Research Article

Subcutaneously administered Menopur®, a new highly purified human menopausal gonadotropin, 
causes significantly fewer injection site reactions than Repronex® in subjects undergoing in vitro fertilization
William R Keye¹ , Bobby Webster² , Richard Dickey³ , Stephen Somkuti⁴ , Jack Crain⁵ and M Joseph Scobey^6 
1William Beaumont Hospital, In Vitro Fertility Clinic, Royal Oak, Michigan, USA
²Woman's Center for Fertility, Baton Rouge, Louisiana, USA
³Fertility Institute of New Orleans, New Orleans, Louisiana, USA
⁴Abington Reproductive Medicine, Abington, Pennsylvania, USA
⁵Reproductive Endocrine Associates of Charlotte, Charlotte, North Carolina, USA
⁶Ferring Pharmaceuticals Inc., Suffern, New York, USA

Research: (continued)

Results
A total of 190 subjects were randomized and included in the analysis of safety. The initial study contained a third arm consisting of 65 subjects who received Menopur® IM, however these data were not included in this analysis, as the focus of this report is to compare the safety and tolerability of Repronex® SC and Menopur® SC. The remaining 125 subjects were randomized to receive Menopur® SC (n = 61) or Repronex® SC (n = 64). Due to subject noncompliance or loss at follow-up, certain safety outcomes such as exit physical examination variables and injection site pain are missing a few data points.

Subject demographic characteristics are summarized in Table 1. Overall, subjects in the two treatment groups were comparable both demographically and medically. The only statistically significant difference between the groups was race, with African-Americans comprising 11.5% of the Menopur® group compared with 1.6% of the Repronex® group (P = 0.039). The impact of this difference is unknown.

There were no statistically significant differences between the treatment groups in the number of subjects with any AEs, severe AEs, or serious AEs, as shown in Table 2. There were five serious AEs during the study (1 subject in the Menopur® group had OHSS and four subjects in the Repronex® group had one of the following serious AEs: dehydration, an ectopic pregnancy, a right ruptured ovary with secondary hemothorax, and a pelvic abscess). A total of three cases of OHSS were reported (1 subject in the Menopur® group, which was severe and 2 subjects in the Repronex® group, which were mild or moderate).

Table 3 lists the AEs with an incidence of ≥ 5% (2 or more subjects). Among these AEs, there were no significant differences between the two groups in the percentage of subjects with any AE and no difference in the intensity of injection site pain. However, there were numerically fewer total AEs in the Menopur® group (n = 131) compared to the Repronex® group (n = 198). As shown in Figure 1, this difference was largely attributed to the number of injection site reactions, the single most common AE. When only hMG injections were considered, there were only three (4.9%) subjects in the Menopur® group that reported injection site reactions, whereas 22 (34.4%) subjects in the Repronex® group reported injection site reactions (P < 0.001). Among the three Menopur® subjects with local injection site reactions, all were transient and mild to moderate in intensity, none developed welts/inflammation, and only one subject had localized swelling. These findings contrasted with the 22 subjects in the Repronex® group with injection site reactions, among whom eight developed welts/inflammation (P < 0.001) and four developed swelling (P = 0.328). Conversely, there was no difference in mean scores for injection site pain between the two groups, 2.6 for Menopur® and 2.3 for Repronex® (P = 0.615). 

Discussion
Overall, the safety profile of Menopur® in this study was similar to that of Repronex® . Human-derived gonadotropins have been used safely and effectively in ART protocols for over forty years. However, the injection of partially purified hMG is associated with more injection site reactions than highly purified gonadotropins. Removal of nearly all uncharacterized proteins from hMG in the manufacturing process for Menopur® has resulted in significantly fewer reported injection site reactions in IVF subjects. There was a seven-fold difference in the percentage of subjects with injection site reactions, 4.9% and 34.4% of subjects in the Menopur® and Repronex® groups, respectively. When the incidence of reactions that involved swelling, inflammation, or welts was examined, 98% of subjects receiving Menopur® completed their cycle without such reactions while only 81% of subjects receiving Repronex® did not experience such events (P = 0.001).

An analysis of Menopur® has shown that its purity and quality is comparable to recombinant gonadotropin preparations [7]. In addition, Menopur® has been shown to have a similar safety and tolerability profile as recombinant FSH in women undergoing IVF/ICSI treatment cycles [8]. Collectively, these observations and studies, combined with the data from this study demonstrate that Menopur® is at least as efficacious and safe as any existing gonadotropin.
The results from this study demonstrate that Menopur® , a new highly purified hMG, can be administered SC with significantly fewer injection site reactions than Repronex® , a partially purified hMG. Thus, advanced manufacturing techniques have produced the first ever highly purified form of hMG resulting in a markedly improved safety and tolerability profile compared with previously available hMG products.

Authors contributions
Drs. Keye, Webster, Dickey, Somkuti, and Crain contributed to the treatment of subjects, collection of data and writing of the manuscript. Dr. Scobey was instrumental in data analysis and writing of the manuscript.

References
1. Zondek B: Weitere untersuchungen zur darstellung, biologie und klinik des hypophysenvorderlappenhormons (Prolan). Zentralbl Gynako 1929, 53:834-847.  

2. Fevold HL, Hisaw FL, Leonard SL: The gonad stimulating and the luteinizing hormones of the anterior lobe of the hypophysis. Am J Physiol 1931, 97:291-301.

3. Gemzell CA, Diczfalusy E, Tillinger G: Clinical effect of human pituitary follicle-stimulating hormone (FSH).
J Clin Endocrinol Metab 1958, 18:1333-1348. [PubMed Abstract]

4. Lunenfeld B, Sulimovici S, Rabau E, Eshkol A: L'induction de l'ovulation dans les amenorrhees hypophysaires par un traitement combine de gonadotrophines urinaires menopausiques et de gonadotrophines chorioniques.
CR Soc Fr Gyncol 1962, 32:347-351.

5. Lunenfeld B: Historical perspectives in gonadotrophin therapy.
Hum Reprod Updat 2004, 10:453-467. [Publisher Full Text]

6. Reichl H, Balen A, Jansen CAM: Prion transmission in blood and urine: what are the implications for recombinant and urinary-derived gonadotrophins? Hum Reprod 2002, 17:2501-2508. [PubMed Abstract][Publisher Full Text]

7. Wolfenson C, Groisman J, Couto AS, Hedenfalk M, Cortvrindt RG, Smitz JE, Jesperson S: Batch-to-batch consistency of human-derived gonadotrophin preparations compared with recombinant preparations.
Reprod Biomed Online 2005, 10:442-454. [PubMed Abstract][Publisher Full Text]

8. European and Israeli Study Group: Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial.
Fertil Steri 2002, 78:520-528. [Publisher Full Text]

Tables and Figures (click thumbnails to open full-size image in a new window)

 Reproductive Biology and Endocrinology 2005 published by BioMed Central
An Open Access Research article
Published 9 November 2005
© 2005 Keye et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.