Assessment of endometrial receptivity during implantation window in women with unexplained infertility.

This study aimed to assess the endometrial receptivity during implantation window in women with unexplained infertility. A prospective study recruited 168 women with unexplained infertility and 169 fertile women. Ultrasonic parameters and biomarkers in the uterine fluid were detected. The endometrial vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were significantly higher in fertile women as compared with unexplained infertile women, and the integrin αvß3, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), and leukemia inhibitory factor (LIF) levels in uterine fluid were significantly higher in fertile women. The biochemical pregnancy rate, clinical pregnancy rate, and ongoing pregnancy rate in fertile women were 20.12%, 18.34%, and 17.75%, respectively, which were significantly higher compared with unexplained infertile women (7.14%, 5.36%, and 4.17%, respectively). Endometrial thickness (ET), endometrial volume (EV), VI, FI, and VFI measured by ultrasound, and the integrin αvß3, VEGF, TNF-α, and LIF levels in uterine fluid were all significantly higher in pregnant women as compared with nonpregnant women. The best parameters of ultrasonic indicators for predicting endometrial receptivity in women with unexplained infertility were FI(AUC = 0.894, sensitivity 93.8%, and specificity 83.1%). Integrin αvß3 had the best predictive value for endometrial receptivity among biomarkers in the uterine fluid (AUC = 0.921, sensitivity 96.7%, and specificity 89.5%). Women with unexplained infertility present declined endometrial receptivity. Endometrial ultrasonic parameters detected by three-dimensional power Doppler and biomarkers in the uterine fluid may be effective indicators to predict endometrial receptivity.

Comparison of sonohysterography to hysterosalpingogram for tubal patency assessment in a multicenter fertility treatment trial among women with polycystic ovary syndrome.

PURPOSE: To compare saline infusion sonohysterography (SIS) versus hysterosalpingogram (HSG) for confirmation of tubal patency. METHODS: Secondary analysis of a randomized controlled trial, Pregnancy in Polycystic Ovary Syndrome II (PPCOS II). Seven hundred fifty infertile women (18-40 years old) with polycystic ovary syndrome (PCOS) were randomized to up to 5 cycles of letrozole or clomiphene citrate. Prior to enrollment, tubal patency was determined by HSG, the presence of free fluid in the pelvis on SIS, laparoscopy, or recent intrauterine pregnancy. Logistic regression was conducted in patients who ovulated with clinical pregnancy as the outcome and HSG or SIS as the key independent variable. RESULTS: Among women who ovulated, 414 (66.9%) had tubal patency confirmed by SIS and 187 (30.2%) had at least one tube patent on HSG. Multivariable analysis indicated that choice of HSG versus SIS did not have a significant relationship on likelihood of clinical pregnancy, after adjustment for treatment arm, BMI, duration of infertility, smoking, and education (OR 1.14, 95% CI 0.77, 1.67, P = 0.52). Ectopic pregnancy occurred more often in women who had tubal patency confirmed by HSG compared to SIS (2.8% versus 0.6%, P = 0.02). CONCLUSIONS: In this large cohort of women with PCOS, there was no significant difference in clinical pregnancy rate between women who had tubal patency confirmed by HSG versus SIS. SIS is an acceptable imaging modality for assessment of tubal patency in this population.

Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups (GDGs), and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (a) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (b) reducing unnecessary testing; (c) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (d) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.

Intracytoplasmic sperm injection use in states with and without insurance coverage mandates for infertility treatment, United States, 2000-2015.

OBJECTIVE: To compare indications and trends in intracytoplasmic sperm injection (ICSI) use for in vitro fertilization (IVF) cycles among residents of states with and without insurance mandates for IVF coverage. DESIGN: Cross-sectional analysis of the National Assisted Reproductive Technology Surveillance System from 2011 to 2015 for the main outcome and from 2000 to 2015 for trends. SETTING: IVF cycles performed in U.S. fertility clinics. PATIENT(S): Fresh IVF cycles. INTERVENTION(S): Residency in a state with an insurance mandate for IVF (n = 8 states) versus no mandate (n = 43 states, including DC). MAIN OUTCOME MEASURE(S): ICSI use by insurance coverage mandate status stratified by male-factor infertility diagnosis. RESULT(S): During 2000-2015, there were 1,356,377 fresh IVF cycles, of which 25.8% (n = 350,344) were performed for residents of states with an insurance coverage mandate for IVF. ICSI use increased significantly during 2000-2015 in states both with and without a mandate; however, for non-male-factor infertility cycles, the percentage increase in ICSI use was greater among nonmandate states (34.6% in 2000 to 73.9% in 2015) versus mandate states (39.5% in 2000 to 63.5% in 2015). For male-factor infertility cycles, this percentage increase was ∼7.3% regardless of residency in a state with an insurance mandate for IVF. From 2011 to 2015, ICSI use was lower in mandate versus nonmandate states, both for cycles with (91.5% vs. 94.5%), and without (60.3% vs. 70.9%) male-factor infertility. CONCLUSION(S): Mandates for IVF coverage were associated with lower ICSI use for non-male-factor infertility cycles.

Assessment of Fallopian Tube Fimbria Patency With 4-Dimensional Hysterosalpingo-Contrast Sonography in Infertile Women.

OBJECTIVES: The purpose of this study was to evaluate the performance of 4-dimensional (4D) hysterosalpingo-contrast sonography (HyCoSy) for assessing fallopian tube fimbria patency in infertile women. METHODS: Seventy-seven infertile female patients with obstruction at the tubal fimbria or partial obstruction with pelvic adhesions were included. All of the patients underwent 4D HyCoSy enhanced by dynamic observation after a flush of normal saline and were followed with laparoscopic chromopertubation using methylene blue within 6 months. RESULTS: The overall accordance between 4D HyCoSy and laparoscopic chromopertubation was 92.9%. The sensitivity and specificity of 4D HyCoSy with laparoscopic chromopertubation as a reference standard were 93.8% and 92.2%, respectively. CONCLUSIONS: Four-dimensional HyCoSy can be the preferred method for assessment of tubal fimbria patency and pelvic adhesions surrounding the ovaries, with its advantages of accuracy, noninvasiveness, and a good safety profile.

New methods to improve the safety assessment of cryopreserved ovarian tissue for fertility preservation in breast cancer patients.

OBJECTIVE: To develop a novel molecular panel of markers to detect breast cancer (BC) disseminated malignant cells in ovarian tissue, and to improve the safety of ovarian tissue transplantation. DESIGN: Experimental study. SETTING: University hospital. PATIENT(S): Ten ovarian biopsies from healthy patients, 13 biopsies with diagnosed BC metastasis, and 4 biopsies from primary BC tumor for designing a diagnostic panel of BC cell contamination; 60 ovarian biopsies from BC patients undergoing fertility preservation for validating the panel. ANIMAL(S): Female nude mice. INTERVENTION(S): A novel panel for BC malignant cell detection by reverse-transcription polymerase chain reaction (RT-PCR), inmmunohistochemical analysis, in vitro invasion assay and xenotransplantation assayed in ovarian tissue from BC patients. MAIN OUTCOME MEASURE(S): Expression of GCDFP15, MGB1, SBEM, MUC1, WT-1, and NY-BR-01, selected as markers, assessed by quantitative RT-PCR in samples with confirmed BC metastasis. The most sensitive markers were confirmed by immunohistochemistry, and tested in vitro and in vivo. RESULT(S): GCDFP15, MGB1, and SBEM were the most sensitive and specific markers to detect BC metastatic cells when at least one was expressed by quantitative RT-PCR. The panel was validated in 60 patients and confirmed in an in vitro invasion assay, where no invasive cells were observed. Samples negative for BC cells cannot develop disease when xenografted. CONCLUSION(S): GCDFP15, MGB1, and SBEM were the most sensitive molecules to create a diagnostic panel for BC malignant cell contamination, which may make ovarian tissue cryopreservation and transplantation a safe technique for fertility preservation in BC patients.

The oviduct: a neglected organ due for re-assessment in IVF.

The oviduct has long been considered a 'pipeline', a tube allowing transit of spermatozoa and embryos; this perspective has been reinforced by the success of human IVF. Evidence accumulated over several decades, however, indicates that embryos can modulate the metabolism of tubal cells in their environment. Human IVF culture media is based on formulations that pass mouse embryo assays as quality control: the requirements of mouse embryos differ from those of human embryos, and therefore conditions for human IVF are far removed from the natural environment of the oviduct. The preimplantation environment, both in vitro and in vivo, is known to affect the health of offspring through mechanisms that influence imprinting. Recent studies also show that male accessory glands act in synergy with the oviduct in providing an optimal environment, and this represents a further perspective on the oviduct's contribution to harmonious embryo development and subsequent long-term health. The metabolism of the human embryo is far from being understood, and a 'return' to in-vivo conditions for preimplantation development is worthy of consideration. Although results obtained in rodents must be interpreted with caution, lessons learned from animal embryo culture must not be neglected.

Anti-Müllerian hormone and assessment of ovarian reserve after ovarian toxic treatment: a systematic narrative review.

Since serum anti-Müllerian hormone (AMH) levels enable quantitative evaluation of ovarian damage, we conducted a computer-based search, using key words, of all articles published in English through the PubMed database from inception until September 2013 to summarize available studies evaluating ovarian reserve after ovarian toxic interventions to discuss the usefulness of serum AMH levels. We found that most of the studies demonstrated a decline in serum AMH levels when compared to control or pretreatment levels, with levels dependent on the type of treatment modality. Measurement of serum AMH levels enables quantitative evaluation of ovarian damage caused by ovarian toxic interventions, such as chemotherapy and radiotherapy, instead of qualitative evaluation using menstrual condition or basal follicle-stimulating hormone levels. Serum AMH levels are becoming indispensable to assess the ovarian reserve of patients who desire preservation of ovarian function for fertility and endogenous sex steroid hormones.

Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus ανß3 testing in women with unexplained infertility.

OBJECTIVE: To evaluate endometrial leukemia inhibitor factor (LIF) expression as a marker of endometrial receptivity in women with unexplained infertility (UI). DESIGN: Prospective case-control study. SETTING: University-associated infertility clinics. PATIENT(S): Women with UI for more than 1 year and healthy control women. INTERVENTION(S): Endometrial biopsy. MAIN OUTCOME MEASURE(S): Time to pregnancy was compared between patients with UI who were evaluated for endometrial LIF protein as well as ανß3 integrin expression. Endometrium was evaluated using immunohistochemistry (IHC) and messenger RNA by real time reverse transcriptase-polymerase chain reaction (PCR) (quantitative real-time reverse transcriptase-PCR) in samples from women with UI as well as healthy control women. RESULT(S): Leukemia inhibitor factor was expressed in epithelial cells in a cyclic fashion in controls, and overall expression in the secretory phase was similar between controls and women with UI, whereas ανß3 integrin expression was reduced. However, using quantitative real-time PCR, LIF messenger RNA abundance was 4.4-fold lower in women with low levels of ανß3 integrin expression compared with samples with normal integrins. By immunohistochemistry, ανß3 integrin expression was always lacking when the histology was out of phase, whereas LIF expression was only negative in a subset of those samples. Reduced endometrial LIF expression was strongly associated with poor reproductive outcomes. CONCLUSION(S): Endometrial LIF expression peaks in the midsecretory phase and is reduced in some women with UI. The use of LIF in combination with ανß3 integrin as biomarkers appears to be superior to integrin testing alone when evaluating endometrial receptivity, primarily because of its earlier pattern of expression during the secretory phase.

Use of fertility treatment modalities in a large United States cohort of professional women.

OBJECTIVE: To evaluate the use of fertility treatments among a large cohort of women in the United States. DESIGN: Cohort study. SETTING: Nurses' Health Study II. PATIENT(S): Ten thousand thirty-six women who reported having used fertility treatment on biennial questionnaires from 1993-2009. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Data on patterns of treatment modality were collected via self-report from validated mailed questionnaires. Information on clomiphene, gonadotropin injections alone, and gonadotropin injections as part of intrauterine insemination (IUI) and in vitro fertilization (IVF) was queried. RESULT(S): Most women who reported fertility treatment used clomiphene (94%), with a large majority reporting clomiphene as their only form of treatment (73%). Of women who reported treatment more advanced than clomiphene, 13% had used gonadotropin injections alone, 11% IUI treatment, and 11% IVF. Several subgroups were more likely to use multiple treatment modalities and to initiate treatment with gonadotropins rather than clomiphene, including women living in states with insurance coverage of fertility procedures, with higher household income, younger in age, who remained nulliparous at the study close, and treated after 2000. CONCLUSION(S): Results should be interpreted cautiously, but to our knowledge, this represents the first study of fertility treatment patterns in the United States and could inform public health planning.

Antimüllerian hormone, the assessment of the ovarian reserve, and the reproductive outcome of the young patient with cancer.

The accurate assessment of the ovarian reserve has long been a key goal in reproductive medicine. The recognition that serum antimüllerian hormone provides an indirect measure of the ovarian reserve has led to its rapid adoption in assisted conception, and wide exploration of its potential across the reproductive lifespan from the neonate to the menopause. In this short review we discuss its relationship with the ovarian reserve in its varied meanings, and in various contexts. These include in childhood and adolescence, and in the assessment of the impact of cancer therapy on the female reproductive tract. These therapies can adversely impact all aspects of female reproduction, including hypothalamic, pituitary, and ovarian hormonal activity, and the ability of the uterus to support a successful pregnancy.

Levels and associations among self-esteem, fertility distress, coping, and reaction to potentially being a genetic carrier in women with diminished ovarian reserve.

OBJECTIVE: To measure the level of distress and its relationship with other psychologic factors in women with diminished ovarian reserve (DOR) who participated in a fragile X genetics study. DESIGN: Longitudinal data analyzed with structural equation modeling. SETTING: Four U.S. private and academic fertility centers. PATIENT(S): Sixty-two infertile patients with DOR. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fertility Problem Inventory, Coping Scale for Infertile Couples, Rosenberg Self-Esteem, Health Orientation Scale. RESULT(S): Nineteen percent had low fertility distress, 56% had average fertility distress, and 24% had high fertility distress. Thirty-six percent self-reported a "favorable" or "very favorable" emotional response to potentially being a fragile X carrier (termed "emotions"), 53% were "ambivalent," and 11% had an unfavorable reaction. Three months after learning that they were not a carrier, these percentages were 91%, 9%, and 0%, respectively. Emotions at this second time point were significantly more positive than at pretesting. At baseline, higher self-esteem was a significant predictor of reduced fertility distress both directly and indirectly through emotions. Fertility distress was not associated with coping. Self-esteem, fertility distress, pretesting emotions, and coping were unrelated to posttesting emotions. CONCLUSION(S): The potential of having an explanation for one's DOR condition may have a beneficial impact on women's psychologic states during the process of genetic testing, and this appeared to be especially true for women with higher self-esteem. Psychologic interventions targeted to women with low self-esteem may reduce distress and improve reactions to genetic testing.

Assessment and treatment of repeated implantation failure (RIF).

Repeated implantation failure (RIF) is determined when embryos of good quality fail to implant following several in vitro fertilization (IVF) treatment cycles. Implantation failure is related to either maternal factors or embryonic causes. Maternal factors include uterine anatomic abnormalities, thrombophilia, non-receptive endometrium and immunological factors. Failure of implantation due to embryonic causes is associated with either genetic abnormalities or other factors intrinsic to the embryo that impair its ability to develop in utero, to hatch and to implant. New methods of time-lapse imaging of embryos and assessment of their metabolic functions may improve selection of embryos for transfer, and subsequent outcomes for IVF patients, as well as for those diagnosed with RIF. This review discusses the various causes associated with RIF and addresses appropriate treatments.

Assessment of FSHR variants and antimüllerian hormone in infertility patients with a reduced ovarian response to gonadotropin stimulation.

OBJECTIVE: To study women with a poor response to ovarian hormone stimulation, known as low responders. Genetic defects in the FSH receptor gene (FSHR) were analyzed as well as antimüllerian hormone (AMH) for ovarian reserve. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): Two hundred fifty-nine patients total: 74 low responders; 88 patients receiving assisted reproduction therapy (ART) with a normal ovarian response; and 97 women with a normal fertility status. INTERVENTION(S): DNA from patients was analyzed using real-time polymerase chain reaction. Serum concentrations of AMH were assessed using ELISA. MAIN OUTCOME MEASURE(S): The FSHR variants Asn680Ser (rs6166), Ala189Val (rs121909658), Ile160Thr (rs121909659), Thr449Ile (rs28928870) and the serum AMH concentrations were assessed. RESULT(S): With the exception of the frequent Asn680Ser polymorphism, no homozygotic SNPs of FSHR were found. In the group of ART patients, Thr160/Ile160 variants were more frequent in comparison with women with normal fertility. The Ser680/Ser680 was more frequent in ART patients than in women with normal reproductive function. The rate of live births was markedly reduced, particularly in the low responder group. No difference was noted in the distribution of the Ala189Val and Thr449Ile variant. Low serum AMH values were observed in 75% of the low responder group. CONCLUSION(S): FSHR gene variations such as Asn680Ser, Ala189Val, Thr449Ile, and Ile160Thr did not seem to be a decisive factor of poor response to fertility treatment, whereas the low ovarian reserve determined by AMH is considered more crucial.

Fertility preservation for social indications: a cost-based decision analysis.

OBJECTIVE: Age-related infertility remains a problem that assisted reproductive techniques (ART) have limited ability to overcome. Correspondingly, because an increasing number of women are choosing to delay childbearing, fertility preservation strategies, initially intended for patients undergoing gonadotoxic therapies, are being applied to this group of healthy women. Studies supporting the effectiveness of this practice are lacking. DESIGN: Decision analytic techniques. SETTING: We compared the cost-effectiveness of three strategies for women planning delayed childbearing until age 40: oocyte cryopreservation at age 25, ovarian tissue cryopreservation (OTC) at age 25, and no assisted reproduction until spontaneous conception had been attempted. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Cost-effectiveness, which was defined as the cost per live birth. RESULT(S): In this analysis, the strategy of foregoing fertility preservation at age 25 and then choosing ART only after not spontaneously conceiving at age 40 was the most cost-effective option. OTC was dominated by the other strategies. Sensitivity analyses demonstrated the robustness of the model; no analysis existed in which OTC was not dominated by oocyte cryopreservation. Increasing the cost of an IVF cycle beyond $22,000 was the only situation in which oocyte cryopreservation was the most preferred strategy. CONCLUSION(S): Neither oocyte cryopreservation nor OTC appear to be cost-effective under current circumstances for otherwise healthy women planning delayed childbearing. This analysis should give pause to the current practice of offering fertility preservation based only on the desire for delayed childbearing.

Childless women's knowledge of fertility and assisted human reproduction: identifying the gaps.

OBJECTIVE: To determine the knowledge about fertility and assisted human reproduction (AHR) treatments of a large sample of childless women. DESIGN: Self-report questionnaire comprising two self-ratings of current fertility and AHR knowledge, and 16 knowledge questions related to fertility and AHR. SETTING: Online. PATIENT(S): A total of 3,345 childless women between the ages of 20 and 50. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Knowledge of fertility and AHR. RESULT(S): The majority of participants rated themselves as having some knowledge or being fairly knowledgeable about fertility and AHR. However, on the 16 knowledge questions, overall knowledge was low, with 50% or more of the sample answering only 6 of 16 questions correctly. CONCLUSION(S): The data suggest that the women in the study have no coherent body of knowledge regarding age-related fertility and AHR treatment options. With an increasing number of women electing to delay childbearing, there is a critical need for public education regarding age-related fertility declines and the availability, costs, and limitations of AHR. This study offers important mental health contributions to infertility prevention and public health education efforts.

An assessment of female university students' attitudes toward screening technologies for ovarian reserve.

OBJECTIVE: To assess female university students' attitudes toward screening technologies for ovarian reserve and their potential influence on career and family planning decisions. DESIGN: Online survey. SETTING: Not applicable. PATIENT(S): Respondents from 4 universities in Northern California. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Proportion with interest in screening technologies for ovarian reserve. RESULT(S): Of the 328 respondents, 79% were interested in learning about the current status of their ovarian reserve. Hypothetically, if informed that ovarian reserve was very low, 53% would consider oocyte cryopreservation (even when informed that it is experimental); however, only 29% would consider stopping educational or professional pursuits to focus on conceiving. Participants also demonstrated gaps in knowledge, believing that the decline in ovarian reserve starts later than it actually does, that diet and nutrition can preserve ovarian reserve, and that infertility treatments are highly effective regardless of how severe the depletion of the egg supply is. CONCLUSION(S): Women attending universities are interested in assessing their own ovarian reserve. Gaps in knowledge about ovarian reserve exist among these reproductive-aged women.