Recombinant follicle stimulating hormone: development of the first biotechnology product for the treatment of infertility. Recombinant Human FSH Product Development Group.
Genes encoding the common gonadotrophin alpha subunit and follicle stimulating hormone (FSH)-specific beta subunit were isolated from a DNA library derived from human fetal liver cells, and inserted into separate expression vectors containing a selectable/amplifiable gene. These vectors were inserted into the genome of the Chinese hamster ovary cell line, resulting in expression of large amounts of biologically active human (h)FSH. This cell line was cultured on microcarrier beads in a large-scale bioreactor. hFSH in the cell culture supernatant was purified to homogeneity by a multistep process. The mature beta subunit had seven fewer amino acid residues than reported in the literature and three other differences were found in the sequence. Similar oligosaccharide structures were present on recombinant (r)-hFSH and a purified urinary (u)-hFSH preparation. In-vitro and in-vivo, the biological activities of u- and r-hFSH were indistinguishable. r-hFSH was formulated in ampoules containing 75 IU FSH activity (approximately 7.5 microg FSH), which accounts for >99% of the protein content of the preparation. Studies in non-human primates and human volunteers showed the pharmacokinetics of u- and r-hFSH to be similar. In healthy volunteers, r-hFSH stimulated follicular development and induced significant increases in serum oestradiol and inhibin. Clinical experience with r-hFSH has shown it is more effective at stimulating ovarian follicle growth than urinary gonadotrophins. It is also effective at initiating spermatogenesis when given together with human chorionic gonadotrophin. (+info)
The clinical efficacy of low-dose step-up follicle stimulating hormone administration for treatment of unexplained infertility.
The present study was designed to compare the clinical efficacy of low-dose step-up follicle stimulating hormone (FSH) administration with conventional FSH protocol (FSH was injected daily starting with a dose of 150 IU), both combined with intrauterine insemination (IUI), for the treatment of unexplained infertility. A total of 97 unexplained infertility couples was randomly assigned to one or other of the two treatment groups, either conventional FSH with IUI (48 patients) or low-dose step-up FSH with IUI (49 patients), and only the first treatment cycle was evaluated in each protocol. The difference in pregnancy rates per cycle was not statistically significant between the low-dose FSH group and the conventional group [seven of 49 (14.3%) and seven of 48 (14.6%) respectively]. A significant reduction in the incidence of ovarian hyperstimulation syndrome (OHSS) was observed in the low-dose group (8.3% versus 27.1%, P < 0.05). The incidence of moderate OHSS requiring hospitalization was reduced significantly in the low-dose group (low-dose 0% versus conventional 16.7%, P < 0.01). However, the low-dose protocol did not completely prevent multiple pregnancies. Our results suggest that the low-dose step-up FSH treatment appeared to be useful for the treatment of unexplained infertility because of the high pregnancy rates and the significant decrease in the incidence of OHSS. (+info)
Infertility services and managed care.
The birth of the McCaughey septuplets in Iowa in November 1997 brought issues of fertility assistance and their potential outcomes to worldwide attention. This Pergonal-stimulated multiple pregnancy ended successfully, but not without health hurdles and economic consequences for the new siblings and their family. This article reviews the general situation surrounding infertility services and, within the current debate of epidemiological, economic, legal and social issues, posits that managed care may be able to make greater strides than the present fee-for-service system in providing more accessible and comprehensive care to the 5.3 million US citizens at risk for infertility. Our conclusions suggest that managed care plans for infertility can aid in assuring quality and decreasing unnecessary costs. Managed care organizations should take the lead in providing infertile couples with an organized, humanistic approach that is mindful of the attending social issues. On May 5, 1997, a US District court in Chicago ruled that infertility fits the definition of a disability, and thus is subject to the antidiscrimination enforcement under the Americans with Disabilities Act. (+info)
Parentage testing implications of male fertility after allogeneic bone marrow transplantation.
Fertility is expected to be reduced after the extensive chemotherapy and/or radiotherapy that is needed for conditioning prior to bone marrow transplantation. However, a male patient can be fertile, and in very rare situations such as reported here, this may confuse subsequent paternity testing. The patient, initially excluded as the biological father by red cell types but not by HLA, was subsequently included after the history of his previous marrow transplant was revealed, a review of the HLA results and further RFLP testing on buccal mucosal cells. This case points to the need for good history taking before performing paternity testing. (+info)
Effects of mutations in DNA repair genes on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae.
A cause of aging in Saccharomyces cerevisiae is the accumulation of extrachromosomal ribosomal DNA circles (ERCs). Introduction of an ERC into young mother cells shortens life span and accelerates the onset of age-associated sterility. It is important to understand the process by which ERCs are generated. Here, we demonstrate that homologous recombination is necessary for ERC formation. rad52 mutant cells, defective in DNA repair through homologous recombination, do not accumulate ERCs with age, and mutations in other genes of the RAD52 class have varying effects on ERC formation. rad52 mutation leads to a progressive delocalization of Sir3p from telomeres to other nuclear sites with age and, surprisingly, shortens life span. We speculate that spontaneous DNA damage, perhaps double-strand breaks, causes lethality in mutants of the RAD52 class and may be an initial step of aging in wild-type cells. (+info)
The Caenorhabditis elegans mel-11 myosin phosphatase regulatory subunit affects tissue contraction in the somatic gonad and the embryonic epidermis and genetically interacts with the Rac signaling pathway.
Caenorhabditis elegans embryonic elongation is driven by cell shape changes that cause a contraction of the epidermal cell layer enclosing the embryo. We have previously shown that this process requires a Rho-associated kinase (LET-502) and is opposed by the activity of a myosin phosphatase regulatory subunit (MEL-11). We now extend our characterization and show that mel-11 activity is required both in the epidermis during embryonic elongation and in the spermatheca of the adult somatic gonad. let-502 and mel-11 reporter gene constructs show reciprocal expression patterns in the embryonic epidermis and the spermatheca, and mutations of the two genes have opposite effects in these two tissues. These results are consistent with let-502 and mel-11 mediating tissue contraction and relaxation, respectively. We also find that mel-11 embryonic inviability is genetically enhanced by mutations in a Rac signaling pathway, suggesting that Rac potentiates or acts in parallel with the activity of the myosin phosphatase complex. Since Rho has been implicated in promoting cellular contraction, our results support a mechanism by which epithelial morphogenesis is regulated by the counteracting activities of Rho and Rac. (+info)
How concordant are the estimated rates of natural conception and in-vitro fertilization/embryo transfer success?
Knowledge of the chance to conceive for the subfertile couple is important in the process of counselling and clinical decision making. There are no data available on the reproducibility of the clinician's ability to assess the chance to conceive, both after expectant management or treatment with in-vitro fertilization and embryo transfer (IVF-embryo transfer). We evaluated this reproducibility by means of a set of case histories presented to a panel of gynaecologists and endocrinologists. A poor reproducibility would indicate a strong need for the use of prognostic models. In 1995, 57 gynaecologists and 32 reproductive endocrinologists were asked to appraise the 1 year spontaneous conception chance as well as the cumulative success rate of three cycles for IVF-embryo transfer of four couples with different medical histories. The clinical and laboratory data of these couples were presented as case histories. The difference between the estimated spontaneous pregnancy chances and the success rate of IVF-embryo transfer was also calculated. Calculation of intra-class correlation coefficients, which can be considered as measures of the reproducibility, demonstrated a substantial reproducibility of the assessment of spontaneous conception chances, but a slight to fair reproducibility of the assessment of IVF-embryo transfer success rates. We conclude that the use of reliable prognostic models for IVF-embryo transfer in the management of subfertility is warranted. (+info)
Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome.
A total of 811 intrauterine insemination (IUI) cycles in which clomiphene citrate/human menopausal gonadotrophin (HMG) was used for ovarian stimulation were analysed retrospectively to identify prognostic factors regarding treatment outcome. The overall pregnancy rate was 12.6% per cycle, the multiple pregnancy rate 13.7%, and the miscarriage rate 23.5%. Logistic regression analysis revealed five predictive variables as regards pregnancy: number of the treatment cycle (P = 0.009), duration of infertility (P = 0.017), age (P = 0.028), number of follicles (P = 0.031) and infertility aetiology (P = 0.045). The odds ratios for age < 40 years, unexplained infertility aetiology (versus endometriosis) and duration of infertility < or = 6 years were 3.24, 2.79 and 2.33, respectively. A multifollicular ovarian response to clomiphene citrate/HMG resulted in better treatment success than a monofollicular response, and 97% of the pregnancies were obtained in the first four treatment cycles. The results indicate that clomiphene citrate/HMG/IUI is a useful and cost-effective treatment option in women < 40 years of age with infertility duration < or = 6 years, who do not suffer from endometriosis. (+info)