Safety of Follitropin Alfa/Lutropin Alfa for Stimulation of Follicular Development.

INTRODUCTION: Recombinant human luteinizing hormone (r-hLH) is used in a fixed-ratio combination with recombinant human follicle-stimulating hormone (r-hFSH) for the stimulation of follicular development. OBJECTIVE: The objective of this article was to conduct a review of safety data to evaluate the risks of r-hFSH/r-hLH treatment. METHODS: Data were retrieved from the Global Safety Database (Merck KGaA, Darmstadt, Germany) including reports from healthcare professionals, patients, health authorities, clinical trials, non-interventional studies, and the literature. Reports of important risks (identified and potential) as per the risk management plan applicable at the time of data retrieval were obtained up to December 2017. The estimated patient exposure to r-hFSH/r-hLH in the post-marketing setting was 427,012 treatment cycles. Nine hundred patients received r-hFSH/r-hLH during company-sponsored clinical trials (pre- and post-marketing). RESULTS: We identified 72 case reports describing important risks related to r-hFSH/r-hLH use, including 46 cases of ovarian hyperstimulation syndrome (10.8 per 100,000 treatment cycles) and 24 of hypersensitivity reaction (5.6 per 100,000 treatment cycles). No thromboembolic events were reported. One congenital anomaly, not suspected to be related to r-hFSH/r-hLH use, was reported during a clinical trial; the event was resolved by corrective surgery. Two fatal cases were identified; one case of recurrent malignant melanoma (suspected to be related to r-hFSH/r-hLH use) and one case resulting from complications of ovarian hyperstimulation syndrome. CONCLUSION: Cumulative reporting rates of important identified and potential risks of r-hFSH/r-hLH during a 10-year surveillance period demonstrate the benefit-risk balance is positive. This post-marketing surveillance and continued surveillance of safety events should provide reassurance about the use of r-hFSH/r-hLH in clinical practice.

An observational study of assisted reproductive technology outcomes in new European Union member states: an overview of protocols used for ovarian stimulation.

BACKGROUND: The development of new fertility treatment options has facilitated individualized assisted reproductive technology (ART) protocols to improve outcomes. Manufacturing improvements to recombinant human follitropin alfa have allowed precise dosing based on mass (filled-by-mass; FbM) rather than bioactivity (filled-by-bioassay; FbIU). Continued monitoring and reporting of follitropin alfa treatment outcomes in routine clinical practice is essential. OBJECTIVE: To provide an overview of the frequency of different controlled ovarian-stimulation protocols used in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles in new European Union member states, and to provide post-registration efficacy and safety data on follitropin alfa. RESEARCH DESIGN AND METHODS: A 2-year, prospective, observational, multicentre, Phase IV study conducted at ART clinics in the Czech Republic, Estonia, Latvia, Lithuania, Poland, Slovakia and Slovenia. Women aged 18-47 years undergoing ovarian stimulation with follitropin alfa for conventional IVF or ICSI were eligible for inclusion. The main treatment outcome was cumulative clinical pregnancy rate. Data were analysed descriptively. RESULTS: Clinical pregnancy outcomes were available for 4055 of 4085 (99.3%) patients. In total, 1897 (46.8%) patients used follitropin alfa FbIU; 2133 (52.6%) used follitropin alfa FbM. Clinical pregnancy was achieved by 39.5% (1603/4055) of patients. A greater proportion of patients with polycystic ovary syndrome achieved a clinical pregnancy than those with endometriosis (41.8% vs 37.8%, respectively). A higher cumulative pregnancy rate was observed with the use of follitropin alfa FbM than follitropin alfa FbIU (41.3% vs 37.8%, respectively; p = 0.02). CONCLUSIONS: This study represents the most comprehensive audit of individualized ART in clinical practice in Central and Eastern Europe. Overall, clinical pregnancy was achieved by 39.5% of patients after stimulation with follitropin alfa. The use of follitropin alfa FbM resulted in a higher cumulative pregnancy rate than did the FbIU formulation. However, limitations of the study include the observational and non-comparative study design, and descriptive nature of statistical analyses; furthermore, the study was not designed to make direct comparisons between the success rates of different ovarian-stimulation protocols.

Safety and efficacy of mixing cetrorelix with follitropin alfa: a randomized study.

OBJECTIVE: To assess the safety and efficacy of mixing cetrorelix with follitropin alfa (rFSH) in assisted reproductive technology. DESIGN: Prospective, randomized study. SETTING: An IVF center in a teaching hospital. PATIENT(S): One hundred forty patients undergoing intracytoplasmic sperm injection were randomized into mixed (M) or separate (S) injection groups. INTERVENTION(S): In the M group, rFSH and cetrorelix were mixed immediately before administration, whereas in the S group, rFSH and cetrorelix were administered separately. MAIN OUTCOME MEASURE(S): The primary efficacy end point was the incidence of premature LH surge. The secondary efficacy endpoints included estradiol levels on the day of hCG injection, numbers of oocytes obtained, implantation, and ongoing pregnancy rates. The safety endpoints included ovarian hyperstimulation syndrome, and adverse events related to injections including local tolerability. RESULT(S): Excluding eight patients who dropped out of the study, there were 66 patients in each group for analysis. Patients in the M group received significantly fewer injections than patients in the S group (9.1 vs. 13.9). Other outcome parameters, including incidences of premature LH surge, numbers of oocytes retrieved, fertilization, implantation, and ongoing pregnancy rates were similar between the two groups. CONCLUSION(S): Cetrorelix and rFSH can be mixed together without compromising their reported safety and efficacy. This observation is in line with the reported safety and efficacy profile of the products listed in their current package inserts.

Outcomes of new quality standards of follitropin alfa on ovarian stimulation: meta-analysis of previous studies.

BACKGROUND: Human follicle-stimulating hormone (hFSH; follitropin alfa) can be employed therapeutically to induce ovarian follicular development in assisted reproduction treatments. Current recombinant hFSH (r-hFSH) preparations available for clinical use are labeled either in terms of the bioactivity expressed in international units (IU) or in mass (microg). Several clinical trials have tried to assess the clinical implications of the physicochemical improvements in the dosing of follitropin alfa filled by mass (FbM). The aim of this study was to perform a meta-analysis of previous studies in order to assess the efficacy and safety of ovarian stimulation using follitropin alfa FbM compared with follitropin alfa filled by international units (FbIU). METHODS: A literature search was carried out in scientific databases to find published articles and abstracts comparing both hormone preparations. A fixed effects model meta-analysis was performed. The variables studied include the average dose (IU), days of treatment, estradiol peak, follicles >14 mm, number of extracted oocytes, number of embryos obtained, number of cases of ovarian hyperstimulation syndrome (OHSS), and clinical pregnancies. RESULTS: A total of six studies met the stated criteria and were included in the meta-analysis. In these studies, the average r-hFSH dose per patient was 230.29 IU less with administration of follitropin alfa FbM compared with FbIU, and the number of days of treatment was reduced by 0.48. In addition, a significantly greater number of oocytes (0.84) were extracted, more embryos (0.88) were obtained, and a higher peak level of estradiol (613.08 pmol/L) was achieved in the patients undergoing ovarian stimulation with follitropin alfa FbM. However, no statistically significant differences were observed in the number of follicles >14 mm, clinical pregnancies, or OHSS cases. CONCLUSION: Follitropin alfa FbM, a technologically modified formulation of r-hFSH, is as safe as follitropin alfa FbIU but requires a smaller dose over a shorter period to produce more oocytes and final embryos.

Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f): long-term treatment in azoospermic men with hypogonadotropic hypogonadism.

OBJECTIVE: To demonstrate the efficacy and safety of follitropin alfa administered with hCG on spermatogenesis in adult male hypogonadotropic hypogonadism (HH) patients. DESIGN: Phase III, multicenter, open-label, noncomparative. SETTING: Seven US medical centers. PATIENT(S): A total of 36 adult males with severe HH. INTERVENTION(S): A total of 1,000 U hCG on alternate days for 3 to 6 months, with dose adjustments after 2 months, if necessary, to normalize T levels, followed by follitropin alfa 150 U and hCG on the same alternate days for 18 months, with dose adjustments as necessary. MAIN OUTCOME MEASURE(S): Proportion of patients with sperm density > or =1.5 x 10(6)/mL. Pubertal advancement and long-term safety and tolerability were also evaluated. RESULT(S): In total, 22 of 29 patients (75.9%) who received > or =1 dose of follitropin alfa and 20 of 25 patients (80%) who completed 18 months of hCG + follitropin alfa treatments achieved a sperm concentration > or =1.5 x 10(6)/mL. A sperm concentration >20 x 10(6)/mL was achieved by 8 of 29 men (27.5%). Median sperm concentration at 18 months was 5.2 x 10(6)/mL. Pubertal development continued during the study, and testis volumes increased. Five clinical pregnancies were achieved. Acne (52% of patients) was the most common side effect, and gynecomastia was reported in 10% of patients. CONCLUSION(S): Long-term treatment of azoospermic HH men using follitropin alfa and hCG is effective for stimulating spermatogenesis and is well-tolerated.

A comparison of the efficacy, tolerability, and convenience of two formulations of follitropin-alpha in Iranian woman undergoing intracytoplasmic sperm injection cycles.

OBJECTIVE: To compare the efficacy, tolerability, and convenience of two formulations of the follitropin-alpha (Gonal-f) pen device versus the conventional form in Iranian women undergoing ovarian stimulation for intracytoplasmic sperm injection. DESIGN: Randomized, single-center trial, parallel-group, single blind. SETTING: Tertiary referral center, University Hospital. PATIENT(S): A total of 100 patients undergoing intracytoplasmic sperm injection. INTERVENTION(S): After down-regulation with busereline acetate, patients were randomized to receive the pen device or the conventional syringe of follitropin-alpha. A computer-generated randomization list was used to allocate the patients to one of these two groups. MAIN OUTCOME MEASURE(S): The primary outcomes were patients' satisfaction, convenience, occurrence of local tolerance symptoms, and pain. Total dose of follitropin-alpha, duration of follitropin-alpha treatment, number of oocyte retrieved, number of viable embryos, and clinical pregnancies were secondary outcome measures. Data collection was performed by means of a questionnaire designed for the purpose of this study. The pain scored according to the Visual Analogue Scale. RESULT(S): Self-administration and patients' satisfaction were significantly higher in the pen device group than the conventional syringe group. Local reactions at injection sites and pain were significantly higher in the conventional syringe group than in the pen device group. There were no statistically differences in secondary outcome measures and convenience between two groups. CONCLUSION(S): Among the Iranian patients that we studied, the pen device of Gonal-f is safe, convenient, and less painful, with more patients' satisfaction than the conventional syringe form, but both forms have equal efficacy in intracytoplasmic sperm injection cycles.

[Ischemic cerebral infarction in a young woman undergoing gonadotropin treatment for infertility]. / Iskaemisk cerebralt infarkt hos en ung kvinde i behandling med gonadotropin på grund af infertilitet.

We describe a case of a 27-year-old previously healthy woman with a homonymous hemianopsia caused by thrombosis of a branch of the posterior cerebral artery. The woman had been treated with gonadotropin due to infertility and gone through in vitro fertilisation before the symptoms started. She was pregnant in the first trimester when we first saw her. We did not find any predisposing factors, and the clinical examination, including biochemical analysis, MRI arteriography and echocardiography, did not reveal any cause for the cerebral infarction (CI). The risk of CI during pregnancy itself is less than among non-pregnant women (0, 7) but increases in the postpartum period (8, 7). The cause of cerebral infarction in this case was idiopathic, but we must be aware of the possible link between treatment with gonadotropin for infertility and the development of cerebral infarction.

Transexualismo / Transsexualism

La demanda para la cirugía de reasignación de sexo en pacientes transexuales ha aumentado considerablemente. Los transexuales desean vivir permanentemente como miembros del sexo opuesto. Este deseo, acompañado de un profundo rechazo de sus propios caracteres sexuales primarios y secundarios, es absoluto, sofocante e inmodificable. Como consecuencia de este comportamiento psicológico, la persona transexual busca realizarse corrigiendo la apariencia sexual de su cuerpo mediante métodos quirúrgicos y farmacológicos. En 1979 se creó la Harry Benjamin International Gender Dysphoria Association, que recomendó unas directrices asistenciales que sirvieran de base para atender los trastornos de identidad de género. El tratamiento hormonal representa un importante papel en el proceso, que debe eliminar, idealmente, los caracteres sexuales secundarios del sexo original e inducir los del sexo opuesto tan rápida y completamente como sea posible. Hay tendencia a tomar hormonas cuanto antes y a maximizar las dosis, usando diversas pautas aprendidas de la experiencia de otros transexuales. Esta forma de automedicación con esteroides sexuales incrementa el riesgo de efectos adversos. La aproximación a este trastorno es compleja. Para atenderlo es necesario un equipo multidisciplinario en el marco de la medicina pública, dentro del Sistema Nacional de Salud. Los beneficios son evidentes: mejora la calidad de vida del paciente y su nivel de satisfacción y, desde el punto de vista médico, son importantes los beneficios del tratamiento hormonal y el éxito del tratamiento quirúrgico a corto y a largo plazo (AU)

Lutropin alfa: new preparation. Combined with follitropin for follicular development: no better than menotropin.

(1) The reference ovarian stimulant for women with severe FSH and LH deficiency and pituitary dysfunction is menotropin (postmenopausal urinary human gonadotrophin (hMG)). (2) A recombinant LH, lutropin alfa, has now been licensed for this use, in combination with recombinant FSH (follitropin alfa or follitropin beta). The evaluation file contains no data from trials comparing the follitropin-lutropin alfa combination with menotropin. (3) Two dose-finding studies involving a total of 78 women, and a double-blind trial comparing follitropin + placebo with follitropin + lutropin alfa, have shown that 75 IU/day lutropin alfa yields satisfactory follicular development in two-thirds of women whose plasma LH concentration is below 1.2 IU/I. Efficacy has not been demonstrated in women with higher plasma concentrations of LH. Similar results have been reported with menotropin. (4) The adverse effect profile of the follitropin + lutropin alfa combination is similar to that of menotropin. The main risk is an ovarian hyperstimulation syndrome. Monitoring of plasma estradiol concentrations, pelvic ultrasound findings, and clinical state are required to avoid severe ovarian hyperstimulation. There is no evidence that the risk differs between menotropin and the follitropin + lutropin alfa combination at adjusted doses. (5) In France, the combination of follitropin alfa + lutropin alfa costs about five times more than menotropin. (6) Menotropin remains the first line ovarian stimulant for women with severe deficiency of FSH and LH.