Ovulation induction: Initially IU SC or IM inj daily for 5 days in the 1 st cycle; for subsequent cycles: base initial dose on ovarian response. Ovulation induction or ART: adjust dose based on response in increments of IU at intervals of at least 2 days; max IU daily; usual max 12 days.
Primary ovarian failure. Uncontrolled non-gonadal endocrinopathies eg, thyroid, adrenal, pituitary. Undiagnosed abnormal uterine bleeding. Ovarian cysts or enlargement. Tumor of pituitary, hypothalamus, breast, ovary, or uterus. Pregnancy Cat. Do complete gynecological and endocrinological exam first. There were no differences in the nature or number of adverse events between the treatment groups although Bravelle R injections were reported to be significantly less painful.
Following their discovery in the s, the pituitary gonadotropins, follicle-stimulating hormone FSH and luteinizing hormone LH , were first used successfully for ovulation induction in [ 1 ]. Since then, exogenous hormone preparations of these gonadotropins have been widely used for the treatment of oligoanovulatory infertility, as well as for stimulation of multiple follicular development in assisted reproductive techniques.
The first commercially available gonadotropin preparation, human menopausal gonadotropin hMG , was purified from the urine of postmenopausal women and contained equal amounts of FSH and LH activity [ 2 ]. With the development of sophisticated purification techniques [ 3 ], more purified FSH preparations containing small amounts of LH became available in Thereafter, a highly purified FSH preparation was developed and approved for use in Advances in molecular biology techniques made it possible to produce recombinant FSH, which is secreted from genetically engineered Chinese hamster ovary cells [ 4 ].
Despite identical amino acid sequences, recombinant and natural FSH preparations have different glycosylation patterns, which are known to influence the isoform profile of each product [ 5 , 6 ].
The clinical implications of differing isoform profiles for FSH products are unclear and there are no convincing data to suggest marked superiority of either human-derived or animal-derived FSH formulations for ovarian stimulation in terms of efficacy or safety [ 7 - 14 ]. Nonetheless, since subtle differences due exist between human derived and recombinant forms of FSH, efforts continue to identify clinically relevant differences between the two FSH preparations.
Data were collected from 19 IVF-ET centers, each of which obtained institutional review board approval. Eleven centers participated in the first study while 13 centers participated in the second study. Both studies were conducted in accordance with Good Clinical Practice guidelines and written informed consent was obtained from all participants prior to screening and enrollment. Causes of infertility were attributed to tubal factor, endometriosis American Fertility Society revised stage I or II or unexplained.
Participants had ultrasound-confirmed normal ovaries with healthy uterus and adnexae. Further eligibility criteria included: unremarkable medical history and physical examination with normal baseline hematology and clinical chemistry; normal range serum estradiol E 2 , follicle stimulating hormone FSH , luteinizing hormone LH , testosterone, dihydroepiandrosterone sulfate, prolactin and thyroid stimulating hormone.
All patients needed to be seronegative for hepatitis B and C, HIV and syphilis and have a negative pregnancy test before starting treatment. Male partner or donor semen was required to meet World Health Organization criteria [ 15 ] for normal, within 6 months of study entry. Study center staff administered the first dose of gonadotropin and provided guidance on abdominal injection technique, including alternation of injection sites, for subsequent dosing at home.
Patients were instructed to maintain a daily, gonadotropin diary of the injection site and the presence and intensity of any pain. After the initial 5 days of FSH treatment, ovarian response was evaluated by transvaginal ultrasound and serum E 2 concentrations.
The duration of the controlled ovarian hyperstimulation cycle was not to exceed 12 days. At their discretion, investigators could reduce the dose or discontinue treatment at any time if concerned about patient safety. If the follicular response remained suboptimal, participants were considered non-responders and were withdrawn from the trial.
Intracytoplasmic sperm injection ICSI and assisted hatching were prohibited. A maximum of four embryos were allowed to be transferred to each patient. Transvaginal ultrasound was performed approximately 2 weeks later to verify a clinical pregnancy gestational sac and fetal heart motion and repeated 1 week later to confirm a continuing pregnancy.
The primary efficacy parameter for this single-cycle analysis was the number of oocytes retrieved. The validity of pooling data from the two independent studies was confirmed by statistical examination, which concluded that the two studies were homogeneous by excluding treatment-by-study interaction for the number of oocytes retrieved, using an ANOVA model with factors for 'treatment', 'study' and 'treatment-by-study' interaction.
Data were pooled and adjusted using the 'study' variable as a fixed effect, to account for between-study variability. Safety was evaluated by analysis of the nature and incidence of adverse events, irrespective of their relation to study medications. Injection site pain was self-rated using a daily diary with an analog scale of 1 no pain to 10 severe or unbearable pain. For the first study, sample size calculations were based on the clinical assumption that 10 oocytes per patient would be retrieved in the reference group.
A sample of 60 patients per group was selected. For the second study, the assumption for the number of oocytes retrieved from the reference group was changed to Continuous variables, including primary and secondary outcome parameters, were analyzed using a two-way ANOVA model with treatment and study as fixed effects. Categorical variables, including adverse events, were compared using Cochran-Mantel-Haenszel CMH analyses, stratified by study, and a logistic regression model using treatment, study, baseline age and BMI as covariates.
Injection site pain scores on each day were compared using the two-way ANOVA model with treatment and study as fixed effects and also using a linear mixed model to compare data across all time points. The latter allowed analysis of continuous data to account for intrasubject variability. The Restricted Maximum Likelihood Method was used with a compound symmetric within-subject covariant structure, and the sandwich variance estimator. A total of patients were enrolled in the two studies and received leuprolide acetate for pituitary down-regulation, were randomized between the study arms.
The most common reasons for non-randomization was failure to down-regulate to the protocol-specified criteria or patients had a positive pregnancy test prior to down-regulation on LA therapy. The initial study contained a third arm consisting of 59 patients, which are not included in this pooled analysis.
In the Bravelle and Follistim groups, Therefore, efficacy data presented in this report are based on the primary efficacy responder population for the primary efficacy parameter, number of oocytes retrieved, and subsequent analyses.
The modest difference in BMI was not considered to be clinically meaningful, in addition, for the ANCOVA analysis of efficacy parameters, BMI and age were used as covariates to account for the effect these differences may have had on outcomes.
The implantation rate did not differ between groups, as it was Mean value per patient of oocytes retrieved, oocytes fertilized and embryos transferred. There were no significant differences between groups on any parameter. One patient had a case of OHSS that was deemed severe in nature and required hospitalization.
It was resolved without sequelae. One other patient had OHSS that was deemed moderate in nature, at the time of resolution, she had a continuing twin pregnancy.
The difference had greater significance when a linear mixed model, which controls for intrasubject variation, was used to compare data across all time points [3.
Clinicians continually update their safety and efficacy data as patients are treated, in order to better understand their treatment protocols. This paper is a similar exercise in that it combines two regulatory grade IVF studies to confirm the efficacy and safety results from the previous study 8.
The secreted protein is collected from the culture medium and purified. Efforts have been made in an attempt to identify differences in efficacy between recombinant and human derived gonadotropin preparations. It is recognized that differences exist in the glycosylation patterns of these preparations [ 5 , 6 ]. However, collectively, the results from numerous, prospective, clinical studies [ 7 - 14 ], and recent meta-analyses [ 19 , 20 ] of published data have failed to show any meaningful or reproducible differences.
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