Dose accuracy of the follitropin alfa pen injector 2.0, the follitropin alfa:lutropin alfa 2:1 combination pen injector 2.0 and the choriogonadotropin alfa pen injector 1.0 used for fertility treatment.

BACKGROUND: This study aimed to confirm that the incremental dose/clicks system dispenses accurate doses for the Merck family of fertility pen injectors. RESEARCH DESIGN AND METHODS: Set doses (Vset) for three dose dial settings (minimum dose [Vmin], midpoint dose [Vmid] and maximum dose [Vmax] for the follitropin alfa, choriogonadotropin alfa [D2 classification: single use/variable dose], and follitropin alfa:lutropin-alfa 2:1 combination pen injectors) or a single Vset for the choriogonadotropin alfa (D1 classification: single use/single dose) were assessed. Last dose administered by the multi-dose device was assessed for the 900 IU, 450 IU, 300 IU and 150 IU follitropin alfa, and the 900:450 IU, 450:225 IU and 300:150 IU follitropin alfa:lutropin-alfa 2:1 combination pen presentations. RESULTS: Dose accuracy tests for Vmin, Vmid and Vmax for the follitropin alfa and the follitropin alfa:lutropin-alfa 2:1 combination pen injectors, and last dose administered, were within acceptable limits according to ISO 11,608-1:2012/2014. Dose accuracy tests for the single use/single dose device classification and the single use/variable dose device classification of the choriogonadotropin alfa pen injector were also within the acceptable limits, according to ISO 11608-1:2000/2014. CONCLUSIONS: The Merck family of fertility pen injectors functions reliably and the incremental dose/clicks system dispenses accurate doses.

Fine-tuning the dose of recombinant human follicle-stimulating hormone alfa to individualize treatment in ovulation induction and ovarian stimulation cycles: a real-world database analysis.

Introduction: Fine-tuning of injectable gonadotropin doses during ovulation induction (OI) or ovarian stimulation (OS) treatment cycles with the aim of using doses low enough to minimize the risk of excessive ovarian response while maintaining optimal efficacy may be facilitated by using an adjustable-dose pen injector. We examined the incidence and magnitude of individualized gonadotropin dose adjustments made during cycles of OI or OS, followed by either timed intercourse or intrauterine insemination, with or without oral medications, and assessed the relationship between patient characteristics and dosing changes using real-world evidence. Methods: This was an observational, retrospective cohort study using electronic medical records from a large US database of fertility centers. Data from patients who had undergone a first recombinant human follicle stimulating hormone alfa (r-hFSH-alfa/follitropin alfa) treated OI/OS cycle followed by timed intercourse or intrauterine insemination between 2015 and 2016 were included. Percentages of OI/OS cycles involving r-hFSH-alfa dose adjustments (in increments of ±12.5 IU or greater) with or without oral medications (clomiphene citrate or letrozole) were analyzed. Results: Of 2,832 OI/OS cycles involving r-hFSH-alfa administration, 74.6% included combination treatment with orals; 25.4% involved r-hFSH-alfa alone. As expected, the starting dose of r-hFSH-alfa was lower for cycles that used r-hFSH-alfa with orals than r-hFSH-alfa only cycles (mean [SD]: 74.2 [39.31] vs 139.3 [115.10] IU). Dose changes occurred in 13.7% of r-hFSH-alfa with orals versus 43.9% of r-hFSH-alfa only cycles. Dose adjustment magnitudes ranged from ±12.5 IU to ±450 IU. The smallest adjustment magnitudes (±12.5 IU and ±25 IU) were used frequently and more often for dose increases than for dose decreases. For r-hFSH-alfa with orals and r-hFSH-alfa only cycles, the smallest adjustments were used in 53.5% and 64.5% of cycles with dose increases and in 35.7% and 46.8% of cycles with dose decreases, respectively. Discussion: In OI/OS cycles followed by timed intercourse or intrauterine insemination, r-hFSH-alfa dose adjustments were frequent. In cycles that included orals, r-hFSH-alfa starting doses were lower and dose changes were fewer than with r-hFSH-alfa alone. Smaller dose adjustments facilitate individualized treatment with the goal of reducing the risks of multiple gestation, cycle cancellation, and ovarian hyperstimulation syndrome.

Economic Evaluation of Medically Assisted Reproduction: A Methodological Systematic Review.

BACKGROUND: Medically assisted reproduction (MAR) is a challenging application area for health economic evaluations, entailing a broad range of costs and outcomes, stretching out long-term and accruing to several parties. PURPOSE: To systematically review which costs and outcomes are included in published economic evaluations of MAR and to compare these with health technology assessment (HTA) prescriptions about which cost and outcomes should be considered for different evaluation objectives. DATA SOURCES: HTA guidelines and systematic searches of PubMed Central, Embase, WOS CC, CINAHL, Cochrane (CENTRAL), HTA, and NHS EED. STUDY SELECTION: All economic evaluations of MAR published from 2010 to 2022. DATA EXTRACTION: A predetermined data collection form summarized study characteristics. Essential costs and outcomes of MAR were listed based on HTA and treatment guidelines for different evaluation objectives. For each study, included costs and outcomes were reviewed. DATA SYNTHESIS: The review identified 93 cost-effectiveness estimates, of which 57% were expressed as cost-per-(healthy)-live-birth, 19% as cost-per-pregnancy, and 47% adopted a clinic perspective. Few adopted societal perspectives and only 2% used quality-adjusted life-years (QALYs). Broader evaluations omitted various relevant costs and outcomes related to MAR. There are several cost and outcome categories for which available HTA guidelines do not provide conclusive directions regarding inclusion or exclusion. LIMITATIONS: Studies published before 2010 and of interventions not clearly labeled as MAR were excluded. We focus on methods rather than which MAR treatments are cost-effective. CONCLUSIONS: Economic evaluations of MAR typically calculate a short-term cost-per-live-birth from a clinic perspective. Broader analyses, using cost-per-QALY or BCRs from societal perspectives, considering the full scope of reproduction-related costs and outcomes, are scarce and often incomplete. We provide a summary of costs and outcomes for future research guidance and identify areas requiring HTA methodological development. HIGHLIGHTS: The cost-effectiveness of MAR procedures can be exceptionally complex to estimate as there is a broad range of costs and outcomes involved, in principle stretching out over multiple generations and over many stakeholders.We list 21 key areas of costs and outcomes of MAR. Which of these needs to be accounted for alters for different evaluation objectives (determined by the type of economic evaluation, time horizon considered, and perspective).Published studies mostly investigate cost-effectiveness in the very short-term, from a clinic perspective, expressed as cost-per-live-birth. There is a lack of comprehensive economic evaluations that adopt a broader perspective with a longer time horizon. The broader the evaluation objective, the more relevant costs and outcomes were excluded.For several costs and outcomes, particularly those relevant for broader, societal evaluations of MAR, the inclusion or exclusion is theoretically ambiguous, and HTA guidelines do not offer sufficient guidance.

Dynamic in vitro culture of bovine and human ovarian tissue enhances follicle progression and health.

In vitro ovarian cortical tissue culture, followed by culture of isolated secondary follicles, is a promising future option for production of mature oocytes. Although efforts have been made to improve the culture outcome by changing the medium composition, so far, most studies used static culture systems. Here we describe the outcome of 7 days cultures of bovine and human ovarian cortical tissue in a dynamic system using a novel perifusion bioreactor in comparison to static culture in conventional and/or gas permeable dishes. Findings show that dynamic culture significantly improves follicle quality and viability, percentage and health of secondary follicles, overall tissue health, and steroid secretion in both species. Model predictions suggest that such amelioration can be mediated by an enhanced oxygen availability and/or by fluid-mechanical shear stresses and solid compressive strains exerted on the tissue.

The value of treatment for infertility: A systematic literature review of willingness-to-pay thresholds and approaches for determining the cost effectiveness of fertility therapies.

Willingness to pay (WTP) for an infertility treatment is the maximum amount of money a patient is willing to pay per treatment, or to achieve a live birth or pregnancy. Such thresholds are important to determine the cost effectiveness of a treatment. A systematic review was conducted to identify and explore the studies that attempt to ascertain WTP for infertility and compare them with the cost-effectiveness studies that claimed to use WTP thresholds. For comparison, all the costs were converted and inflated to 2021 euros. The results demonstrated that there were no standard outcomes or WTP thresholds for an outcome/treatment, and the methodologies used vary. Cost-effectiveness studies either used the incremental cost-effectiveness ratio to imply a WTP threshold, or used thresholds that were previously accepted for a quality-adjusted life year outcome converted, inappropriately, to an infertility outcome. There is a need for further research by health economists to develop a consensus for the meaningful assessment of WTP for ART.

Immunobiology of pregnancy: from basic science to translational medicine.

Embryo implantation failure and spontaneous abortions represent the main causes of infertility in developed countries. Unfortunately, incomplete knowledge of the multiple factors involved in implantation and fetal development keeps the success rate of medically assisted procreation techniques relatively low. According to recent literature, cellular and molecular mechanisms of 'immunogenic tolerance' towards the embryo are crucial to establish an 'anti-inflammatory' state permissive of a healthy pregnancy. In this review we dissect the role played by the immune system in the endometrial-embryo crosstalk, with a particular emphasis towards the fork-head-box-p3 (Foxp3+) CD4+CD25+ regulatory T (Treg) cells and discuss the most recent therapeutic advances in the context of early immune-mediated pregnancy loss.

Genetic Variants of Gonadotropins and Their Receptors Could Influence Controlled Ovarian Stimulation: IVF Data from a Prospective Multicenter Study.

BACKGROUND: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing assisted reproductive technologies (ARTs). Data regarding possible interactions of these polymorphisms are still scanty. The aim of this analysis was to evaluate the effect of polymorphisms of gonadotropins and their receptors in women undergoing ART. METHODS: A total of 94 normogonadotropic patients from three public ART units were enrolled. Patients underwent a gonadotropin releasing hormone (GnRH) long down-regulation protocol with a starting dose of 150 IU of recombinant follicular stimulating hormone (FSH) daily. Eight polymorphisms were genotyped. RESULTS: A total of 94 women (mean age 30.71 ± 2.61) were recruited. Fewer fertilized and mature oocytes were retrieved in homozygous carriers of luteinizing hormone/choriogonadotropin receptor (LHCGR) 291 (T/T) than in heterozygous C/T carriers (p = 0.035 and p = 0.05, respectively). In FSH receptor (FSHR) rs6165 and FSHR rs6166 carriers, the ratio between total gonadotropin consumption and number of oocytes retrieved differed significantly among three genotypes (p = 0.050), and the ratio was lower in homozygous A/A carriers than in homozygous G/G and heterozygous carriers. Women who co-expressed allele G in FSHR-29 rs1394205 and FSHR rs6166 and allele C LHCGR 291 rs12470652 are characterized by an increased ratio between total FSH dosage and number of oocytes collected after ovarian stimulation (risk ratio: 5.44, CI 95%: 3.18-7.71, p < 0.001). CONCLUSIONS: Our study demonstrated that specific polymorphisms affect the response to ovarian stimulation. Despite this finding, more robust studies are required to establish the clinical utility of genotype analysis before ovarian stimulation.

The impact of epigenetic landscape on ovarian cells in infertile older women undergoing IVF procedures.

The constant decline in fertility and older reproductive age is the major cause of low clinical pregnancy rates in industrialised countries. Epigenetic mechanisms impact on proper embryonic development in women undergoing in vitro fertilisation (IVF) protocols. Here, we describe the main epigenetic modifications that may influence female reproduction and could affect IVF success.

Biological Assay to Determine Gonadotropin Potency: From In Vivo to In Vitro Sustainable Method.

Various preparations of follicle-stimulating hormone (FSH) are commercially available; however, they differ in glycoforms composition and purity owing to their respective sources. Additional chemical/physical changes can also be introduced during manufacturing and can impact their biological activity (biopotency), which is routinely assessed using an in vivo bioassay (Steelman-Pohley). This study aimed to determine whether an in vitro bioassay could assess biopotency by distinguishing between r-hFSH chemical/physical variants with similar ability to the in vivo bioassay. The specific activity (units of biological activity per mg of product) of variants of r-hFSH generated through enrichment (acidic/basic), stress (oxidative/acidic pH) and enzymatic treatment (desialylation and desialylation/degalactosylation) was compared using the in vivo and in vitro bioassays. The in vitro bioassay reliably detected potential chemical/physical modifications in r-hFSH variants that may impact biopotency. Overall, the methods demonstrated a comparable ability to detect changes in specific activities due to chemical/physical differences in r-hFSH variants. These data indicate that the in vitro bioassay is suitable to replace the in vivo bioassay.