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Human gonadotrophin preparations have been used in the treatment of infertility for almost four decades. The earliest preparations were derived from urine from postmenopausal women and contained approximately equal amounts of follicle stimulating hormone (FSH) and luteinizing hormone (LH) activities. However, with the recognition that FSH is the principal regulator of follicular growth and maturation, these have been largely superseded by highly purified urinary FSH preparations and, more recently, recombinant human FSH (r-hFSH). Because of its complexity, r-hFSH is expressed in mammalian cells grown in culture and, from a manufacturing stand point, offers superior purity and batch-to-batch consistency, compared with urinary preparations. A number of clinical trials have compared the efficacy of r-hFSH and urinary FSH in women undergoing assisted reproductive technologies (ART). In general, these have shown that fewer FSH ampoules are required to achieve ovarian stimulation with r-hFSH, while the number of oocytes retrieved and embryos produced are higher than with urinary FSH. Additionally, the results of a recent meta-analysis have also shown that the clinical pregnancy rate per cycle started is significantly higher with r-hFSH, compared with urinary FSH. Furthermore, in poor responder patients, higher implantation rates were seen in patients treated with r-hFSH than in those treated with urinary FSH, suggesting that embryo viability is increased following use of the recombinant preparations. The finding that FSH preparations produce effective ovarian stimulation compared to human menopausal gonadotrophins in women undergoing ART raises the question of whether LH is required for ovarian stimulation. This has been investigated in a number of recent studies. For example, results have suggested that implantation rates may actually be lower in women who received exogenous LH. Such studies suggest, therefore, that in normogonadotrophic women, the addition of LH to an r-hFSH regimen does not add any further clinical benefit and may actually be detrimental. Hence, it appears that LH administration is necessary only in women with hypogonadotrophic hypogonadism. In conclusion, r-hFSH is a consistently pure and high quality gonadotrophin preparation and contributes to increasing the successful outcome of an ART cycle. Together with careful auditing of routine clinical practice, and the application of evidence-based medicine to facilitate clinical decision making, this means that a total quality management approach can be applied to optimize the outcome of assisted reproduction.
Mol Cell Endocrinol 2000 Mar 30
PMID:Role of LH and FSH in ovarian function. 1077 87

Male hypogonadism is characterised by androgen deficiency and infertility. Hypogonadism can be caused by disorders at the hypothalamic or pituitary level (hypogonadotropic forms) or by testicular dysfunction (hypergonadotropic forms). Testosterone substitution is necessary in all hypogonadal patients, because androgen deficiency causes slight anemia, changes in coagulation parameters, decreased bone density, muscle atrophy, regression of sexual function and alterations in mood and cognitive abilities. Androgen replacement comprises injectable forms of testosterone as well as implants, transdermal systems, sublingual, buccal and oral preparations. Transdermal systems provide the pharmacokinetic modality closest to natural diurnal variations in testosterone levels. New injectable forms of testosterone are currently under clinical evaluation (testosterone undecanoate, testosterone buciclate), allowing extended injection intervals. If patients with hypogonadotropic hypogonadism wish to father a child, spermatogenesis can be initiated and maintained by gonadotropin therapy (conventionally in the form of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) or, more recently, purified or recombinant follicle stimulating hormone (FSH)). Apart from this option, patients with disorders at the hypothalamic level can be stimulated with pulsatile gonadotropin-releasing hormone (GnRH). Both treatment modalities have to be administered on average for 7-10 months until pregnancy is achieved. In individual cases, treatment may be necessary for up to 46 months. Testosterone treatment is interrupted for the time of GnRH of gonadotropin therapy, but resumed after cessation of this therapy.
Mol Cell Endocrinol 2000 Mar 30
PMID:Hormone substitution in male hypogonadism. 1077 95

Oocyte donation is an effective treatment modality for women lacking functioning ovaries, but also for women in whom repetitive in-vitro fertilization (IVF) cycles did not result in the development of adequate number of oocytes as well as for those at risk of transmitting genetic diseases. In women with ovarian failure, artificial menstrual cycles are required in order to produce endometrial growth and differentiation similar to that in women with normal ovarian function. Synchronization of donor's and recipient's cycles is mandatory, since the window of implantation is rather limited. The excellent results of oocyte donation treatment confirm that this assisted reproduction technique can provide a novel approach for the treatment of infertility in these groups of patients. Nevertheless, pregnancies in women of advanced reproductive age are associated with significantly more obstetrical complications and higher perinatal morbidity and mortality rates. Furthermore, aging parents have considerably higher chances to develop serious or life-threatening diseases. Thus, careful medical screening and extensive counselling is mandatory, taking into account the psychosocial ramifications of the procedure and, especially, the best interest of the child-to-be.
Mol Cell Endocrinol 2000 Mar 30
PMID:Oocyte donation: clinical and practical aspects. 1077 97

In this study, we analysed the distribution of beta tubulins to detect spindle and cytoplasmic microtubules, alpha acetylated tubulins for sperm microtubules and chromatin configuration in oocytes showing fertilization failure after conventional IVF or intracytoplasmic sperm injection (ICSI). A total of 450 human oocytes that failed to fertilize were studied 20-40 h after IVF or ICSI. In all, 287 oocytes were stained for immunofluorescence and chromosomal spreads were performed by Tarkowski's air-drying method in 163 IVF or ICSI oocytes that did not develop pronuclei after the extrusion of a second polar body. Immunofluorescence analysis showed that the main reason of fertilization failure after IVF was no sperm penetration (55.5%). The remaining oocytes showed different abnormal patterns, e.g. oocyte activation failure (15.1%) and defects in pronuclei apposition (19.2%). On the other hand, fertilization failure after ICSI was mainly associated to incomplete oocyte activation (39.9%), and to a lesser extent with defects in pronuclei apposition (22.6%) and failure of sperm penetration (13.3%). A further 13.3% of the ICSI oocytes arrested their development at the metaphase of the first mitotic division. The chromosomal spreads allowed the analysis of abortive activations, in which no pronuclei formed but a second polar body was extruded. Immunofluorescence and cytogenetic analysis provided a useful tool to improve infertility diagnosis and prognosis in each particular case.
Mol Hum Reprod 2000 Jun
PMID:Cytoskeletal organization defects and abortive activation in human oocytes after IVF and ICSI failure. 1082 67

Our review of CEA of surgical procedures suggests that much of the existing cost analysis literature does not adhere to basic recommended analytic guidelines. However, those authors who specifically planned to perform a CEA analysis met all or nearly all of the methodologic principles (Table 1). Investigators who conduct CEA are strongly encouraged to use the many outstanding methodologic reviews for CEA. An example of threshold analysis was presented by Gray et al in their CEA of laparoscopy versus laparotomy for the treatment of ectopic pregnancy. They calculated that cost per successful treatment would be equal between the two strategies at an initial failure rate of 32% for laparoscopy (compared with their baseline value of 19%). This type of analysis is helpful, in addition to sensitivity analyses, to identify the value of a variable that results in an equal outcome. In the only cost-utility analysis performed on gynecologic surgery, Sculpher studied the trade-offs between a less invasive, less costly procedure (transcervical resection of the endometrium) with a more invasive, more costly, and more effective procedure (abdominal hysterectomy) to treat menorrhagia. Hysterectomy resulted in an incremental cost of 1,500 British pounds per QALY during 2 years of follow-up. This is much less than the range of $30,000 to $100,000 that represents a currently acceptable C/E ratio. Grover et al evaluated the cost-effectiveness of performing a concurrent hysterectomy in women undergoing bilateral salpingo-oophorectomy. They observed that in 45-year-old women, the additional concurrent procedure dominated the alternative strategy of bilateral salpingo-oophorectomy, being both less expensive and increasing average life expectancy. The concurrent hysterectomy strategy also dominated for women aged 55, but both with less cost-savings and gains in life expectancy compared with 45-year-old women. Selecting an appropriate time frame for the analysis is difficult and may dramatically affect the results of the analysis. The time frame should be long enough to measure all clinically relevant costs and benefits. For example, Kung et al compared the cost per cure of stress urinary incontinence of laparoscopic and open Burch procedures. The probability of cure after each procedure was estimated from a retrospective cohort of 62 women with a mean follow-up of 1.2 years for the laparoscopic Burch strategy and 2.7 years in the open Burch strategy. The authors found that the laparoscopic Burch dominated, with lower costs and a higher cure rate. However, the analysis would be more informative with much longer follow-up, because most women who undergo an incontinence procedure have a life expectancy far greater than 1 to 2 years. Ramsey et al performed an economic analysis to assess the long-term costs of behavioral therapy, pharmacotherapy, and surgical therapy used for stress urinary incontinence. They found that in the short-term, behavioral and pharmacotherapy were less costly. However, if life expectancy was equal to or greater than 3.5 years, surgical therapy was least costly. In many articles that evaluate the cost of managing ectopic pregnancy, only short-term costs of the procedures and follow-up visits are considered. Mol et al considered a longer time frame and also included the costs of infertility management based on the future probability of conception correlated with the different management strategies. Selection of an effectiveness measure after surgical intervention is often difficult and controversial. For benign disease, life years or QALYs will be minimally affected by a reasonably safe intervention. In the short-term, utility may be negatively affected by surgery and recovery. In longer-term analyses, these effects will be diluted by time and be negligible. Intermediate measures such as days of hospitalization averted or lives saved are often more appropriate for gynecologic interventions than are longer-term outcomes such as lif
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PMID:Measuring cost-effectiveness of surgical procedures. 1094 58

Deletions of the AZFc interval of the human Y chromosome are found in >5% of male patients with idiopathic infertility and are associated with a severely reduced sperm count. The most common deletion type is large (>1 Mb) and removes members of the Y-borne testis-specific gene families of BPY2, CDY1, DAZ, PRY, RBMY2 and TTY2, which are candidate AZF genes. Four exceptional individuals who have transmitted a large AZFc deletion naturally to their infertile sons have, however, been described. In three cases, transmission was to an only son, but in the fourth case a Y chromosome, shown to be deleted for all copies of DAZ, was transmitted from a father to his four infertile sons. Here we present a second family of this latter type and demonstrate that an AZFc-deleted Y chromosome lacking not only DAZ, but also BPY2 and CDY1, has been transmitted from a father to his three infertile sons. Polymerase chain reaction (PCR) and Southern blot analyses revealed no difference in the size of the AZFc deletion in the father and his sons. We propose that the father carries rare alleles of autosomal or X-linked loci which suppress the infertility that is frequently associated with the absence of AZFc.
Mol Hum Reprod 2000 Sep
PMID:The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. 1095 50

The mechanisms that regulate the gradual exit of ovarian follicles from the non-growing, primordial pool are very poorly understood. A better understanding of the signals that initiate follicular growth in mammals, and of the conditions necessary for sustained growth of early preantral follicles in vitro, could have practical implications for contraception, alleviation of infertility, and regulation of the rate of follicle depletion (menopause). Our laboratory has developed two experimental systems that can be used to study factors involved in the activation of primordial follicles. In the first experimental system, small pieces of ovarian cortex, containing mostly primordial follicles, are isolated from fetal ovaries of cattle or baboons and cultured in serum-free medium. Under these conditions most primordial follicles become activated between 12 and 24 h of culture; their granulosa cells change shape, from flattened to cuboidal, and begin to express proliferating cell nuclear antigen (PCNA). During 7 days in culture, the newly-formed primary follicles and their oocytes increase significantly in diameter. This wholesale 'spontaneous' activation in serum-free medium is quite different from the much more gradual exit of primordial follicles from the resting pool that occurs in vivo and suggests that primordial follicles in vivo may be subject to a tonic inhibition of growth initiation or, alternatively, that some aspect(s) of the environment in vitro stimulates growth initiation. Recently we developed a second experimental system for studying activation of primordial follicles. Pieces of ovarian cortex from bovine or baboon fetuses were grafted beneath the developing chorioallantoic membrane (CAM) of 6-day-old chick embryos, a site known to support xenografted tissues. The cortical pieces were rapidly vascularized and histological analysis of pieces recovered after 2, 4, 7, or 10 days 'in ovo' revealed no increase in the number of primary follicles and maintenance of original numbers of primordial follicles. Therefore, grafting ovarian cortical pieces beneath the chick CAM provides an experimental system in which follicles remain at the primordial stage in a readily accessible environment and which, thus, may be used to study potential regulators of the initiation of follicle growth. The results suggest that vascularization of isolated pieces of ovarian cortex provides conditions that maintain follicular quiescence, whereas culture in vitro allows unrestrained activation of primordial follicles. Future studies with and comparisons of the in vitro and in ovo models may provide new insight into the mechanisms that regulate the primordial to primary follicle transition.
Mol Cell Endocrinol 2000 May 25
PMID:The primordial to primary follicle transition. 1096 74

Ovarian grafting provides a strategy for clinical infertility treatment and is starting to be used in conjunction with ovarian tissue storage for patients at risk of early ovarian failure. As patients are starting to return for their frozen stored tissue we need to ascertain how to maximise follicle survival when this tissue is grafted back to the patient. For research purposes ovarian tissue is commonly grafted to the kidney capsule as the rich capillary bed at this site favours rapid graft revascularization. This is however not an ideal site for natural conceptions or for the harvest of mature oocytes for in vitro fertilization. While oocytes would be relatively easy to recover from grafts on the abdominal wall or subcutaneous tissue graft revascularization at these sites is slower and evidence indicates that fewer follicles survive. As gonadotropins can upregulate angiogenic growth factors in the ovary this study was designed to test whether the administration of exogenous gonadotropins would increase the number of surviving follicles in grafts placed at less vascularised sites. We showed that exogenous gonadotrophins, given to either the donor or the recipient, could increase the number of developing follicles but the magnitude of this effect was influenced by the timing of the injections relative to the time of grafting.
Mol Cell Endocrinol 2000 May 25
PMID:Gonadotrophin administration can benefit ovarian tissue grafted to the body wall: implications for human ovarian grafting. 1096 86

Deletion of any of three regions of the human Y chromosome results in spermatogenic failure and infertility. We previously sequenced one of these regions, azoospermia factor a (AZFa) and found that it spanned approximately 800 kb. By sequence-tagged site (STS) content mapping, we roughly defined deletion breakpoints in two unrelated, azoospermic men with AZFa deletions. The positions of proximal and distal breakpoints were similar in the two men. Hypothesizing that the deletions might have been generated by homologous recombination, we searched electronically for DNA sequence similarities between the proximal and distal breakpoint regions. These comparisons revealed the most striking sequence similarities anywhere along or near the AZFa region. In the proximal breakpoint region, we identified a 10 kb provirus of the recently defined HERV15 class of endogenous retroviruses. In the distal breakpoint region, we found a second HERV15 provirus, 94% identical in DNA sequence to the first and in the same orientation. (A partial LINE insertion in this distal provirus proved to be the basis of the previously described DYS11/p12f polymorphism.) The AZFa deletions in the two men differed slightly, but all breakpoints fell within the HERV15 proviruses. Indeed, sequencing of deletion junctions from the two men revealed that homologous recombination had occurred within large domains of absolute sequence identity between the proximal and distal proviruses. When combined with published STS mapping data for other AZFa-deleted men, our findings suggest that recombination between these two HERV15 proviruses could account for most AZFa deletions.
Hum Mol Genet 2000 Sep 22
PMID:Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. 1100 32

PEA3, a member of the Ets family of transcriptional regulatory proteins, is expressed in a unique spatial and temporal pattern during mouse embryogenesis; its overexpression is positively correlated with HER2-mediated breast tumorigenesis in both humans and mice. To determine whether PEA3 plays a part in development and oncogenesis and to uncover its normal physiological role, we generated mice lacking functional PEA3 by gene targeting in embryonic stem cells. PEA3(-/-) mice arose from heterozygous crosses with the expected Mendelian frequency, revealing that PEA3 is dispensable for embryogenesis. PEA3 mutant mice displayed no overt phenotype and lived a normal life span. However, PEA3-deficient males failed to reproduce. PEA3 is expressed in several male sexual organs, but gross and histological analyses of the organs from PEA3(-/-) mice revealed no abnormalities. Spermatogenesis and spermiogenesis also appeared normal in mice homozygous for the PEA3 mutation, and their sperm were capable of fertilizing eggs in vitro. PEA3(-/-) males engaged in normal mating behavior, but they did not set copulatory plugs and sperm could not be detected in the uteri of females that had mated with PEA3(-/-) males. Erections could be evoked by abdominal pressure in PEA3-deficient male mice, and the results of in vitro experiments revealed that the corpus cavernosum isolated from PEA3 mutant males relaxed in response to acetylcholine. Therefore, the infertility of PEA3 mutant males involves either mechanisms proximal to the cavernosal smooth muscle or an ejaculatory dysfunction. However, PEA3 mutant mice are phenotypically distinguishable from other knockout mice with such deficits and thus provide a unique model for further investigation of male sexual dysfunction.
Mol Cell Biol 2000 Dec
PMID:Male sexual dysfunction in mice bearing targeted mutant alleles of the PEA3 ets gene. 1109 84


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