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Controlled ovarian hyperstimulation protocols for in vitro fertilization: two decades of experience after the birth of Elizabeth Carr.

OBJECTIVE: To critically discuss the current protocols for the management of controlled ovarian hyperstimulation in assisted reproduction technology. DESIGN: Review of the literature and presentation of our experience. MAIN OUTCOME MEASURE(S): Ovarian response (peak serum estrogen levels, number of oocytes retrieved, quality of oocytes and embryos) and pregnancy outcome (clinical, delivery, and multiple pregnancy rates). RESULT(S): Controversies still exist regarding selection of gonadotropin preparation, choice of adjuvant therapy with GnRH analogues, and use of oral contraceptive pills. Patients identified as intermediate responders have an excellent outcome with adjuvant therapy with either a GnRH agonist (long protocol) or a GnRH antagonist, but tailoring of gonadotropin dose must be performed to achieve optimized results. High responders perform favorably with gentler gonadotropin stimulation that minimizes the occurrence of ovarian hyperstimulation syndrome. On the other hand, results in low responders remain suboptimal both in terms of ovarian response and oocyte/embryo quality in spite of a variety of stimulation regimens used. CONCLUSION(S): Ovarian stimulation is a critical step in in vitro fertilization therapy. A variety of controlled ovarian hyperstimulation regimens are available and efficacious, but individualization of management is essential and depends on assessment of the ovarian reserve. Identification of the etiologies of poor ovarian response constitutes a formidable challenge facing reproductive endocrinologists.

Female↗

To add or not to add LH: comments on a recent commentary.

From a period of time when LH activity supplementation in stimulation protocols for assisted reproductive technology was questioned, recent scientific evidence seems to prove a role of LH activity in optimizing the clinical results of certain subgroups. Until now, apart from the hypogonadotrophic hypogonadal patient, two subgroups of patients have attracted attention: patients over 35 years of age, and normogonadotrophic patients with an initial low response to recombinant FSH (rFSH). However, in a recent paper, another subgroup of patients has been identified: normogonadotrophic patients with high endogenous LH levels (>1.99 IU/l) on day 8 of stimulation after a long GnRH agonist down-regulation. By adding recombinant LH (rLH) from day 8 to the stimulation protocol, this subgroup of patients achieved good implantation rates, similar to those of patients with lower LH levels. Interestingly, the dynamics of the endogenous LH levels during down-regulation in this group of patients differed from those of patients with lower LH levels. The immunoreactivity of the LH molecule does not necessarily reflect the bioactivity, which might explain the beneficial effect of LH activity supplementation in patients with high endogenous LH levels after down-regulation. Future studies should be focused on subgroups to further explore the effect of LH activity supplementation in assisted reproduction techniques.

Adult↗

Preimplantation genetic diagnosis to prevent disorders in children.

Preimplantation genetic diagnosis (PGD) is an alternative reproductive option for couples at risk of having a child affected with a genetic disorder. Although prenatal diagnosis (PND) has been available for many years, it is not acceptable to many owing to issues relating to termination of pregnancy. PGD involves assisted-reproductive technology, even though most couples undertaking it are fertile. However, if the treatment is successful, the couple will not have to consider PND. PGD is only available at a small number of centres and for a limited number of genetic conditions. It is a complex and time-consuming procedure. The success rate is around 20%, consequently, there is a relatively low chance of success and this requires careful consideration by couples who generally can become spontaneously pregnant. However, PGD is now more widely understood and available to all at the point of referral. This article sets out to explain the PGD procedure, its implications, limitations, and regulation in the UK and to discuss associated dilemmas.

Female↗

Sharing your culture with a new partner. Catholic system implements plan to integrate values when it acquires a for-profit hospital.

In 1994 Orange County, CA's St. Joseph Health System (SJHS), aiming to strengthen its position in the regional market, acquired Mission Hospital Regional Medical Center, a for-profit hospital believed to be the premier healthcare facility in the southern part of the county. SJHS's leaders began integrating the two cultures at the top, replacing Mission's board but keeping its top managers in place. A member of the Sisters of St. Joseph joined the managers as the hospital's new vice president of sponsorship. In a series of orientation meetings, the hospital's leaders explained SJHS's mission and values to the staff, announcing that Mission would add a pastoral care department, emphasize care of the medically underserved, and discontinue abortion and sterilization procedures. Some Mission staff were disappointed when the hospital terminated a project that offered assisted reproductive technologies. In addition, capitation and exclusive contracting has caused conflict among area physicians, which affects the hospital. And Mission needs to further educate physicians and staff about bioethical issues. On the other hand, Mission has launched a center to help strengthen area families, a transportation system for senior citizens, and a dental clinic for underserved children. It has also taken over sponsorship of a clinic for underserved families. And, in 1994, the hospital opposed Proposition 187, which called for denying state services to illegal immigrants. Many Mission staff have been heartened to learn that the hospital considers justice a core value.

California↗

Potential researchable areas in ARTs--oocyte maturation and embryo development.

Infertility is a commonly encountered situation occurring equally in both sexes. In vitro fertilization and embryo transfer (IVF-ET) and other assisted reproductive technologies (ARTs) have enhanced the possibilities for successful treatment to tackle infertility. However, ARTs currently face limitations due to the fact that although success rate is high for the initial stages such as ovulation induction and fertilization, it dwindles progressively so that the success rate of a take home baby is as low as 15-20%. Research centred around various stages in an IVF programme is therefore necessary to devise protocols that ensure a higher success rate. This review takes a look at the potential areas currently under research in the field of ARTs, such as, in vitro oocyte maturation, oocyte/embryo cryopreservation, embryo culture, preimplantation genetic diagnosis. Their applications, in clinical conditions such as cancer, have been discussed.

Embryonic and Fetal Development↗

Successful elective single blastocyst transfer in a patient with prior repetitive high-order multiple gestations.

Multiple gestations remain one of the leading causes of morbidity related to infertility therapy. In the realm of assisted reproductive technologies, multiple gestations can be significantly limited by the reduction in the number of embryos transferred. Significant concern remains that a reduction in the number of embryos transferred may appreciably lower overall chances for pregnancy. Promising new developments are unfolding that may permit improved detection of a single human embryo with high implantation potential. One such development is the use of sequential culture media to allow prolonged culture of embryos to the blastocyst stage. We report a case in which sequential culture and elective transfer of one blastocyst was successfully used in a patient with a profoundly poor obstetrical history because of the complications of high-order multiple gestations.

Adult↗

State-of-the-art production, conservation and transfer of in-vitro-produced embryos in small ruminants.

Today, although not efficient enough to replace multiple ovulation and embryo transfer, in vitro embryo production for small ruminants is a platform for new reproductive technologies, such as embryo sexing, transgenesis and cloning. The in vitro embryo-production system developed for sheep and goats is more efficient now than 15 years ago, but could still be improved. Laparoscopic collection of oocytes in live animals treated with gonadotrophin indicates a promising future for the application of this technology to genetic improvement programmes. Oocyte maturation in defined medium with epidermal growth factor and cysteamine appears as efficient as oocyte maturation in follicular fluid-supplemented medium and allows future study of the effect of other factors involved in the cytoplasmic maturation of oocytes from these species. Further efforts have to be made to standardise the semen-capacitating process and to improve the quality and freezability of in-vitro-produced (IVP) embryos. The optimisation of IVP procedures for deer species has required the study of the seasonal variation of oocyte competence and the development of a specific methodology to allow the culture of embryos up to the blastocyst stage.

Animals↗

'We're having trouble conceiving...'.

BACKGROUND: The growing trend for Australian women to delay childbearing has a significant impact on their individual fertility and the consequent need for assisted reproductive technology. OBJECTIVE: This article defines infertility and highlights typical male, female, and unexplained combined causes of infertility. Initial fertility investigations best undertaken in general practice are outlined, and suggestions on when to refer a couple to a fertility specialist is clarified. DISCUSSION: Initial assessment of the subfertile couple is best managed by the general practitioner whose relationship can facilitate quick understanding of how long the couple has been trying to conceive, age, and medical history. The woman can then undergo simple global blood and hormone tests while a semen analysis is appropriate for the man. On review, any abnormal tests can indicate referral to a fertility specialist for review and management.

Adult↗

Buffalo and cattle hybrid embryo development is decreased by caffeine treatment during in vitro fertilization.

Water buffalo are renowned for difficulties in the implementation of assisted reproductive technologies, with both males and females being problematic. In this study, we used cattle oocytes to assess the effect of treatments with heparin and caffeine on buffalo spermatozoa and subsequent fertilization and embryo development in vitro. There was no significant difference between buffalo and bovine spermatozoa in the events associated with fertilization. Fertilization of cattle oocytes with buffalo spermatozoa resulted in 7.8% of oocytes developing into hybrid embryos. A difference in the developmental capability of hybrid embryos compared with the cattle control was observed. This has not been previously reported. The subsequent transfer of a limited number of hybrid embryos did not produce a viable pregnancy. However, control treatments in this experiment also failed to achieve pregnancy, so objective data is not available to provide conclusions about the developmental competence of the buffalo and cattle hybrid embryos. Optimal spermatozoa capacitation treatments achieved 61% fertilization and 21% zygote cleavage into two cell embryos. There was no significant difference in fertilization or development due to heparin or spermatozoa concentrations. However, treatment of buffalo and cattle spermatozoa with caffeine significantly decreased embryo cleavage but also tended to decrease embryo development to the blastocyst stage. These studies suggest that problems with reproduction in buffalo may reside with biological mechanisms associated with the oocyte that are often complicated by poor male reproductive performance. Selection for bull fertility would prevent some of these complications.

Animals↗

Sonographic evidence of minimal and short-term testicular damage after testicular sperm aspiration procedures.

OBJECTIVE: To evaluate ultrasonically the incidence and duration of tissue damage after testicular sperm aspiration (TESA) procedures. DESIGN: Prospective, nonrandomized study. SETTING: Assisted reproductive technology program. PATIENT(S): Thirty-two men with obstructive azoospermia. INTERVENTION(S): Physical and serial testicular ultrasound examinations 1.5, 3, and 6 months after the surgical procedure. MAIN OUTCOME MEASURE(S): Systematic evaluation of the testicular parenchyma and blood flow. RESULT(S): In 93.7% of the patients (30 of 32), no evidence of parenchymal or vascular injuries was found 6 weeks after the procedure. In the remaining 2 patients, transient evidence of tissue damage disappeared after 3 months. CONCLUSION(S): Testicular sperm aspiration is a safe surgical method for sperm retrieval for IVF. Repeated surgical attempts might be considered within 2 months, provided there is no evidence for tissue damage on sonography.

Humans↗

Microsurgical vasoepididymostomy with sperm cryopreservation for future assisted reproduction.

BACKGROUND: Although obstructive azoospermia is treatable with microscopic seminal reconstruction, the number of patients who choose to undergo vasoepididymostomy is limited because of recent advances in assisted reproductive technology (ART). We attempted to define the outcome of surgical reconstruction in patients with suspected epididymal obstruction and no previous history of vasectomy. METHODS: We described 40 eligible end-to-side vasoepididymostomy procedures performed on 24 azoospermic patients who had either bilateral or unilateral epididymal obstruction. RESULTS: The overall patency rate following surgery was 54% (13/24) and for four patients (17%), natural intercourse resulted in pregnancy. Two pregnancies were initiated with intracytoplasmic sperm injections using frozen sperm collected during vasoepididymostomy. CONCLUSIONS: In the era of modern ART, microsurgical vasoepididymostomy with cryopreservation of sperm collected during the operation is recommended for patients with epididymal obstructions.

Adult↗

[The evaluation of 156 cycles of intracytoplasmic sperm injection in the management of male infertility and idiopathic infertility].

OBJECTIVE: The aim of this study was to examine, retrospectively, the efficacy of intracytoplasmic sperm injection (ICSI) in the treatment of male infertility and idiopathic infertility. METHODS: From November 1995 to January 1998, 140 couples (156 cycles) received ICSI because of severe male factor infertility or idiopathic infertility in our assisted reproductive technology center. The treatment cycles were divided into two groups, group I included 74 cycles done before May 1997, group II included 82 cycles done after May 1997. Mature oocytes were selected for microinjection. RESULTS: No differences were observed between the two groups in the number of mature oocyte and the total cleavage rate. Oocyte survival rate, normal fertilization rate, embryos of good morphology rate and clinical pregnancy rate were significantly higher in group II than that in group I. CONCLUSION: ICSI procedure does affect the quality of embryos. With the improvement of ICSI technique, ICSI should be the treatment of choice for male infertility and idiopathic infertility.

Adult↗

Methodological issues in infertility research.

It is now well established that clinical decision-making can be enhanced by incorporating evidence from valid studies. This evidence-based approach to health-care management requires a critical appraisal of the available evidence, most of which is of relatively poor quality. If the best evidence is to be put forward to support clinical decisions then it must be derived from studies of high methodological rigour. This chapter discusses important methodological issues affecting the evaluation of the efficacy of therapeutic interventions; these are supplemented with illustrative examples from the literature. These issues form the basis for establishing an approach to inform gynaecological practice, with particular reference to infertility management using assisted reproductive technology and other therapies. Ten important issues are discussed: the formulation of an appropriate research question, the use of randomization, the importance of concealment of treatment allocation, the importance of blinding or masking to avoid ascertainment bias, the avoidance of cointervention, the requirement of an adequate sample size, the restriction of evaluation to the first cycle of treatment, the avoidance of the crossover trial when pregnancy is the outcome of interest, the importance of analysing data using an intention-to-treat approach, and the clear identification of the orientation of the study from the perspectives of superiority, equivalence or non-inferiority of the interventions being compared.

Clinical Trials as Topic↗

Paternity following treatment for testicular cancer.

BACKGROUND: Studies of fertility in men treated for testicular cancer have mainly addressed serum follicle-stimulating hormone levels and sperm parameters. We assessed post-treatment paternity among long-term survivors of testicular cancer. METHODS: Men (n = 1814) who had been treated for unilateral testicular cancer in Norway during 1980 through 1994 were invited to participate in a national multi-center follow-up survey in 1998 through 2002. The participants were allocated to five groups according to the treatment received after orchiectomy, including treatment at relapse (surveillance, retroperitoneal lymph node dissection, radiotherapy, low-dose chemotherapy [i.e., < or = 850 mg cisplatin], and high-dose chemotherapy [i.e., > 850 mg cisplatin]). Cox proportional hazards analysis was used to assess predictive factors for post-treatment paternity. Statistical tests were two-sided. RESULTS: A total of 1433 men were assessable, of whom 827 were fathers at diagnosis. Post-treatment conception was attempted by 554 men, among whom the overall 15-year actuarial post-treatment paternity rate was 71% (95% confidence interval [CI] = 66% to 75%) without the use of cryopreserved semen. This rate ranged from 48% (95% CI = 30% to 69%) in the high-dose chemotherapy group to 92% (95% CI = 78% to 98%) in the surveillance group (P < .001). The median actuarial time from diagnosis to the birth of the first child after treatment was 6.6 years overall but varied according to treatment. Assisted reproductive technologies were used by 22% of the couples who attempted conception after treatment. Dry ejaculation, treatment group, pretreatment fatherhood, and marital status were statistically significant independent predictors for post-treatment fatherhood, with dry ejaculation as the most important negative factor. CONCLUSIONS: Although the overall paternity rate after treatment for testicular cancer was high, the ability to conceive and the time to conception reflected the intensity of treatment. These data may help inform patients about their future ability to father biological children.

Actuarial Analysis↗

Narrative ARTifice and women's agency.

The choice to pursue fertility treatments is a complex one. In this paper I explore the issues of choice, agency, and gender as they relate to assisted reproductive technologies (ARTs). I argue that narrative approaches to bioethics such as those by Arthur Frank and Hilde Lindemann Nelson clarify judgments about autonomy and fertility medicine. More specifically, I propose two broad narrative categories that help capture the experience of encounters with fertility medicine: narratives of hope and narratives of resistance. This narrative typology captures the inevitable conflict that women feel when they become subjects of fertility medicine. On the one hand, they must remain hopeful; on the other, they must not surrender themselves completely. Nelson's account of counterstories as narratives of resistance helps us see how women can reconcile the experience of a strong desire to have children with the desire to remain authentic and whole.

Coercion↗

In vitro growth of human primordial follicles from frozen-banked ovarian tissue.

The rarity of human oocytes frequently limits the success of assisted reproductive technology and delays research progress. Development of technologies to grow mature oocytes from the more abundant small follicles, perhaps after long-term storage at low temperatures, is a theoretically attractive solution to both problems. The length of the follicular growth span from the primordial to Graafian stage and changes in the trophic requirements of the cells, cellular interactions, morphogenesis and the sheer increase in bulk as the antrum forms are major challenges for cell culture technology. Even so, much progress has been made with animal follicles, and has begun with human tissue. A multi-step procedure, which reflects these changes, is perhaps the most likely to succeed. At present, the best strategy appears to be to initiate follicle growth in situ and isolate the follicles or granulosa-oocyte complexes once they have progressed to preantral stages. The final step is to mature the oocytes within their cumulus cells. The prospects of succeeding at each stage, and producing a fertile gamete at the end, are likely to be greater by preserving cellular interactions and the phenotype of follicle cells as these provide the physiological environment in which oocytes develop.

Animals↗

Womb with a view.

Zygote transfer is a significant limiting factor in pregnancy rates after Assisted Reproductive Technology (ART) treatment. Adequate technique appraisal should be a high priority task for any medical facility that offers this treatment. Although many clinicians have extensive personal experience, it is difficult for trainees to understand the anatomical and mechanical process of safe and adequate placing of zygotes in the uterine cavity. Ultimately, even with ultrasound help, it is a "blind procedure". The experimental module described here allows for direct visualisation of the mechanical passage of a catheter through the cervix and final placement of the tip in relation to the intravaginal visible part of the catheter. It has worldwide practical applicability for trainees and experienced clinicians accompanying the theory and allowing adequate training and retraining of all staff performing zygote transfers.

Education, Medical↗

What is the most relevant standard of success in assisted reproduction? Is BESST (birth emphasizing a successful singleton at term) truly the best?

There is much variability and no consensus on the definition of the most relevant outcome parameter after assisted reproduction technology (ART). Descriptive reports, such as annual statistics from national registries on the success of ART programmes, should present treatment success in terms of live birth per ovarian stimulation started, as this is the most relevant information for patients and doctors alike. Addressing concerns about the high rate of multiple pregnancies, rescaling the outcome of ART in large programmes and national audits to the singleton, live birth, might trigger a global change of attitude towards elective single embryo transfer in addition to any legal restrictions imposed. For clinical studies, the outcome measure will depend on the hypothesis tested, and investigators should remain free to choose the appropriate primary outcome measure.

Embryo Transfer↗