Standardization of therapeutic, urinary gonadotrophins: an update on the use and availability of International Standards for Menotrophin.

The potencies of therapeutic preparations of gonadotrophins of human, urinary origin, which comprise a heterogenous mix of isoforms with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) bioactivities, are standardized by WHO International Standards (IS). We report here, the evaluation, through an international collaborative study, of a candidate preparation, coded 10/286, to replace the 4th IS, 98/704, for human, urinary FSH and LH (Menotrophin) which has been used for many years for the potency assignment of therapeutic preparations using bioassays. The mean FSH and LH bioactivities of 10/286, determined by in vivo bioassays in terms of 98/704, were 183 IU per ampoule (95% confidence limits 165-202) and 177 IU per ampoule (95% confidence limits 159-197), respectively.

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.

Comparative assessment of the consistency and quality of a highly purified FSH extracted from human urine (urofollitropin) and a recombinant human FSH (follitropin alpha).

The revolutionary development of biotechnology-derived therapeutic proteins has provided the expected improvements in quality, purity and consistency, as demonstrated in recombinant human FSH (rhFSH). However, the development of urine-derived gonadotrophins has not always shown comparable improvements. More recently, highly purified urine-derived FSH (uFSH-HP) products have become widely available. The relative purity, level of urine-derived contaminants, and consistency of one such highly purified human uFSH (uhFSH) (urofollitropin) has been assessed and directly compared with rhFSH (follitropin alpha). It has been demonstrated that the highly purified urofollitropin contains variable levels of urine-derived contaminant proteins and demonstrates a variable level of FSH purity, FSH isoforms, and delivered dose. These variable factors may contribute to the control of ovarian stimulation. The relative purity, variable consistency and the presence of contaminants indicates that the urofollitropin is, at best, a partially purified uFSH that is not able to meet the quality attributes of follitropin alpha (rhFSH).

Recombinant gonadotrophins in reproductive medicine: gold standard for ovarian stimulation therapy in the 21st century.

The clinical use of gonadotrophin preparations started in the 1960s when it was possible to extract human menopausal gonadotrophins from urine of post-menopausal women. Recombinant gonadotrophins became available in 1995. Whereas in other therapeutic areas the introduction of pure, recombinant preparations such as insulin and growth hormone has lead to rapid phasing out of biological extraction-based therapies, this is different for gonadotrophins. It is difficult to understand why even today women are exposed to urinary products although the benefits of recombinant gonadotropohins in terms of safety are obvious.

Recombinant follicle-stimulating hormone: gold standard or not?

Recombinant follicle stimulating hormone has been available now for almost 10 years and many couples have benefited from its use. Its clinical efficacy, purity and safety profile have been extensively documented in numerous publications. Because of growing public concerns on the safety of gonadotrophins extracted from human urine, the future will lie in the recombinant technology, which will also enable the design of more convenient tailor-made gonadotrophins.

Respective efficacy of gonadotrophins should be the heart of the debate.

Recombinant gonadotrophins offer future advances in reproductive medicine. It is questionable whether they produce more pregnancies than urinary gonadotrophins. No doubt future advances will permit this goal, but this has not yet been attained.

Recombinant or urinary gonadotrophins - an Australian perspective.

The Australian experience of gonadotrophin stimulation is a useful example of steps that lead to a country deciding to use recombinant FSH solely.

Factors influencing response to ovarian stimulation.

Ovarian stimulation is an integral part of assisted reproduction treatments. Ovarian response to gonadotrophin treatment, besides other factors, determines the outcome of treatment, as the number and quality of oocytes retrieved are related to the chance of achieving a pregnancy. A number of factors have been identified that might predict ovarian response, such as age of the patient and antral follicle count. In addition, it has been shown that genetic factors such as the patient's FSH-receptor genotype also determine individual response to FSH treatment. Besides patient-related factors, the choice of drugs for ovarian stimulation plays a significant role. Until recently, biopotency of gonadotrophin preparations was tested by an in-vivo bioassay with an intrinsic variability up to 20%. Due to a superior manufacturing technique, follitropin alpha can now be filled by mass. This allows assessment of FSH with a precise SE-HPLC assay and variability of the FSH content between production lots has now been estimated at 1.6%. Results of recent studies indicate that treatment with follitropin alpha filled by mass results in consistent ovarian response, fewer treatment days and fewer cancelled cycles. This is an important step towards further minimizing drug-related variability of ovarian response to FSH treatment.

Prevention of menstruation with leuprorelin (GnRH agonist) in women undergoing myelosuppressive chemotherapy or radiochemotherapy for hematological malignancies: a pilot study.

Vaginal bleeding during aplasia can induce transfusion support, infection and discomfort. Oral and intramuscular hormonotherapy can be toxic and/or difficult to manage (mucositis). This single-center pilot study evaluated the efficacy and safety of leuprorelin (L) in preventing heavy vaginal bleeding in 20 nonmenopausal women with leukemia, lymphoma or myeloma and foreseable therapy-induced thrombocytopenia. Until platelet recovery, patients received subcutaneous injections of L, with concomitant nomegestrol acetate (NA) during the first 35 days to prevent flare-up. Median age was 33 years (18-48). Platelet nadir was < 20 x 10(9)/l in 17 patients; 103 L injections were performed (median per patient: 4 [1-14]). No moderate or severe adverse event was related to hormonal therapy. Seventeen patients did not experience any clinically or therapeutically relevant bleeding. Eleven spottings and 8 metrorrhagias (mean duration: 3 days) occurred in 11 patients, requiring enhanced NA in 3 cases (baseline platelet count was < 20 x 10(9)/l in 1 pt, premature termination of NA [the single platelet transfusion for metrorrhagia] in 1 pt, and endometrial hyperplasia (EH) in the third). In patients without EH, only 5 spottings were observed after the third injection, without neither clinical nor therapeutic impact (63 injections). In conclusion, leuprorelin administration is safe and effective in preventing vaginal bleeding. The sustained-release form and subcutaneous administration offer quality of life advantages.

A comparison of the effects of progesterone sponges and ear implants, PGF2alpha, and their combination on efficacy of estrus synchronization and fertility of Mashona goat does.

Efficacy of estrus synchronization and fertility after synchronization of 60 multiparous Mashona goat does using intravaginal progesterone (P4) sponges (Group 1), norgestomet ear implants (Group 2), cloprostenol (Group 3), or a combination of P4 sponges and cloprostenol (Group 4) was compared with untreated does (Group 5). At the end of treatments, all does were mated to intact fertile bucks for 21 d. The number of does bred within 11 to 96 h was significantly higher (P < 0.05) in the treated groups than the untreated control, with rates of 80, 80, 64, 67 and 30% for Groups 1 to 5, respectively. There were no differences (P > 0.05) among treated does. Kidding rates ranged from 64 to 83% but were not different (P > 0.05) between groups. Prolificacy and overall fecundity were similar (P > 0.05) among the groups. The results indicate that all 4 treatment methods were effective in synchronizing estrus and that none of the methods affected overall fertility of the does.

Treatment-related and treatment-independent deliveries among infertile couples, a long-term follow-up.

BACKGROUND: The aim of this hospital based long-term follow-up study was to further elucidate resolved and unresolved infertility in relation to risk factors and perinatal outcome considering treatment-related and treatment independent pregnancies. METHODS: The study included all couples attending the out-patient clinic of the Department of Gynecology in Umeå due to failure to initiate a pregnancy after at least 12 months during the period 1.1.1980-31.12.1989. Data from the Swedish Medical Birth Registry consisting of all registered births during 1.1.1980-31.12.1992 was linked to establish the number of children born. RESULTS: Six hundred and ninety-one couples were analyzed, out of which 42% had a delivery outcome. Of these women, 53% conceived in relation to given treatment whereas 47% conceived treatment-independently. Women with ovulatory disorder had a cumulative delivery rate of 82%, whereas those with unexplained infertility and tubo-peritoneal pathology displayed delivery rates of 57% and 31% respectively. Duration of infertility > 3 years was the major negative prognostic factor among patients with unexplained infertility. The frequency of premature deliveries, low birth weight and perinatal mortality was increased among patients with treatment related pregnancies. CONCLUSION: For ovulatory disorders the prognosis for a resolved infertility is good. The results among patients with tubo-peritoneal pathology emphasizes the need of in vitro fertilization in modern treatment of infertility. Unexplained infertility is accompanied with a high rate of spontaneous pregnancies but prolonged duration is a negative prognostic factor for these patients. Irrespective of diagnosis, the perinatal outcome is worse in patients with treatment-related pregnancies.

Evaluation of different ovarian stimulation protocols for in vitro fertilization.

In this study we evaluated retrospectively the efficacy of five different ovarian stimulation protocols in an in vitro fertilization program, in which 512 women were involved. Ovulation was induced by the following protocols: group I (271 cycles): buserelin short protocol (1 mg/day, intranasally) with human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG); group II (45 cycles): buserelin (short protocol) with pure follicle stimulating hormone (p-FSH)/hMG/hCG; group III (24 cycles): clomiphene citrate (100 mg/day) with hMG/hCG; group IV (122 cycles): hMG (3 ampules/day) and hCG; group V (113 cycles): hMG/hCG and prednisolone (7.5 mg/day) after cycle programming with oral contraceptives. The lowest cancellation rate (3.3%) was noted in group I, followed by group V (9.7%). The highest number of follicles was observed in groups I (8.3 +/- 0.3; mean +/- SEM) and V (7.8 +/- 0.5). Also, more oocytes were retrieved in group I (7.2 +/- 0.3, p < 0.001), which were of good quality based on oocyte maturity as well as on the fertilization rate, and more embryos (4.5 +/- 0.3, p < 0.05) were developed. The correlation between estradiol and the total follicular volume on the day of hCG administration was also examined in the five groups. The best correlation (r = 0.6502) was found in group I, followed by group V (r = 0.5810). Significant differences were observed in the five groups with regard to the number of hMG ampules administered (p < 0.0001, F = 15.393) and the stimulation days (p < 0.0001, F = 35.32). Sixty-six clinical pregnancies were achieved: 37 (17.5%) in group I, seven (25.9%) in group II, one (10%) in group III, ten (15.6%) in group IV and 11 (15.5%) in group V (differences were not statistically significant). In conclusion, all five protocols were satisfactory in ovarian stimulation for in vitro fertilization, and gonadotropin releasing hormone (GnRH) analogs seemed to be more advantageous by reducing the cancellation rate, enhancing the number of oocytes retrieved and embryos developed and by improving the pregnancy rates.