The potential role of follicle-stimulating hormone in the cardiovascular, metabolic, skeletal, and cognitive effects associated with androgen deprivation therapy.

PURPOSE: To explore how follicle-stimulating hormone (FSH) may contribute to cardiovascular, metabolic, skeletal, and cognitive events in men treated for prostate cancer, with various forms of androgen deprivation therapy (ADT). MATERIALS AND METHODS: A colloquium of prostate cancer experts was convened in May 2015, to discuss the role of FSH in the development of unwanted effects associated with ADT. Subsequently, a literature review (Medline, PubMed, and relevant congress abstract databases) was performed to further explore and evaluate the collected evidence. RESULTS: It has become evident that, in the setting of ADT, FSH can promote the development of atherosclerotic plaque formation, metabolic syndrome, and insulin resistance. Data also suggest that FSH is an important mediator of bone remodeling, particularly bone resorption, and thereby increases the risk for bone fracture. Additional evidence implicates a role for FSH in bone metastasis as well. The influence of FSH on ADT-induced cognitive deficits awaits further elucidation; however, the possibility that FSH may be involved therein cannot be ruled out. CONCLUSIONS: The widespread molecular and physiological consequences of FSH system activation in normal and pathological conditions are becoming better understood. Progress in this area has been achieved by the development of additional investigative and clinical measures to better evaluate specific adverse effects. More research is needed on FSH function in the development of cancer as well as its association with cardiovascular, metabolic, musculoskeletal, and cognitive effects in ADT.

Serum magnesium concentrations in patients receiving sodium picosulfate and magnesium citrate bowel preparation: an assessment of renal function and electrocardiographic conduction.

BACKGROUND: We performed a post hoc analysis of two clinical trials to assess whether sodium picosulfate and magnesium (Mg(2+)) citrate (Prepopik(®) [P/MC]), a dual-action bowel preparation for colonoscopy, has an impact on serum Mg(2+) levels and cardiac electrophysiology. Although rare, hypermagnesemia has been reported in patients consuming Mg(2+)-containing cathartics, especially patients who are elderly and have renal impairment. METHODS: Data were analyzed from two prospective, Phase III, randomized, assessor-blinded, active-control, multicenter, pivotal studies that investigated split-dose/day-before P/MC. Serum Mg(2+) and creatinine clearance (CrCl) were measured at screening, on the day of colonoscopy, and 24-48 hours, 7 days, and 4 weeks after colonoscopy; electrocardiograms also were obtained at these time points. RESULTS: In total, 304 patients received split-dose P/MC and 294 patients received day-before P/MC. Only 10% of the patients had serum Mg(2+) above the upper limit of normal (1.05 mmol/L) on the day of colonoscopy. There was a slight inverse correlation between CrCl and Mg(2+) levels on the day of colonoscopy; however, even at the lowest CrCl, serum Mg(2+) remained below clinically significant levels of 2.0 mmol/L. Increases in serum Mg(2+) were transient, with levels returning to baseline within 24-48 hours, regardless of renal function. No patients with elevated Mg(2+) experienced a corrected QT (QTc) interval >500 milliseconds or a QTc interval increase of ≥60 milliseconds from baseline. P/MC had no impact on PR or QRS interval. CONCLUSION: P/MC produces little impact on serum Mg(2+) levels with no clinically significant effect on cardiac conduction in patients, including those with mild-to-moderate renal impairment.

Review of the economic evaluations of hormonal therapy for patients with locally advanced prostate cancer.

Androgen deprivation therapy (ADT) is used as first-line therapy for locally advanced or metastatic prostate cancer aiming to reduce testosterone to castrate levels. The authors present an overview of the existing cost-effectiveness studies of ADT in prostate cancer. Cost-effectiveness of ADT was reviewed using a systematic search of the peer-reviewed literature, as well as research abstracts presented at various scientific and industry meetings. Most cost-effectiveness analyses of ADT reported results within the accepted societal threshold of US$50,000 cost/quality-adjusted life year needed to adopt new technology.

Cost-effectiveness analysis comparing degarelix with leuprolide in hormonal therapy for patients with locally advanced prostate cancer.

Degarelix, approved in the USA in 2008, is a gonadotropin-releasing hormone antagonist, representing one of the latest additions to androgen deprivation therapy (ADT). ADT is used as first-line therapy for locally advanced or metastatic prostate cancer with the aim to reduce testosterone to castrate levels. Like other gonadotropin-releasing hormone-antagonists, degarelix treatment results in rapid decrease in luteinizing hormone, follicle-stimulating hormone and testosterone levels without the associated risk of flare. Using one registration trial for degarelix with leuprolide as the active control, a cost-effectiveness analysis with a Markov model and a 20-year time horizon found the incremental cost-effectiveness ratio for degarelix to be US$245/quality-adjusted life years. Degarelix provides a cost-effective treatment for ADT among patients with locally advanced prostate cancer.

Mixed protocols: multiple ratios of FSH and LH bioactivity using highly purified, human-derived FSH (BRAVELLE) and highly purified hMG (MENOPUR) are unaltered by mixing together in the same syringe.

BACKGROUND: The use of mixed or blended protocols, that utilize both FSH and hMG, for controlled ovarian hyperstimulation is increasing in use. To reduce the number of injections a patient must administer, many physicians instruct their patients to mix their FSH and hMG together to be given as a single injection. Therefore, the goal of this study was to definitively determine if the FSH and LH bioactivities of highly purified, human-derived FSH (Bravelle) and highly purified hMG (Menopur) were altered by reconstituting in 0.9% saline and mixing in the same syringe. METHODS: Bravelle and Menopur were reconstituted in 0.9% saline and mixed in a Becton Dickinson plastic syringe. The FSH and LH bioactivities of the products were determined after injecting female and male rats, respectively, with Bravelle, Menopur, or a mixture of Bravelle and Menopur. Ratios of FSH:LH activity tested were 150:75 IU (1 vial Bravelle: 1 vial Menopur), 300:75 IU (3 vials Bravelle: 1 vial Menopur) or 300:225 IU (1 vial Bravelle: 3 vials of Menopur). RESULTS: There were no statistically significant changes in either FSH or LH bioactivity that occurred after mixing Bravelle with Menopur in the same syringe. The theoretical vs. actual FSH bioactivity for Bravelle and Menopur were 75 vs. 76.58 IU/mL and 75 vs. 76.0 IU/mL, respectively. For the 3 ratios of FSH:LH activity tested, 150:75 IU (1 vial Bravelle: 1 vial Menopur), 300:75 IU (3 vials Bravelle: 1 vial Menopur) or 300:225 IU (1 vial Bravelle: 3 vials of Menopur) tested, the theoretical vs. actual FSH bioactivities were 150 vs. 156.86 IU/mL, 300 vs. 308.69 IU/mL and 300 vs. 306.58 IU/mL, respectively. The theoretical vs. actual LH bioactivity for Menopur in the above mentioned ratios tested were 75 vs. 77.50 IU/mL. For the 3 ratios of FSH:LH activity tested, 150:75 IU (1 vial Bravelle: 1 vial Menopur), 300:75 IU (3 vials Bravelle: 1 vial Menopur) or 300:225 IU (1 vial Bravelle: 3 vials of Menopur), the theoretical vs. actual LH bioactivities were 75 vs. 78.38 IU/mL, 75 vs. 78.63 IU/mL and 225 vs. 233.48 IU/mL, respectively. CONCLUSION: Mixing human-derived FSH (Bravelle) with highly purified hMG (Menopur) in the same diluent, 0.9% NaCL, does not alter the FSH or LH bioactivity of either gonadotropin preparation.

A Markov model of the cost-effectiveness of human-derived follicle-stimulating hormone (FSH) versus recombinant FSH using comparative clinical trial data.

This study compared the cost and effectiveness of highly purified, human-derived follicle-stimulating hormone (FSH) (Bravelle) to recombinant FSH (Follistim) using Markov modeling and Monte Carlo simulation. One IVF treatment cycle resulted in costs of 11,584 dollars +/- 211 dollars for human-derived FSH and 12,762 dollars +/- 170 dollars for recombinant FSH, while three treatment cycles, holding the transition probabilities of the first cycle constant for the next two cycles, resulted in costs of 22,712 dollars +/- 1,107 dollars for human-derived FSH and 24,935 dollars +/- 1,205 dollars for recombinant FSH.

Evaluation of mixed protocols with Bravelle (human-derived FSH) and Repronex (hMG) to assess clinical efficacy (EMBRACE) in women undergoing in vitro fertilization.

OBJECTIVE: To compare the efficacy and safety of three different ratios of human-derived follicle-stimulating hormone/human menopausal gonadotropin (human-derived FSH:hMG, Bravelle and Repronex) mixed together in the same syringe and administered subcutaneously once daily, to in vitro fertilization (IVF) patients <34 years or 34 to 40 years of age. DESIGN: Two randomized, prospective, age stratified, IVF studies. SETTING: Twenty-one academic and private clinics with experience in IVF/embryo transfer (ET). PATIENT(S): Infertile premenopausal women undergoing IVF-ET. INTERVENTION(S): Pituitary suppression with leuprolide acetate, randomization to one of three treatment groups, followed by gonadotropin stimulation (GS) for up to 15 days. The human-derived FSH:hMG ratios were the following: Group 1, a 1:1 ratio throughout; Group 2, a 3:0 ratio that was changed to 1:1 after GS day 5; Group 3, a 2:1 ratio that was increased to 3:1, 4:1, or 5:1 after GS day 5, as needed. MAIN OUTCOME MEASURE(S): Mean number of oocytes retrieved; peak estradiol levels; dose and duration of stimulation; implantation rates; adverse events; injection site pain; and pregnancy and live birth rates. RESULT(S): Overall, women <34 years had higher E(2) levels, more oocytes retrieved, and improved implantation and live birth rates compared with women 34 to 40 years old. Nonetheless, each ratio of human-derived FSH:hMG produced comparable implantation rates, and continuing pregnancy and take-home baby rates. CONCLUSION(S): All three ratios of human-derived FSH:hMG in both age groups produced comparable pregnancy and live birth rates with similar safety results.

Highly purified human-derived follicle-stimulating hormone (Bravelle) has equivalent efficacy to follitropin-beta (Follistim) in infertile women undergoing in vitro fertilization.

BACKGROUND: These data compare the efficacy and safety of highly purified human-derived follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta (Follistim) in women undergoing in vitro fertilization. METHODS: This report describes the pooled data from two, nearly identical, randomized, controlled, parallel-group, multicenter studies conducted in a total of 19 academic and private IVF-ET centers in the United States. Infertile premenopausal women underwent pituitary down-regulation using leuprolide acetate followed by a maximum of 12 days of subcutaneous Bravelle (n = 120) or Follistim (n = 118), followed by administration of human chorionic gonadotropin, oocyte retrieval and embryo transfer. The primary efficacy measure was the mean number of oocytes retrieved; secondary efficacy measures included the total dose and duration of gonadotropin treatment; peak serum estradion levels; embryo transfer and implantation rates; chemical, clinical and continuing pregnancies; and live birth rates. All adverse events were recorded and injection site pain was recorded daily using a patient, self-assessment diary. RESULTS: Similar efficacy responses were observed for all outcome parameters in the two treatment groups. Although patients receiving Bravelle consistently reported a greater number of chemical, clinical and continuing pregnancies, as well as an increased rate of live birth, the data did not attain statistical significance (P > 0.05). The overall incidence of adverse events was similar in both groups, but compared to Follistim, injections of Bravelle were reported by patients to be significantly less painful (P < 0.001). CONCLUSIONS: Bravelle and Follistim had comparable efficacy in controlled ovarian hyperstimulation in women undergoing IVF-ET. There were no differences in the nature or number of adverse events between the treatment groups although Bravelle injections were reported to be significantly less painful.

Comparison of the efficacy and safety of a highly purified human follicle-stimulating hormone (Bravelle) and recombinant follitropin-beta for in vitro fertilization: a prospective, randomized study.

OBJECTIVE: To compare the efficacy and safety of Bravelle s.c., Bravelle i.m., and Follistim s.c. in patients undergoing controlled ovarian hyperstimulation for IVF-ET. DESIGN: Open-label, randomized, parallel group, multicenter study. SETTING: Eleven academic and private fertility clinics with experience in IVF-ET. PATIENT(S): Infertile premenopausal women with regular ovulatory menstrual cycles undergoing IVF-ET. INTERVENTION(S): Down-regulation with leuprolide acetate followed by up to 12 days of Bravelle s.c. (n = 60), Bravelle i.m. (n = 59), or Follistim s.c. (n = 58); hCG administration, oocyte retrieval, and ET. MAIN OUTCOME MEASURE(S): Mean number of oocytes retrieved; patients with ET, chemical, clinical and continuing pregnancies; mean peak serum E2 levels; adverse events and injection site pain scores. RESULT(S): There were no significant differences among treatment groups in mean number of oocytes retrieved, peak serum E2 levels, patients with ET, continuing pregnancies, or live births. There were no significant differences among the treatment groups in the number, nature, or intensity of adverse events. Patients treated with Bravelle s.c. or Bravelle i.m. experienced significantly less injection site pain than patients treated with Follistim s.c. CONCLUSION(S): Bravelle s.c. and Bravelle i.m. are comparable in efficacy and safety to Follistim s.c. in patients undergoing controlled ovarian hyperstimulation for IVF-ET.