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.

Recombinant Human Follicle-Stimulating Hormone Alfa Dose Adjustment in US Clinical Practice: An Observational, Retrospective Analysis of a Real-World Electronic Medical Records Database.

Purpose: To determine the pattern of dose adjustment of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) during ovarian stimulation (OS) for assisted reproductive technology (ART) in a real-world setting. Methods: This was an observational, retrospective analysis of data from an electronic de-identified medical records database including 39 clinics in the USA. Women undergoing OS for ART (initiated 2009-2016) with r-hFSH-alfa (Gonal-f® or Gonal-f RFF Redi-ject®) were included. Assessed outcomes were patients' baseline characteristics and dosing characteristics/cycle. Results: Of 33,962 ART cycles, 13,823 (40.7%) underwent dose adjustments: 23.4% with ≥1 dose increase, 25.4% with ≥1 dose decrease, and 8.1% with ≥1 increase and ≥1 decrease. Patients who received dose adjustments were younger (mean [SD] age 34.8 [4.58] years versus 35.9 [4.60] years, p<0.0001) and had lower BMI (25.1 [5.45] kg/m2 versus 25.5 [5.45] kg/m2, p<0.0001) than those who received a constant dose. The proportion of patients with non-normal ovarian reserve was 38.4% for those receiving dose adjustment versus 51.9% for those with a constant dose. The mean (SD) number of dose changes/cycle was 1.61 (0.92) for cycles with any dose adjustment, 1.72 (1.03) for cycles with ≥1 dose increase, 2.77 (1.00) for cycles with ≥1 dose increase and ≥1 decrease (n=2,755), and 1.88 (1.03) for cycles with ≥1 dose decrease. Conclusions: Dose adjustment during OS is common in clinical practice in the USA and occurred more often in younger versus older patients, those with a high versus non-normal ovarian reserve or those with ovulation disorders/polycystic ovary syndrome versus other primary diagnoses of infertility.

Live birth rates, infertility diagnosis, and infertility treatment in women with and without multiple sclerosis: Data from an administrative claims database.

BACKGROUND: Real-world data regarding live birth rates (LBRs) and infertility in women with multiple sclerosis (MS) are lacking. This study compared LBRs, infertility diagnoses, and infertility treatments in women with and without MS. METHODS: Using a retrospective US administrative claims database, patients 18-55 years with MS were matched 1:1 to patients without MS to compare LBRs, infertility diagnoses, and infertility treatments used between cohorts. RESULTS: Overall LBRs were lower in women with MS (n=96,937) versus women without (n=96,937; 5.0% vs 7.0%; p<0.0001). A greater proportion of women with MS than without had a diagnosis of infertility (8.5% vs 8.1%; p=0.0006). Fewer women with MS than without used any infertility treatment (1.0% vs 1.2%; p=0.0002). Among women with or without MS who received infertility treatments, no significant difference was observed in LBRs with oral (32.2% vs 31.5%; p=0.8536) or injectable (44.0% vs 49.3%; p=0.2603) treatment. CONCLUSION: Women with MS had a lower LBR, received more infertility diagnoses, and were less likely to receive infertility treatment than women without MS. There was no difference in LBRs following infertility treatment. Claims-data studies provide valuable exploratory analyses that reflect interactions between patients and the healthcare system.

The Human Oocyte Preservation Experience (HOPE) Registry: evaluation of cryopreservation techniques and oocyte source on outcomes.

BACKGROUND: This prospective, Phase IV, multicenter, observational registry of assisted reproductive technology clinics in the USA studied outcomes of first cycles using thawed/warmed cryopreserved (by slow-freezing/vitrification) oocytes (autologous or donor). METHODS: Patients were followed up through implantation, clinical pregnancy, and birth outcomes. The main outcome measure was live birth rate (LBR), defined as the ratio of live births to oocytes thawed/warmed minus the number of embryos cryopreserved for each cycle, averaged over all thawing cycles. Clinical pregnancy rate (CPR) was also evaluated, and was defined as the presence of a fetal sac with heart activity, as detected by ultrasound scan performed on Day 35-42 after embryo transfer. RESULTS: A total of 16 centers enrolled 204 patients; data from 193 patients were available for analyses. For donor oocytes, in the slow-freezing (n = 40) versus vitrification (n = 94) groups, respectively, CPR and LBR were significantly different: 32.4% versus 62.6%, and 25.0% versus 52.1%; outcomes from Day 3 transfers did not differ significantly. For vitrified oocytes, in the autologous (n = 46) versus donor (n = 94) group, respectively, CPR and LBR were significantly different: 30.0% versus 62.6% and 17.4% versus 52.1%. This was largely due to a significant difference in CPR with Day 5/6 transfers. CONCLUSIONS: In two subgroup data analyses, in women who received cryopreserved oocytes from donors, CPR and LBR were significantly higher in cycles using oocytes cryopreserved via vitrification versus slow-freezing, reflecting differences in methodologies and more Day 5/6 transfers; in women who received vitrified oocytes, CPR and LBR were significantly higher in cycles using donor versus autologous oocytes with Day 5/6 transfers. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00699400 . Registered June 13, 2008.

Human factors engineering and design validation for the redesigned follitropin alfa pen injection device.

OBJECTIVES: To demonstrate, using human factors engineering (HFE), that a redesigned, pre-filled, ready-to-use, pre-asembled follitropin alfa pen can be used to administer prescribed follitropin alfa doses safely and accurately. METHODS: A failure modes and effects analysis identified hazards and harms potentially caused by use errors; risk-control measures were implemented to ensure acceptable device use risk management. Participants were women with infertility, their significant others, and fertility nurse (FN) professionals. Preliminary testing included 'Instructions for Use' (IFU) and pre-validation studies. Validation studies used simulated injections in a representative use environment; participants received prior training on pen use. RESULTS: User performance in preliminary testing led to IFU revisions and a change to outer needle cap design to mitigate needle stick potential. In the first validation study (49 users, 343 simulated injections), in the FN group, one observed critical use error resulted in a device design modification and another in an IFU change. A second validation study tested the mitigation strategies; previously reported use errors were not repeated. CONCLUSIONS: Through an iterative process involving a series of studies, modifications were made to the pen design and IFU. Simulated-use testing demonstrated that the redesigned pen can be used to administer follitropin alfa effectively and safely.

Effect of tibolone and its metabolites on vascular endothelial growth factor isoforms 121 and 165 and thrombospondin-1 mRNA in Ishikawa cells.

OBJECTIVE: To compare the mRNA expression of vascular endothelial growth factor (VEGF) 121 and 165 isoforms and thrombospondin-1 (TSP-1) after incubation with tibolone and tibolone metabolites 3alpha-hydroxytibolone, 3beta-hydroxytibolone, Delta4-tibolone, and 17beta-estradiol (E2) in cultured Ishikawa cells. DESIGN: Ishikawa cells (immortalized from a well-differentiated human adenocarcinoma cell line) were cultured in vitro to confluence. Tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, Delta4-tibolone and E2 at concentrations of 1.0, 0.1 and 0.01 micromol/L were added to confluent cells and further cultured for an additional 24 h. Control cells were treated with medium in absence of hormone. Total RNA was extracted from control and treated Ishikawa cells. After reverse transcription, VEGF, TSP-1 and the housekeeping gene, beta-actin cDNAs, were amplified in a polymerase chain reaction spiked with 33p-dCTP. Relative abundance of VEGF 121 and 165 isoforms and TSP-1 mRNA was measured by scintillation spectroscopy. RESULTS: E2, tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone increased both VEGF 121 and 165 mRNA compared with the control. However, Delta4-tibolone had no effect on either VEGF 121 or 165 mRNA compared with the control. Delta4-Tibolone increased TSP-1 mRNA expression compared with control levels. E2, tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone did not increase TSP-1 mRNA expression at any concentration. CONCLUSIONS: Tibolone and the 3alpha- and 3beta-tibolone metabolites with E2 increased VEGF 121 and 165 isoforms. Conversely, Delta4-tibolone, which is reported to have progestational-like activity, did not stimulate VEGF 121 and VEGF 165 but increased TSP-1 mRNA synthesis in cultured Ishikawa cells. We hypothesize, based on these data, that the clinical finding of no endometrial growth in women using tibolone may be partly related to alterations in these angiogenic factors.

Evidence that anandamide-signaling regulates human sperm functions required for fertilization.

Ejaculated mammalian sperm require several hours exposure to secretions in female reproductive tracts, or incubation in appropriate culture medium in vitro, before acquiring the capacity to fertilize eggs. Arachidonylethanolamide (AEA), also known as anandamide, is a novel lipid-signal molecule that is an endogenous agonist (endocannabinoid) for cannabinoid receptors. We now report that AEA is present in human seminal plasma, mid-cycle oviductal fluid, and follicular fluid analyzed by high-performance liquid chromatography/mass spectrometry. Sperm are sequentially exposed to these reproductive fluids as they move from the vagina to the site of fertilization in the oviduct. Specific binding of the potent cannabinoid agonist [(3)H]CP-55,940 to human sperm was saturable (K(D) 9.71 +/- 1.04 nM), suggesting that they express cannabinoid receptors. R-methanandamide [AM-356], a potent and metabolically stable AEA analog, and (-)delta(9) tetrahydrocannabinol (THC), the major psychoactive constituent of Cannabis, modulated capacitation and fertilizing potential of human sperm in vitro. AM-356 elicited biphasic effects on the incidence of hyperactivated sperm motility (HA) between 1 and 6 hr of incubation: at (2.5 nM) it inhibited HA, while at (0.25 nM) it stimulated HA. Both AM-356 and THC inhibited morphological alterations over acrosomal caps between 2 and 6 hr (IC(50) 5.9 +/- 0.6 pM and 3.5 +/- 1.5 nM, respectively). Sperm fertilizing capacity, measured in the Hemizona Assay, was reduced 50% by (1 nM) AM-356. These findings suggest that AEA-signaling may regulate sperm functions required for fertilization in human reproductive tracts, and imply that smoking of marijuana could impact these processes. This study has potential medical and public policy ramifications because of the incidence of marijuana abuse by adults in our society, previously documented reproductive effects of marijuana, and the ongoing debate about medicinal use of marijuana and cannabinoids.