Assisted reproduction: Ethical and legal issues.

Since inception, the use of assisted reproductive technologies (ART) has been accompanied by ethical, legal, and societal controversies. Guidelines have been developed to address many of these concerns; however, the rapid evolution of ART requires their frequent re-evaluation. We review the literature on ethical and legal aspects of ART, highlighting some of the most visible and challenging topics. Of specific interest are: reporting of ART procedures and outcomes; accessibility to ART procedures; issues related to fertility preservation, preimplantation genetic testing, gamete and embryo donation, and reproductive outcomes after embryo transfer. Improvements in ART reporting are needed nationally and worldwide. Reporting should include outcomes that enable patients to make informed decisions. Improving access to ART and optimizing long-term reproductive outcomes, while taking into account the legal and ethical consequences, are challenges that need to be addressed by the entire community of individuals involved in ART with the assistance of bioethicists, legal counselors, and members of society in general.

How to recognize PCOS: results of a web-based survey at IVF-worldwide.com.

This retrospective evaluation of a web-based survey posted from 1 to 30 September 2010 was to determine which diagnostic tools physicians are currently utilizing to diagnose polycystic ovary syndrome (PCOS). Responses from 262 IVF centres in 68 countries are included in the study. Providers used various diagnostic criteria to diagnose PCOS, including the Rotterdam criteria (82%), National Institutes of Health criteria (8%), Androgen Excess Society 2006 criteria (3%) and other classification systems (7%). Many providers utilized diagnostic tools not necessarily included in traditional classification systems: 58% of respondents evaluated LH/FSH ratio in addition to androgen concentrations to define patients with PCOS; physicians also commonly obtain measurement of anti-Müllerian hormone (22%) and impaired glucose tolerance (74%) in diagnosing PCOS. Many respondents (64%) felt that polycystic-appearing ovaries on ultrasound with anovulation and a normal serum prolactin should be adequate criteria to diagnose PCOS. In conclusion, while the majority of centres (82%) uses the Rotterdam criteria to diagnose PCOS, other criteria and diagnostic tools are commonly used in evaluating patients with suspected PCOS. This study highlights the need for continual re-evaluation of PCOS diagnostic criteria with an ultimate goal of developing a consensus definition for the disorder in the future.

The impact of luteal phase support on endometrial estrogen and progesterone receptor expression: a randomized control trial.

BACKGROUND: To assess the impact of luteal phase support on the expression of estrogen receptor (ER) alpha and progesterone receptors B (PR-B) on the endometrium of oocyte donors undergoing controlled ovarian hyperstimulation (COH). METHODS: A prospective, randomized study was conducted in women undergoing controlled ovarian hyperstimulation for oocyte donation. Participants were randomized to receive no luteal support, vaginal progesterone alone, or vaginal progesterone plus orally administered 17 Beta estradiol. Endometrial biopsies were obtained at 4 time points in the luteal phase and evaluated by tissue microarray for expression of ER alpha and PR-B. RESULTS: One-hundred and eight endometrial tissue samples were obtained from 12 patients. No differences were found in expression of ER alpha and PR-B among all the specimens with the exception of one sample value. CONCLUSIONS: The administration of progesterone during the luteal phase of COH for oocyte donor cycles, either with or without estrogen, does not significantly affect the endometrial expression of ER alpha and PR.

In vitro fertilization: four decades of reflections and promises.

BACKGROUND: In 2010, Robert Edwards was awarded the Nobel Prize in Medicine for his pioneering work in the development of in vitro fertilization, a field that has touched millions of lives across the globe. Edwards dedicated his career to helping couples overcome infertility. He first established principles of early embryo development that served as the foundation for his later work. In the 1960s, he achieved the first human fertilized oocyte in vitro while at the Johns Hopkins Hospital. He then continued his work at Cambridge University. In 1978, the world witnessed the birth of the first "test tube baby". This achievement is a landmark not only in the reproductive sciences but also in the history of mankind's technological evolution. SCOPE OF REVIEW: This article outlines the development and progression of IVF from its infancy to the refined and broadly utilized technology offered to patients today. We describe the evolution of the field and the current state of IVF, including its current technological and social challenges. MAJOR CONCLUSIONS: We congratulate Professor Edwards for his well-deserved recognition as Nobel Laureate in Medicine. GENERAL SIGNIFICANCE: This article is a tribute to Edwards for his exceptional accomplishments in this specific and rewarding field of modern medicine.

A modern trends retrospective.

Editorship of the Modern Trends section has been a great ride. The section raised the level of interest and readership of Fertility and Sterility, while providing important, up-to-date material for students, scientists and practitioners.

At home testing: optimizing management for the infertility physician.

OBJECTIVE: To review and describe various over-the-counter testing products available to the infertility patient, a billion-dollar a year industry that continues to grow. DESIGN: Methodology involved a detailed Medline search of literature, use of online search engines, and focused communications with various manufacturers to determine the usefulness and validity of existing products. CONCLUSION(S): Although some home tests have been subjected to scientific scrutiny, others have not. At-home testing represents an opportunity for physicians to involve patients actively in their care. When properly used, these tests also may result in cost savings. However, physicians and consumers must understand the limitations of these tests. Many of the technologies used are innovative and, with proper evaluation and implementation, could serve as valuable adjuncts to medical practice.

Pelvic pain and surgeries in women before interstitial cystitis/painful bladder syndrome.

OBJECTIVE: The objective of the study was to compare subjects with interstitial cystitis/painful bladder syndrome (IC/PBS) with controls on prior surgeries. STUDY DESIGN: IC/PBS subjects were compared with matched controls on surgeries and possible surgical indications prior to their index dates. RESULTS: Adjusted for demographic variables, logistic regression showed subjects exceeded controls in surgeries longer than 12 months and less than 1 month before the index date. However, addition of possible surgical indications showed chronic pelvic pain (CPP) to have a strong association with IC/PBS, whereas associations with surgeries were reduced to nonsignificance. CONCLUSION: Although women with IC/PBS were more likely to have experienced prior surgeries than controls, the apparent indications for surgeries, not the surgeries themselves, were stronger risk factors for IC/PBS. In particular, a prior history of CPP had a strong association with IC/PBS. Several features of study design, including extensive medical record review, suggest that prior CPP was not undiagnosed IC/PBS. Further investigation of CPP may yield insight into the pathogenesis of IC/PBS.

Fertility patients' views about frozen embryo disposition: results of a multi-institutional U.S. survey.

OBJECTIVE: To describe fertility patients' preferences for disposition of cryopreserved embryos and determine factors important to these preferences. DESIGN: Cross-sectional survey conducted between June 2006 and July 2007. SETTING: Nine geographically diverse U.S. fertility clinics. PATIENT(S): 1020 fertility patients with cryopreserved embryos. INTERVENTION(S): Self-administered questionnaire. MAIN OUTCOME MEASURE(S): Likelihood of selecting each of five conventional embryo disposition options: store for reproduction, thaw and discard, donate to another couple, freeze indefinitely, and donate for research; likelihood of selecting each of two alternative options identified in previous research: placement of embryos in the woman's body at an infertile time, or a disposal ceremony; importance of each of 26 considerations to disposition decisions; and views on the embryo's moral status. RESULT(S): We found that 54% of respondents with cryopreserved embryos were very likely to use them for reproduction, 21% were very likely to donate for research, 7% or fewer were very likely to choose any other option. Respondents who ascribed high importance to concerns about the health or well-being of the embryo, fetus, or future child were more likely to thaw and discard embryos or freeze them indefinitely. CONCLUSION(S): Fertility patients frequently prefer disposition options that are not available to them or find the available options unacceptable. Restructuring and standardizing the informed consent process and ensuring availability of all disposition options may benefit patients, facilitate disposition decisions, and address problems of long-term storage.

Effects of utero-ovarian anastomoses on basal follicle-stimulating hormone level change after uterine artery embolization with tris-acryl gelatin microspheres.

PURPOSE: To assess the prevalence of anastomoses between uterine and ovarian arteries on angiography and their impact on changes in basal follicle-stimulating hormone (FSH) level after uterine artery embolization (UAE). MATERIALS AND METHODS: Consecutive premenopausal women who underwent UAE for symptomatic uterine leiomyomata according to a uniform embolization technique with tris-acryl gelatin microspheres at a single institution were included in the study. Basal FSH levels before UAE and 6 months after UAE were compared for patients with and without anastomoses between uterine and ovarian arteries on angiography. RESULTS: Among 124 patients included in the study (mean age, 43.1+/-5.7 years), patent anastomoses between the uterine and ovarian arteries were detected by angiography in 55 patients (44.4%). Overall, 11.3% of 124 patients showed an increase in basal serum FSH level of greater than 20 mIU/mL after UAE. In patients with utero-ovarian anastomoses, 18.2% showed an increase of greater than 20 mIU/mL after UAE, compared with 5.8% of patients without such anastomoses (P=.03). Mean basal FSH increase after UAE in patients with anastomoses was 8.4+/-20.2 mIU/mL, compared with 2.7+/-10.6 mIU/mL in patients without anastomoses (P=.047). Among patients with anastomoses, the 50- to 54-year age group had the highest percentage of patients with an FSH increase greater than 20 mIU/mL (50.0%) after UAE, followed by patients in the 45- to 49-year age group (15.4%). CONCLUSIONS: Angiographically detected anastomoses between the uterine artery and the ovarian artery are not uncommon. UAE in patients with anastomoses is associated with a greater risk of significant increase of basal FSH level than in UAE in patients without anastomoses. The pathophysiologic processes resulting in change of FSH level may be a reflection of diminished ovarian function, but further study is warranted to delineate the precise mechanism.

Effects of utero-ovarian anastomoses on clinical outcomes and repeat intervention rates after uterine artery embolization.

PURPOSE: To assess the prevalence of anastomoses between uterine and ovarian arteries on angiography and their association with clinical outcome after uterine artery embolization (UAE). MATERIALS AND METHODS: Consecutive patients who underwent UAE for symptomatic uterine leiomyomata according to a uniform embolization technique by a single operator at a single institution were included in the study. Patients' angiographic images, pre- and postoperative magnetic resonance (MR) images, and clinical symptom evaluations were reviewed. MR imaging was performed 6 months after UAE, and clinical evaluation with symptom severity score (SSS) measurement was performed at 6-month and yearly intervals afterward. Leiomyomata volume change, SSS, and repeat intervention rates were compared for patients with and without anastomoses between uterine and ovarian arteries on angiography. RESULTS: Of 288 consecutive patients in the study (mean age, 43.8 +/- 6.4 y), patent anastomoses between the uterine and ovarian arteries were detected in 116 patients (40.3%) by angiography. On follow-up, there was a mean leiomyomata volume reduction of 50.4% and an improvement in mean transformed SSS of 38.2 points. In patients with anastomoses, mean leiomyomata volume reduction was 49.5% and mean transformed SSS improvement was 38.1 points. In patients without anastomoses, mean leiomyomata volume reduction was 50.4% and mean transformed SSS improvement was 38.4 points. At a mean follow-up of 21.5 months, 16 patients (5.6%) elected to undergo further therapy for residual symptoms, including seven hysterectomies, four myomectomies, and five repeat UAE procedures. There were statistically significant differences in repeat intervention rates between the two groups: 14 patients with anastomoses (12.1%) underwent five hysterectomies, four myomectomies, and five repeat UAE procedures, whereas two patients without anastomoses (1.2%) elected to undergo hysterectomy (P < .0001). CONCLUSION: Anastomoses between the uterine artery and ovarian artery were demonstrated on angiography in 40.3% of 288 consecutive patients studied. Although the overall repeat intervention rate after initial UAE is only 5.6%, UAE in patients with anastomoses is associated with a significantly higher incidence of repeat intervention than UAE in patients without anastomoses.

Factors that affect infertility patients' decisions about disposition of frozen embryos.

OBJECTIVE: To describe factors that affect infertility patients' decision making regarding their cryopreserved embryos. DESIGN: Forty-six semistructured in-depth interviews of individuals and couples participating in IVF programs. SETTING: Two major southeastern academic medical centers. PATIENT(S): Fifty-three individuals, including 31 women, 8 men, and 7 couples. MAIN OUTCOME MEASURE(S): Qualitative analysis of interview transcripts. INTERVENTION (S): None. RESULT(S): Seven broad themes informed participants' decisions about embryo disposition: family and personal issues, trust, definition of the embryo, prospective responsibility to the embryo, responsibility to society, adequacy of information, and lack of acceptable disposition options. Many wished for alternative options, such as a ceremony at the time of disposal or placement of embryos in the woman's body when pregnancy was unlikely. CONCLUSION(S): Recent debates regarding embryo disposition do not reflect the range of values that infertility patients consider when deciding about frozen embryos. In addition to questions about the embryo's moral status, decision making about embryos is informed by a range of factors in the lives of individuals who created them. These perspectives may have important implications for the content and timing of informed consent, facilitating embryo disposition, and advancing policy debates about the ethics of frozen embryo use.

The social implications of embryo cryopreservation.

OBJECTIVE: To summarize the existing literature regarding the social implications of embryo cryopreservation and outline areas in need of further study. RESULT(S): The potential social impact of oocyte cryopreservation has not been investigated. Embryo cryopreservation has been increasingly used to improve the cost-effectiveness of in vitro fertilization (IVF) and expand the options available to infertile couples, yet its widespread adoption has occurred more rapidly than our ability to study the social consequences for the couples and health professionals involved. For maintaining cryopreserved embryos, the existing literature is fragmented and incompletely explores the effects on an infertile couple's psychosocial health and personal relationships, their family planning strategies, or their preferences for the disposition of the embryos. Managing unclaimed embryos continues to create challenges for assisted reproduction professionals. CONCLUSION(S): We currently lack a thorough understanding of the numerous social implications of cryopreservation. Major areas for future research include the impact of stored embryos on couples' fertility intentions and psychosocial health, factors that affect couples' decisions about embryo disposition, strategies to minimize unclaimed embryos, and the consequences of oocyte/ovarian cryopreservation.

Effect of ejaculatory abstinence period on the pregnancy rate after intrauterine insemination.

OBJECTIVE: To determine the optimal interval of ejaculatory abstinence for couples undergoing IUI. DESIGN: Retrospective analysis. SETTING: Reproductive endocrinology and infertility center. PATIENT(S): Infertile couples undergoing ovulation induction and IUI with partner's semen. INTERVENTION(S): Ovulation induction with clomiphene citrate and a single IUI procedure per cycle. MAIN OUTCOME MEASURES(S): Clinical pregnancy rates as a function of abstinence intervals. RESULT(S): Four hundred seventeen women underwent 929 cycles from June 1999 to October 2002 for a median of 4 IUI attempts per couple. The median ejaculatory abstinence interval was 4 days (range 0-30) with an overall pregnancy rate of 12% per cycle. Abstinence correlated positively with inseminate sperm count but negatively with motility. Variations in inseminate parameters did not correlate with pregnancy rates. However, abstinence intervals significantly affected pregnancy rates. The highest pregnancy rate was observed with an abstinence interval of 3 days or less (14%) and the lowest pregnancy rate seen with an abstinence interval of 10 days or more (3%). CONCLUSION(S): An abstinence interval of 3 days or less was associated with higher pregnancy rates following IUI. Prolonged abstinence decreases pregnancy rates, independent of other sperm parameters, perhaps as a result of sperm senescence and functional damage not readily identified by standard semen analysis. Abstinence intervals should be controlled for in studies examining pregnancy outcome in assisted reproduction.

Women with ovulatory dysfunction undergoing ovarian stimulation with clomiphene citrate for intrauterine insemination may benefit from administration of human chorionic gonadotropin.

OBJECTIVE: To investigate factors that may affect pregnancy outcome following ovarian stimulation with clomiphene citrate (CC) combined with intrauterine insemination (IUI). DESIGN: Retrospective cohort study. SETTING: University teaching hospital. PATIENT(S): Three hundred and twenty women who underwent 691 ovarian stimulation cycles with CC for IUI. INTERVENTION(S): Ovarian stimulation with CC followed by a single IUI either 24 hours after a spontaneous serum LH surge (>25 mIU/mL) or 36 hours after intramuscular human chorionic gonadotropin (hCG) administration (10,000 IU) when the largest follicle had reached a diameter of 17 mm. MAIN OUTCOME MEASURE(S): Clinical pregnancies. RESULT(S): Women with ovulatory dysfunction who received hCG had significantly higher pregnancy rates (24.6%) compared with women with other types of infertility. There were no differences in pregnancy rates between the LH surge group and the hCG group (14.3% vs 12.4%). A spontaneous LH surge was noted in a variety of follicular sizes (14 to 35 mm). There was no correlation for age, body mass index, follicular diameter, number of mature follicles, other sperm characteristics, and pregnancy outcome in either group. CONCLUSION(S): After ovarian stimulation with CC, IUI is equally effective 24 hours after a spontaneous LH surge or 36 hours after administration of hCG. Spontaneous LH surges were observed at a variety of follicular sizes with comparable pregnancy rates. In women with ovulatory dysfunction, hCG administration before insemination may be beneficial.

Differential expression of L-selectin ligand in the endometrium during the menstrual cycle.

OBJECTIVE: To evaluate the expression of L-selectin ligand in the endometrium during the menstrual cycle. DESIGN: Retrospective study. SETTING: University teaching hospital. PATIENT(S): Endometrial samples from regularly cycling women. INTERVENTION(S): Tissue microarray and immunohistochemical staining were performed using L-selectin ligand monoclonal antibody (MECA-79). MAIN OUTCOME MEASURE(S): Expression of L-selectin ligand in the various phases of menstrual cycle was measured by a semiquantitative analysis (HSCORE) for the intensity of immunohistochemical reactivity. RESULT(S): In the luminal epithelium, there were significant differences in L-selectin ligand expression during the proliferative, interval, early secretory, and midsecretory phases. The expression of L-selectin ligand was greatest from the periovulatory interval through midsecretory phase. In the glandular epithelium, the expression of L-selectin ligand was greatest in midsecretory phase with significant differences between proliferative phase and the midsecretory phase and between the interval phase and the midsecretory phase. CONCLUSION(S): Increased expression of L-selectin ligand in the human endometrium during the early and midsecretory phases of the menstrual cycle may be related to the process of implantation.

Uterine myomas: an overview of development, clinical features, and management.

OBJECTIVE: To review the biology and the pathophysiology of uterine myomas, focus on options for management, and emphasize principles that will render the decision-making process as logical as possible. DESIGN: Literature review and synthesis of the authors' experience and philosophy. RESULTS: Uterine myomas are the most common solid pelvic tumors in women. There is increasing evidence that they have a genetic basis and that their growth is related to genetic predisposition, hormonal influences, and various growth factors. Treatment choices are wide and include pharmacologic, surgical, and radiographically directed intervention. Most myomas can be followed serially with surveillance for development of symptoms or progressive growth. CONCLUSION: The past century has witnessed development of highly sophisticated diagnostic and therapeutic technology for myomas. The tools currently at our disposal permit greater management flexibility with safe options, which must be tailored to the individual clinical situation.

Impact of semen characteristics on the success of intrauterine insemination.

PURPOSE: To evaluate the influence of sperm characteristics on the outcome of infertility treatment using intrauterine insemination (IUI). METHODS: Retrospective study of 431 infertility couples who underwent 1007 IUI treatment cycles from June 1999 to October 2002. Sperm parameters before and after preparation for IUI were evaluated and correlated with pregnancy outcome. RESULTS: Clinical pregnancy occurred in 12% of cycles and 28% of patients. Initial sperm motility and processed forward progression were independently associated with pregnancy after IUI. The mean number of cycles per patient was 4.3. Although pregnancy rate per cycle did not differ from cycle to cycle, the cumulative pregnancy rate approached plateau after five cycles. CONCLUSIONS: Sperm motility is an independent factor influencing IUI-related pregnancy. A forward progression score of 3 to 4 in a processed specimen is necessary for IUI success. The number of IUI attempts per patient should be individualized depending upon the needs of patients.

Clinical outcome of using ganirelix acetate versus a 4-day follicular phase leuprolide acetate protocol in unselected women undergoing in vitro fertilization.

OBJECTIVE: To compare the clinical outcome of controlled ovarian hyperstimulation (COH) in unselected patients undergoing IVF using multidose ganirelix acetate versus 4 days of administration of leuprolide acetate. DESIGN: Retrospective cohort study. SETTING: A fertility and IVF center. PATIENT(S): Two hundred forty-seven women who underwent COH-IVF between April 1, 1999, and January 30, 2001. INTERVENTION(S): Pituitary suppression according to a 4-day follicular phase leuprolide acetate protocol (236 women) or a multidose ganirelix acetate regimen (133 women). MAIN OUTCOME MEASURE(S): Amount of gonadotropin used, days of stimulation, cancellation rate, number of oocytes retrieved, implantation rate, and clinical pregnancy rate. RESULT(S): Compared with leuprolide acetate recipients, ganirelix recipients required significantly less gonadotropin and the mean day of hCG administration was 4 days earlier. Among women younger than 35 years of age, the implantation rate (15% vs. 6%) and the clinical pregnancy rate per initiated and transferred cycle (27% vs. 12% and 32% vs. 15%, respectively) were significantly higher in the ganirelix group than the leuprolide acetate group. CONCLUSION(S): Compared with a 4-day leuprolide acetate protocol, COH-IVF using a multidose ganirelix acetate protocol reduces treatment duration and amount of gonadotropin used. In younger women, the latter protocol is associated with significantly better pregnancy and implantation rates.