Reproductive BioMedicine Online (2014) 28, 183– 190

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REVIEW

Ovarian response markers lead to appropriate and effective use of corifollitropin alpha in assisted reproduction Antonio La Marca *, Giovanni D’Ippolito Mother-Infant Department, Institute of Obstetrics and Gynecology, University of Modena and Reggio Emilia, 41100 Modena, Italy * Corresponding author. E-mail address: [email protected] (A La Marca). Antonio La Marca is a professor for reproductive medicine at the Mother-Infant Department, University of Modena and Reggio Emilia, Modena, Italy. He trained at the University of Siena, where he graduated in medicine in 1996 and completed his residency in obstetrics and gynaecology in 2001. His PhD was on biology of germ cells. Since 2004, he has worked at the unit for reproductive medicine and surgery of the University Hospital of Modena. His research areas are the physiology of ovarian function and its pharmacological manipulation. In the last years, his research has been focused particularly on anti-Mu ¨llerian hormone, antral follicle count and ovarian reserve.

Abstract Corifollitropin alpha is a highly effective gonadotrophin, which maintains multifollicular growth for a week. The advan-

tages of its administration include ease of use of the drug, making the treatment more patient friendly, resulting in a lower level of distress for the patient. At the same time, the pregnancy rate resulting from its use in IVF/intracytoplasmic sperm injection cycles is similar to that found when daily recombinant FSH is administered. The ovarian response to corifollitropin alpha is dependent on clinically established predictors such as baseline FSH, antral follicle count (AFC) and age. There is a general trend towards a higher ovarian response with an increasing AFC and the number of oocytes per attempt decreased with increasing baseline FSH and age. Even if the risk of ovarian hyperstimulation syndrome following corifollitropin alpha is very similar to the rate reported in literature for young women undergoing IVF, the risk of overstimulation may be reduced by avoiding maximal ovarian stimulation in women anticipated to be hyperresponders. High basal anti-Mu ¨llerian hormone and/or AFC can identify women with enhanced functional ovarian reserve at risk of overstimulation, and the risk is even higher if maximally stimulated with corifollitropin alpha or high dose of daily recombinant FSH. RBMOnline ª 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: antral follicle count, anti-Mu ¨llerian hormone, corifollitropin alpha, IVF, OHSS, ovarian stimulation

Introduction Many infertility treatment protocols have been proposed over the last decades, but all of them consisted in daily injection of gonadotrophins in combination with

gonadotrophin-releasing hormone (GnRH) analogues. In recent years, many therapeutic areas shifted from more complex drug delivery regimens, for example with daily injections, to drugs that require reduced frequency of administration. Many are the advantages from such kind of

1472-6483/$ - see front matter ª 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rbmo.2013.10.012

184 administration including the easy use of the long-acting drugs which makes the treatment more patient friendly and gives lower level of distress to the patient. Another advantage is that fewer injections may improve drug compliance and, as in IVF treatment, prevent errors during gonadotrophin administration, which are very common (Fauser et al., 2009; Verberg et al., 2008). Corifollitropin alpha is a new sustained recombinant gonadotrophin able to promote and to maintain multifollicular growth throughout the first 7 days of ovarian stimulation. The pharmacokinetic profile of corifollitropin alpha is characterized by a slow absorption after subcutaneous absorption, resulting in peak concentrations 2 days after injection with a steady decline afterwards. Its very long elimination half-life leads to serum FSH concentrations above the threshold window, hence efficiently supporting ovarian stimulation over an entire week (Fauser et al., 2010). This sustained activity may be perceived by many clinicians as it could increase the risk for overstimulation in some patients undergoing IVF. The objective of this article is to summarize the most relevant pharmacological characteristics of this drug and suggest how to use markers predicting ovarian response in order to guide an appropriate drug prescription in the clinical practice.

From daily to once-a-week FSH injection In the 1990s, the more common used gonadotrophins to induce ovulation were the human menopausal gonadotrophins that have FSH and LH activity, while the first recombinant FSH preparation became commercially available in 1996 (De Leeuw et al., 1996; Howles, 1996; Olijve et al., 1996). Recombinant FSH has a relatively short half-life and requires daily injections in order to maintain the serum FSH concentration beyond the threshold useful for the production of ovarian stimulation. Recombinant FSH has a t1/2 of about 30 h and after each injection the peak FSH serum concentrations are reached in 10–12 h. Steady-state concentrations are reached after 3–5 days. Of course, all of these pharmacodynamic and pharmacokinetic properties are influenced by individual characteristics such as gender and weight, but also by route of administration (Fauser et al., 2010; le Cotonnec et al., 1998). Structure analyses of gonadotrophins revealed the importance of O-linked and N-linked glycosylation sites and their impact on the prolongation of hormone half-life (Loumaye et al., 1996; Porchet et al., 1994; Quinton et al., 1996). For instance, the human chorionic gonadotrophin (HCG) C-terminal region, which has four serine O-linked oligosaccaride chains, was absent in the other glycoprotein gonadotrophin hormones and was thought to be responsible for the prolonged half-life and the slower metabolic clearance compared with LH. As a matter of fact, the deletion of the C-terminal peptide (CTP) of the HCG b-subunit resulted in a derivative that was 3-fold less active than the native HCG, confirming the importance of this small peptide. In order to reduce the frequency of injections necessary during ovarian stimulation for IVF, longacting FSH molecules have been developed. One sustained

A La Marca, G D’Ippolito FSH preparation was recently developed and called corifollitropin alpha. Professor Irving Boime at Washington University developed the CTP technology on which corifollitropin alpha was based in the 1990s. Corifollitropin alpha consists of a a-subunit identical to that FSH and a b-subunit produced by fusing the CTP of the b-subunit of HCG with the b-subunit of FSH. (Fares et al., 1992; LaPolt et al., 1992). The advantage of this preparation is that corifollitropin alpha interacts only with the FSH-receptor and lacks LH activity (Fauser et al., 2009; LaPolt et al., 1992; Loutradis et al., 2010), but it has a longer half-life and an extended time-interval to peak serum concentrations than recombinant FSH. After a single corifollitropin alpha injection, the time to reach the serum peak concentrations is about 44 h and its elimination half-life is approximately 69 h (Corifollitropin Alfa Dose-finding Study Group, 2008). Once it was proven that the corifollitropin alpha’s half-life is approximately twice as long as that of recombinant FSH (Balen et al., 2004; Bouloux et al., 2001; Duijkers et al., 2002) and that its administration is well tolerated, the aim was to find the right dose to sustain a multifollicular growth during ovarian stimulation within a protocol that entails the daily administration of GnRH antagonist to prevent the LH surge. Devroey et al. (2004), using single doses of 120, 180 or 240 lg in a GnRH antagonist protocol, showed that this range dose was effective to induce and sustain multifollicular growth for 7 days. Four years later, the Corifollitropin Alfa Dose-finding Study Group (2008) designed a phase-II study to investigate the dose–response relationship according to the number of retrieved oocytes. Modelling and simulation techniques were then used to explore the impact on treatment outcome of various doses of corifollitropin alpha as well as the influence of patient characteristics. Bodyweight was a major determinant of exposure to corifollitropin alpha and treatment outcome. It was concluded that the recommended dose of corifollitropin alpha was 150 lg for patients with a bodyweight >60 kg and 100 lg for patients with a bodyweight 60 kg (De Greef et al., 2010).

Corifollitropin alpha is a highly effective ovarian stimulator The calculated dose of corifollitropin alpha was then tested in the ENGAGE trial (Devroey et al., 2009), including 1509 women with a bodyweight >60 kg and in which efficacy and safety of a single injection of 150 lg corifollitropin alpha was compared with the daily injection of 200 IU recombinant FSH. Women included in the study were aged 18–36 years, with a bodyweight of 60–90 kg, regular menstrual cycles, with an antral follicle count (AFC) of less than 20 in both ovaries and a serum day-3 FSH 60 kg and 60 kg bodyweight, respectively, produced higher ovarian responses in terms of number of growing follicles and oocytes retrieved than daily recombinant FSH (200 IU and 150 IU daily, respectively; Table 1). Data from the two trials were applied to evaluate potential predictors of ovarian response for the selected doses (Ledger et al., 2010; Figure 1). The ovarian response was demonstrated to be dependent on clinically established predictors such as baseline FSH, AFC and age, whereas it was not dependent on drug exposure or bodyweight in those subjects correctly treated with the selected doses for their bodyweight (corifollitropin alpha 100 lg for subjects 60 kg

185 and corifollitropin alpha 150 lg for subjects >60 kg). Figure 1 shows that the mean number of oocytes retrieved is stable across the quartiles of drug-exposure area under curve, whereas the mean number of oocytes retrieved per attempt was higher with increasing basal AFC and lower with increasing basal FSH and age. Since corifollitropin alpha has proven to be a very effective drug in inducing and maintaining the growth of all FSH-sensitive ovarian follicles, it could be the first choice drug in poor responders (Polyzos et al., 2013a) or in aged women (Boostanfar et al., 2012b). The obvious advantages are related to the association of use of corifollitropin with the GnRH antagonist, which in recent times seems to be the most used GnRH analogue in poor responders. Moreover, the use of corifollitropin alpha in patients as poor responders usually undergoing repetitive cycles of ovarian stimulation, may help in reducing the burden of treatment and consequently the drop out rate. Anyway, in clinical practice, the use of corifollitropin has not been limited to women with poor ovarian reserve but also extended to women with a very good expected ovarian response as oocyte donors with remarkable good results (Requena et al., 2013).

Playing with corifollitropin alpha dose and bodyweight In the two phase-III trials, it was concluded that patients eligible for corifollitropin alpha are potential normal responders and that in individual patients ovarian response cannot be modified by decreasing corifollitropin alpha exposure, this because a single, selected for their weight, dose injected in patients produces a maximal response. For example, in patients weighing 60 kg treated with an higher than established dose of corifollitropin alpha (such as 150 lg), there will not be an improvement in follicle recruitment, but ovarian stimulation will be sustained longer than 1 week and some subjects will reach the criteria for HCG injection after only 7 days. Hence, a higher dose of corifollitropin alpha will not improve the ovarian response, but will maintain the activity beyond stimulation day 8 (De Greef et al., 2010). On the other hand, a lower than established-for-weight dose of corifollitropin alpha (100 lg) administered in women weighing >60 kg increases the risk of cycle cancellation and will not result in a milder stimulation. Also by using this dose there will be a recruitment of a nearly maximum number of follicles, but ovarian stimulation will be sustained only for the first 5 days. Even in high-responder women weighing >60 kg, a corifollitropin alpha 100 lg injection can result in a cycle cancellation and will not produce a milder ovarian stimulation.

Corifollitropin alpha and the risk of OHSS Corifollitropin alpha appears to be a potent and highly effective gonadotrophin, able to induce and sustain the maximal possible ovarian follicular growth in women undergoing IVF. For this reason and in accordance with the summary product characteristics provided by the manufacturer, corifollitropin alpha is contraindicated in women with a history of OHSS, an earlier stimulation cycle that resulted

186 Table 1

A La Marca, G D’Ippolito Characteristics of patients and outcome of stimulation in the ENGAGE and ENSURE trials.

Characteristic

ENGAGEa

ENSUREb

x

150 lg corifollitropin alpha (n = 756)

200 IU recombinant FSH (n = 750)

100 lg corifollitropin alpha (n = 268)

150 IU recombinant FSH (n = 128)

Age (years) Bodyweight (kg) Basal AFC Follicles >11 mm on HCG day Oocytes retrieved

31.5 ± 3.3 68.8 ± 7.6 12.8 ± 6.7 16.0 ± 7.0

31.5 ± 3.2 68.4 ± 7.3 11.6 ± 6.0 13.9 ± 6.1

30.9 ± 3.2 54.1 ± 4.2 11.8 ± 6.1 14.9 ± 6.6

31.1 ± 3 54.4 ± 4.2 10.6 ± 5.3 12.9 ± 5.8

13.7 ± 8.2

12.5 ± 6.7

13.3 ± 7.3

10.6 ± 5.9

Values are mean ± standard deviation. a Devroey et al. (2009). b Corifollitropin Alfa ENSURE Study Group (2010).

Figure 1 Relationship between number of oocytes and potential predictors of ovarian response in women after treatment with recommended dose of corifollitropin alpha (from Ledger et al., 2010). (a) According to data from the ENGAGE and ENSURE trials, the mean number of oocytes retrieved was not dependent on drug exposure for women treated with the correct dose of 100 or 150 lg corifollitropin alpha based on their bodyweight. (b–d) As expected, the ovarian response depended mainly on predictors of ovarian response such as baseline FSH (b), AFC (c) and age (d). AUC = area under the receiver operating characteristic curve.

in more than 30 follicles >11 mm or AFC >20 (in both ovaries). A very recent review by Tarlatzis et al. (2012) compared the incidence of OHSS occurred in the patients involved in the ENGAGE and ENSURE trials. Overall the inci-

dence of OHSS in patients that received corifollitropin alpha was 6.9% (71/1023) comparable with 6.0% (53/880) in the recombinant FSH group. The incidence of mild, moderate and severe OHSS was 3.0%, 2.2% and 1.8%, respectively in

Ovarian response prediction and corifollitropin alpha

Figure 2 OHSS in patients treated with corifollitropin alpha or recFSH. Data from the ENGAGE and ENSURE trials (pooled) (from Tarlatzis et al., 2012).

the corifollitropin alpha patients, with 1.9% requiring hospitalization, and 3.5%, 1.3% and 1.3%, respectively in the recombinant FSH patients, with 0.9% requiring hospitalization. Adjusted for trial the odds ratio for OHSS was 1.18 (95% CI 0.81–1.71) indicating that the risk for OHSS in the corifollitropin alpha group patients was similar to that for recombinant FSH group patients (Tarlatzis et al., 2012; Figure 2). This pooled analysis of data from the two trials indicated that the risk of OHSS following corifollitropin alpha treatment for ovarian stimulation is not significantly different from recombinant FSH treatment and globally is very similar to the rate of OHSS reported in literature for young women undergoing IVF (Pundir et al., 2012; Zivi et al., 2010). In the same analysis (Tarlatzis et al., 2012), it was seen that women with OHSS (n = 124) were younger and had a lower basal FSH and a higher AFC than patients without OHSS (n = 1679). This finding clearly indicates that women who developed OHSS in the two trials had higher functional ovarian reserve than women without OHSS;

187 hence, it explains why they had exaggerated ovarian response when maximally stimulated. But this also highlights the relevance of the measurement of functional ovarian reserve markers in order to possibly prevent OHSS in IVF cycles. Table 2 compares the OHSS rate reported in the ENGAGE and ENSURE trials for women treated with follitropin beta with several historical sponsored trials investigating the use of follitropin beta in association with the GnRH antagonist. It is quite clear that the OHSS rate in the two recent trails was very similar to what reported in historical trials. However, potential hyperresponders were not excluded from those old trials. In fact, while in all historical trials women were excluded if expected poor responders, high AFC, indicative of a hyperovarian response, was not an exclusion criteria. On the contrary, only expected normal responders (on the basis of AFC 3.52 ng/ml and AFC >16 were associated to very high diagnostic performance (sensitivity and specificity were 89.5 and 83.8% for AMH and 80 and 84.5% for AFC, respectively) in predicting women with more than 20 oocytes at retrieval, hence confirming the reliability of values already reported in the literature for the two markers. Table 3

AFC 30 25 20

15

10 95° 75° 50° 25° 5°

5

20

25

30

35

40

45

Age (years)

Figure 3 The normogram of antral follicle count (AFC) in healthy eumenorrhoeic women. Using AFC >20 to exclude potential hyperresponder women from a treatment would result in the exclusion of a very low percentage of women (modified from La Marca et al., 2011). AFC (n)

AMH (ng/ml)

Risk of OHSS

Appropriateness of maximal ovarian stimulation

high

unsafe

low

safe

5 20 4 15 3 10 2 5

1

0

0

Figure 4 The relationship between functional ovarian reserve as measured by anti-Mu ¨llerian hormone (AMH) or antral follicle count (AFC) and the risk of ovarian hyperstimulation syndrome (OHSS). The linear relationship existing between AMH or AFC and ovarian response in IVF permits to predict increasing risk of OHSS for women with high AMH or AFC. Consequently maximal ovarian stimulation, however obtained, with either long or daily gondotrophins, should be avoided.

Diagnostic performance of antral follicle count (AFC) in predicting hyperresponse to ovarian stimulation in IVF cycles.

Publication

Design

N

AFC cut off

Sensitivity (%)

Specificity (%)

Ng et al. (2005) van Rooij et al. (2002)) Eldar-Geva et al. (2005) Kwee et al. (2008) Aflatoonian et al. (2009) Ocal et al. (2011) Polyzos et al. (2013b)

Prospective Prospective Prospective Prospective Prospective Retrospective Retrospective

128 114 56 110 159 82 210

9 14 14 14 16 8a 16

60 92 94 81 89 78 80

71 63 33 89 92 65 84.5

a

Prediction of ovarian hyperstimulation syndrome.

Ovarian response prediction and corifollitropin alpha

Conclusion Corifollitropin alpha is a very effective and potentially widely administrable drug. Of the benefits arising from its use, there is the reduced number of injections that the patient must administer and the easy use. However, the use of corifollitropin alpha requires the correct prediction of the expected high responders for whom the drug is contraindicated. The safe clinical use of corifollitropin alpha is only secondary to a consistent in label use and to a good capability of the clinician to predict the maximal potential ovarian response of the patient. If the clinician would consider the patient as being at high risk to develop an OHSS, the use of the corifollitropin alpha should be avoided. Conversely, if the clinician would consider the patient as a low or a normal responder and not at risk of developing the OHSS, its use is a really valid treatment option in IVF. In conclusion, the correct and effective use of drugs as the sustained FSH is secondary to a very good knowledge of diagnostic tools predicting ovarian response and their clinical application.

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Ovarian response markers lead to appropriate and effective use of corifollitropin alpha in assisted reproduction.

Corifollitropin alpha is a highly effective gonadotrophin, which maintains multifollicular growth for a week. The advantages of its administration inc...
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