has led to the development of Corifollitropin alfa, which has increased in vivo FSH bioactivity.
Other approaches to sustained-release drug delivery systems for long-acting recombinant human FSH that are currently being developed include encapsulation of the drug into small polymeric microspheres, which degrade slowly, releasing the drug at a controlled rate [18].
Corifollitropin Alfa: A Long-acting Recombinant FSH Compound
Recombinant DNA technologies have led to the development of a new recombinant molecule, which consists of the α-subunit of human FSH and a hybrid subunit consisting of the carboxyl-terminal peptide of the β-subunit of hCG, coupled with the FSH β-subunit. This design was a result of the observation that CTP is the main distinguishing feature between LH and hCG and is most likely, responsible for the extended plasma half-life of hCG as compared to LH [18]. This recombinant molecule is a long-acting FSH compound, named Corifollitropin alfa or FSH-CTP [8]. Similar to the wild-type FSH, Corifollitropin alfa interacts only with the FSH receptor and lacks LH activity [19]. However, Corifollitropin alfa has a longer plasma half-life and an extended time interval to reach peak serum levels [20]. In controlled ovarian stimulation, a single subcutaneous dose of Corifollitropin alfa has been shown to have the ability to initiate and sustain multifollicular growth for 7 days. Subsequently, controlled ovarian stimulation for follicular development may be continued with daily FSH injections until the criteria for final oocyte maturation have been reached. In order to improve treatment simplicity, Corifollitropin alfa has been developed in combination with GnRH antagonist co-treatment.
Pharmacokinetics
Exposure after injection of Corifollitropin alfa can be measured most reliably with the help of a specific enzyme immunoassay, which does not cross-react with native or recombinant FSH [21]. Studies have demonstrated that the mean plasma half-life of Corifollitropin alfa is ∼65 h for all doses tested between 60 and 240 μg, compared with ∼35 h for r-FSH [21]. A single-dose of Corifollitropin alfa is slowly absorbed resulting in peak levels within 2 days after injection. Subsequently, serum Corifollitropin alfa levels decrease steadily, though the FSH activity may remain above the FSH threshold for an entire week in order to initiate and sustain multifollicular growth. The dose of the long-acting FSH compound should be as low as possible to avoid ovarian hyperstimulation syndrome (OHSS) but high enough to support controlled ovarian stimulation and follicular development over the 7-day period.
The efficacy of the long-acting FSH formulation, Corifollitropin alfa, has been tested in multicentre trials. In phase I clinical trials, the recombinant FSH molecule was administered to male hypogonadotrophic hypogonadal volunteers who received four subcutaneous injections of 15 μg Corifollitropin alfa to examine its safety and possible immunogenicity [22]. The plasma t½ of Corifollitropin alfa in humans was found to be 94.7 ± 26.2 h, approximately two- to threefold longer than the t½ of r-FSH.
Subsequently, the pharmacokinetics and ovarian response to a single dose of 30–120 μg Corifollitropin alfa were investigated in pituitary-suppressed female volunteers [20]. Twenty-four participants were treated with a high-dose oral contraceptives to suppress pituitary function. Participants were given a single dose of 15, 30, 60, or 120 μg of Corifollitropin alfa. The median time to reach maximal serum concentrations (tmax) ranged from 36 h in the 15, 60 and 120 μg groups to 48 h after administration of 30 μg. The calculated elimination half-lives (t1/2) ranged from 60 h in the 30 μg group to 75 h in the 120 μg group. Other studies have also suggested that the serum concentration of Corifollitropin alfa is proportional to the dose within the 15–60 μg dose range [23]. Corifollitropin alfa administration also showed an inverse relationship with bodyweight, which was found to be a significant covariate of clearance and volume of distribution [24].
Several studies have examined the efficacy of Corifollitropin alfa, in doses ranging 60–240 μg in women undergoing IVF. All these studies used GnRH antagonist to prevent premature LH surges. These studies suggest that the pharmacokinetic parameters of Corifollitropin alfa in IVF patients are similar to those noted in previous studies, with Cmax being reached on day 2 after injection (tmax 25–46 h) and plasma t½ being approximately 65 h [20, 22].
The long-acting FSH preparations have an approximately two-fold longer elimination half-life and an almost four-fold extended time to peak serum levels as compared with the r-FSH compounds currently used [25]. Due to this pharmacokinetic profile of sustained FSH bioactivity, a single dose of long-acting FSH can maintain the circulating FSH level above the threshold necessary to support multifollicular growth over a 7-day period [25]. A single injection of long-acting FSH on the first day of the stimulation can replace the first seven daily injections of r-FSH, thereby improving patient compliance.
Safety and Efficacy of the Long-acting FSH Formulation: Corifollitropin alfa
Corifollitropin appears to have a favourable safety profile similar to daily r-FSH injections. Moreover, the Corifollitropin molecule does not seem to be immunogenic. The safety and efficacy of Corifollitropin alfa have been evaluated in several randomized controlled trials (RCTs). In all these RCTs, GnRH antagonist was used to prevent premature LH surges. All the studies included women who were younger than 40 years of age and had regular menstrual cycles. Women with polycystic ovary syndrome (PCOS) and those with a history of over or poor response to gonadotropin stimulation or recurrent implantation failure were excluded.
In the first feasibility study, the efficacy and safety of a single dose of Corifollitropin alfa were investigated in IVF patients undergoing controlled ovarian stimulation with a flexible GnRH antagonist protocol. Participants were randomized to receive a single dose of 120 μg (n = 25), 180 μg (n = 24) or 240 μg (n = 25) Corifollitropin alfa or to start daily fixed doses of 150 IU r-FSH (n = 24). Subjects who received a single dose of Corifollitropin alfa continued 1 week after injection with fixed daily doses of 150 IU r-FSH until the day of triggering final oocyte maturation. The terminal half-life of Corifollitropin alfa was found to be, on average, 65 h and dose-independent. Headache and nausea were the commonest reported adverse effects. In this study, the authors reported that 12 subjects (17.6 %) in the Corifollitropin alfa groups and two subjects (8.3 %) in the r-FSH group experienced a premature LH rise (defined as LH ≥10 IU/L) before the start of the GnRH antagonist though this did not reach statistical significance. The authors suggested that this relatively high incidence of women demonstrating an early LH rise in the Corifollitropin alfa groups may be related to the higher initial rises of serum estradiol and the use of a flexible GnRH antagonist protocol. The mean number of oocytes recovered per started cycle was higher in the Corifollitropin alfa group compared with r-FSH-treated patients, but no difference could be noted between the number of good quality embryos and equal numbers of embryos were available for embryo transfer.
The second RCT was a dose-finding study, evaluating three different doses of Corifollitropin alfa [24]. A total of 315 women were randomized and received a single injection of 60 μg (n = 78), 120 μg (n = 77), or 180 μg Corifollitropin alfa (n = 79) or daily injections of 150 IU r-FSH (n = 81) from cycle days 2–3. If patients allocated to the Corifollitropin alfa group needed further stimulation to meet the hCG trigger criteria, they received a fixed dose of 150 IU/day r-FSH from stimulation day 8 onwards. Patients received a GnRH antagonist (Ganirelix 0.25 mg/day) from stimulation day 5 until the day of hCG. The authors reported that the number of cumulus-oocyte complexes retrieved showed a clear dose-response relationship (P < 0.0001), being 5.2 (5.5), 10.3 (6.3) and 12.5 (8.0) in the three dose groups, respectively. The authors concluded that the optimal dose for a 1-week interval is higher than 60 μg and lower than 180 μg [24].
In a large, double-blind, randomized, non-inferiority trial, involving 1506 patients (ENGAGE 2009), the ongoing pregnancy rates were assessed after a single subcutaneous injection of 150 μg Corifollitropin alfa during the first week of stimulation and compared with daily injections of 200 IU r-FSH using a standard GnRH antagonist protocol. In both treatment groups, the median duration of stimulation was 9 days, implying that patients treated with Corifollitropin alfa needed, on average, 2 days of r-FSH to complete their treatment cycle prior to the hCG trigger. This study reported ongoing pregnancy rates of 38.9 % for the Corifollitropin alfa group and 38.1 % for r-FSH, with an estimated non-significant difference of 0.9 % [95 % confidence interval (CI): −3.9; 5.7] in favour of Corifollitropin alfa. The incidence of (moderate/severe) ovarian hyperstimulation syndrome was comparable (4.1 and 2.7 %, respectively; P = 0.15) [25]. It is noteworthy that the incidence of premature LH rise was 7 % versus 2.1 % (P < 0.01) in the Corifollitropin alfa and r-FSH arms of the ENGAGE trial. However, the pregnancy rates for women with premature LH rises were not significantly different between Corifollitropin alfa (45.3 %) and r-FSH (31.3 %) groups [25].
In another double-blind randomized trial (ENSURE 2010), 396 women weighing 60 kg or less, who underwent controlled ovarian stimulation prior to IVF or ICSI, were randomized in a 2:1 ratio to a single dose of 100 μg Corifollitropin alfa or daily 150 IU r-FSH for the first 7 days of stimulation in a GnRH antagonist protocol. The mean ± SD number of oocytes retrieved per started cycle was 13.3 ± 7.3 for Corifollitropin alfa versus 10.6 ± 5.9 for r-FSH. The incidence of moderate and severe ovarian hyperstimulation syndrome was 3.4 % for Corifollitropin alfa and 1.6 % for r-FSH [26].
In a recent meta-analysis of four randomized controlled multicentre trials, involving 2335 participants, Pouwer and colleagues [27] evaluated the effectiveness of long-acting FSH versus daily FSH on pregnancy and safety outcomes in women undergoing IVF or ICSI treatment cycles. They compared subgroups by the dose of long-acting FSH administered, mainly low dose (60–120 μg), medium dose (150–180 μg) and high dose (240 μg) [27].
The age of the included participants in the four included trials ranged from 18 to 39 years, and the range of body mass index (BMI) was 17–32 kg/m2. All the studies excluded poor responders, patients with a history of OHSS or PCOS and patients with explained fertility. None of the studies evaluated patient satisfaction. All included studies compared long-acting FSH with daily FSH in combination with a GnRH antagonist protocol. The studies varied in initial dose of long-acting FSH administered: 454 women received a low dose (60–120 μg), 869 women received a medium dose (150–180 μg) and 25 women received a high dose (240 μg). All studies used r-FSH for the control group: three studies used 150 IU r-FSH while the ENGAGE 2009 study used 200 IU r-FSH. ENSURE 2010 and ENGAGE 2009 used a body weight-adjusted dose of long-acting and daily FSH [27].
In this meta-analysis, there was evidence of a reduced live birth rate in women who received lower doses (60–120 μg) of long-acting FSH compared to daily FSH (OR 0.60; 95 % CI 0.40–0.91, 3 RCTs, 645 women, I2 = 0 %). There was no evidence of effect on live births in the medium-dose subgroup (OR 1.03; 95 % CI 0.84–1.27). There was no evidence of effect on clinical pregnancy rate or ongoing pregnancy rates [27].
Likewise, there was no evidence of a difference in adverse events for rates of OHSS, multiple pregnancy, miscarriage and ectopic pregnancy between long-acting and daily FSH preparations. Additionally, treatment with Corifollitropin alfa did not induce hypersensitivity reactions. The authors concluded that the use of a medium dose of long-acting FSH is a safe treatment option and equally effective compared to daily FSH [27].
The effect of repeated ovarian stimulation with Corifollitropin alfa was assessed in the TRUST trial [28]. Most frequent adverse events reported included procedural pain, headache and pelvic pain. The cumulative ongoing pregnancy rate after three cycles, including frozen-thawed embryo transfer cycles and spontaneous pregnancies, was 61 % (95 % CI: 56–65 %) after censoring for patients who discontinued treatment. No clinically relevant immunogenicity or drug-related hypersensitivity was observed [28].
Conclusion
In controlled ovarian stimulation, long-acting gonadotropins have the ability to initiate and sustain multifollicular growth for 7 days. Current evidence suggests that the use of a medium dose of long-acting FSH is a safe treatment option and equally effective compared to daily FSH. This simplified treatment approach may provide a more patient-friendly approach to controlled ovarian stimulation. Studies seem to suggest that Corifollitropin alfa is an effective treatment option for potential normal responder patients undergoing ovarian stimulation with the GnRH antagonist protocol for IVF, resulting in an ongoing pregnancy rate comparable to that achieved with daily r-FSH. However, it is noteworthy that there are still no patient satisfaction studies or studies seeking input from healthcare providers, which could help in evaluating whether the long-acting FSH preparations truly decrease stress and improve patient compliance and satisfaction.
Further research is needed to determine whether long-acting FSH is safe and efficacious in patients at risk of ovarian hyperstimulation or in poor responders. There is currently one ongoing trial relating to long-acting FSH in combination with a GnRH agonist protocol. Future trials, involving Corifollitropin alfa, are required to compare the clinical efficacy and safety outcomes using GnRH antagonist co-treatment with those achieved using long GnRH agonist protocols. Studies are also needed to assess patient satisfaction and overall patient experience with the long-acting FSH preparations. Novel drug delivery systems could lead to the development of less invasive methods, more long-acting compounds and various routes of administration that may include transdermal, inhaled or orally active gonadotropins. These developments would ultimately lead to greater ease of administration, more simplified and convenient dosing regimens and superior safety and efficacy, ultimately leading to greater patient satisfaction and improved patient experience.
References
1.
Edwards RG, Steptoe PC. Induction of follicular growth, ovulation and luteinization in the human ovary. J Reprod Fertil Suppl. 1975;(22):121–63.
2.
Brown JB. Pituitary control of ovarian function--concepts derived from gonadotropin therapy. Aust N Z J Obstet Gynaecol. 1978;18:46–54.CrossRefPubMed
3.
Baird DT. A model for follicular selection and ovulation: lessons from superovulation. J Steroid Biochem. 1987;27:15–23.CrossRefPubMed
4.
Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev. 2006;27:170–207.CrossRefPubMed
5.
Fauser BC, Van Heusden AM. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocr Rev. 1997;18:71–106.PubMed
6.
Schroder AK, Katalinic A, Diedrich K, Ludwig M. Cumulative pregnancy rates and drop-out rates in a German IVF programme: 4102 cycles in 2130 patients. Reprod Biomed Online. 2004;8:600–6.CrossRefPubMed
7.
Scholtes MC, Schnittert B, van Hoogstraten D, Verhoeven HC, Zrener A, Warne DW. A comparison of 3-day and daily follicle-stimulating hormone injections on stimulation days 1–6 in women undergoing controlled ovarian hyperstimulation. Fertil Steril. 2004;81:996–1001.CrossRefPubMed
8.
Fauser BC, Mannaerts BM, Devroey P, Leader A, Boime I, Baird DT. Advances in recombinant DNA technology: corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency. Hum Reprod Update. 2009;15:309–21.CrossRefPubMed
9.
Chappel SC. Heterogeneity of follicle stimulating hormone: control and physiological function. Hum Reprod Update. 1995;1:479–87.CrossRefPubMed
10.
Stockell Hartree A, Renwick AG. Molecular structures of glycoprotein hormones and functions of their carbohydrate components. Biochem J. 1992;287(Pt 3):665–79.PubMedCentralCrossRefPubMed
11.
Amin HK, Hunter WM. Human pituitary follicle-stimulating hormone: distribution, plasma clearance and urinary excretion as determined by radioimmunoassay. J Endocrinol. 1970;48:307–17.CrossRefPubMed
12.
Kohler PO, Ross GT, Odell WD. Metabolic clearance and production rates of human luteinizing hormone in pre- and postmenopausal women. J Clin Invest. 1968;47:38–47.PubMedCentralCrossRefPubMed
13.
Matzuk MM, Hsueh AJ, Lapolt P, Tsafriri A, Keene JL, Boime I. The biological role of the carboxyl-terminal extension of human chorionic gonadotropin [corrected] beta-subunit. Endocrinology. 1990;126:376–83.CrossRefPubMed
14.
Weenen C, Pena JE, Pollak SV, Klein J, Lobel L, Trousdale RK, et al. Long-acting follicle-stimulating hormone analogs containing N-linked glycosylation exhibited increased bioactivity compared with o-linked analogs in female rats. J Clin Endocrinol Metab. 2004;89:5204–12.CrossRefPubMed
15.
Perlman S, van den Hazel B, Christiansen J, Gram-Nielsen S, Jeppesen CB, Andersen KV, et al. Glycosylation of an N-terminal extension prolongs the half-life and increases the in vivo activity of follicle stimulating hormone. J Clin Endocrinol Metab. 2003;88:3227–35.CrossRefPubMed
16.
Klein J, Lobel L, Pollak S, Ferin M, Xiao E, Sauer M, et al. Pharmacokinetics and pharmacodynamics of single-chain recombinant human follicle-stimulating hormone containing the human chorionic gonadotropin carboxyterminal peptide in the rhesus monkey. Fertil Steril. 2002;77:1248–55.CrossRefPubMed
17.
Fares FA, Suganuma N, Nishimori K, LaPolt PS, Hsueh AJ, Boime I. Design of a long-acting follitropin agonist by fusing the C-terminal sequence of the chorionic gonadotropin beta subunit to the follitropin beta subunit. Proc Natl Acad Sci U S A. 1992;89:4304–8.PubMedCentralCrossRefPubMed
18.
Ludwig M, Felberbaum RE, Diedrich K, Lunenfeld B. Ovarian stimulation: from basic science to clinical application. Reprod Biomed Online. 2002;5 Suppl 1:73–86.CrossRefPubMed
19.
LaPolt PS, Nishimori K, Fares FA, Perlas E, Boime I, Hsueh AJ. Enhanced stimulation of follicle maturation and ovulatory potential by long acting follicle-stimulating hormone agonists with extended carboxyl-terminal peptides. Endocrinology. 1992;131:2514–20.PubMed
20.
Duijkers IJ, Klipping C, Boerrigter PJ, Machielsen CS, De Bie JJ, Voortman G. Single dose pharmacokinetics and effects on follicular growth and serum hormones of a long-acting recombinant FSH preparation (FSH-CTP) in healthy pituitary-suppressed females. Hum Reprod. 2002;17:1987–93.CrossRefPubMed
21.
Devroey P, Fauser BC, Platteau P, Beckers NG, Dhont M, Mannaerts BM. Induction of multiple follicular development by a single dose of long-acting recombinant follicle-Stimulating hormone (FSH-CTP, corifollitropin alfa) for controlled ovarian stimulation before in vitro fertilization. J Clin Endocrinol Metab. 2004;89:2062–70.CrossRefPubMed
22.
Bouloux PM, Handelsman DJ, Jockenhovel F, Nieschlag E, Rabinovici J, Frasa WL, et al. First human exposure to FSH-CTP in hypogonadotrophic hypogonadal males. Hum Reprod. 2001;16:1592–7.CrossRefPubMed
23.
Balen AH, Mulders AG, Fauser BC, Schoot BC, Renier MA, Devroey P, et al. Pharmacodynamics of a single low dose of long-acting recombinant follicle-stimulating hormone (FSH-carboxy terminal peptide, corifollitropin alfa) in women with World Health Organization group II anovulatory infertility. J Clin Endocrinol Metab. 2004;89:6297–304.CrossRefPubMed
24.
The Corifollitropin Alfa Dose-finding Study Group. A randomized dose–response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation†. Hum Reprod. 2008;23:2484–92.CrossRef
25.
Devroey P, Boostanfar R, Koper NP, Mannaerts BMJL, Ijzerman-Boon PC, Fauser BCJM. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2009;24:3063–72.PubMedCentralCrossRefPubMed
26.
The Corifollitropin Alfa Ensure study group. Corifollitropin alfa for ovarian stimulation in IVF: a randomized trial in lower-body-weight women. Reprod Biomed Online. 2010;21:66–76.CrossRef
27.
Pouwer AW, Farquhar C, Kremer JA. Long-acting FSH versus daily FSH for women undergoing assisted reproduction. Cochrane Database Syst Rev. 2012;(6):CD009577.
28.
Norman RJ, Zegers-Hochschild F, Salle BS, Elbers J, Heijnen E, Marintcheva-Petrova M, et al. Repeated ovarian stimulation with corifollitropin alfa in patients in a GnRH antagonist protocol: no concern for immunogenicity. Hum Reprod. 2011;26:2200–8.PubMedCentralCrossRefPubMed