Long-term reproductive outcomes in patients with unexplained infertility: follow-up of the Fast Track and Standard Treatment Trial participants.

OBJECTIVE: To evaluate long-term reproductive outcomes in couples who were enrolled in a large randomized controlled trial that studied optimal treatment for unexplained infertility. DESIGN: Telephone survey, administered between March 2019 and February 2020. SETTING: Large urban university-affiliated fertility center. PATIENT(S): Couples who enrolled in the Fast Track and Standard Treatment Trial (FASTT). INTERVENTION(S): None. MAIN OUTCOMES MEASURE(S): Number of live births, methods of conception, adoption, and satisfaction regarding family size. RESULT(S): Of the 503 couples enrolled in FASTT, 311 (61.8%) were contacted and 286 (56.9%) consented to participate. The mean age and follicle-stimulating hormone level at the time of enrollment in FASTT were 33.1 ± 3.2 years and 6.8 ± 2.2 mIU/mL, respectively, for those who participated in this study. The mean age at follow-up was 49.5 ± 3.4 years. Of the 286 women, 194 (67.8%) had a live birth during the trial and 225 (78.7%) continued to try to conceive after FASTT. Of those who tried to conceive without treatment, 101 of 157 (64.3%) had a successful live birth, whereas 12 (5.3%) women had a live birth via intrauterine insemination and 82 (36.4%) via autologous oocyte in vitro fertilization. Overall, 182 (80.9%) women achieved a live birth after FASTT. CONCLUSION(S): The majority of couples were able to achieve a live birth after FASTT. Only 19 (6.6%) never achieved a live birth during their reproductive years. Moving to treatment sooner allows the opportunity to achieve >1 live birth, which is associated with increased satisfaction regarding family size. This further supports access to care and insurance coverage for infertility treatment.

Simulation training for embryo transfer: findings from the American Society for Reproductive Medicine Embryo Transfer Certificate Course.

OBJECTIVE: To assess the value of the American Society for Reproductive Medicine Embryo Transfer Certificate Course in confidence and skill building for performing a live embryo transfer (ET). DESIGN: Prospective cohort study. SETTING: Two-day simulation workshops of reproductive endocrine and infertility (REI) fellows from American Board of Obstetrics and Gynecology-approved training programs, using four different uterine models (A-D). PATIENT(S): None. INTERVENTION(S): Didactic and hands-on simulation training program. MAIN OUTCOME MEASURE(S): Primary outcomes included ET simulation scores of all exercises analyzed at various points of the training and self-assessed confidence before and after the completion of the Embryo Transfer Certificate Course based on a 6-point Likert scale and association of both with extent of prior live ET experience and year of fellowship. RESULT(S): Data were collected for 78 REI fellows who completed the Embryo Transfer Certificate Course and demonstrated significant improvements in both skill and confidence. The data for a subset of 58 fellows who performed five direct transfers on both Embryo Transfer Certificate Course uterine models A and B demonstrated significant overall improvement in ET simulation scores between the first and fifth direct transfers. A separate data subset of 57 fellows who performed five afterload transfers for each exercise on all four uterine models demonstrated differences in difficulty among them. Embryo transfer simulation using the uterine A model was consistently the easiest. The ET simulation scores for fellows using the uterine B and C models showed a progressive and significant increase across the five afterload ETs. When using the uterine D model, ET simulation scores increased significantly between the first and second transfers but remained at the same level for the remaining three transfers. Except for uterus A, a significant increase in ET simulation scores between the first and last transfers was observed for fellows overall in all afterload transfers and for those fellows with <50 prior live transfers. Data for all 78 fellows demonstrate a significant gain of self-confidence for all parameters, with the highest overall increase (78%) observed for first-year fellows as well as for fellows of any year with no prior live transfer experience (109%). Fellows with the largest number of prior live ET experience started with higher confidence, which also increased significantly, although they had a lower gain in confidence compared with fellows with less experience. CONCLUSION(S): The American Society for Reproductive Medicine Embryo Transfer Certificate Course data analysis demonstrates the effectiveness of simulator-based ET training for REI fellows across the 3 years of training, regardless of prior experience with live ET.

Genes invoked in the ovarian transition to menopause.

Menopause and the associated declines in ovarian function are major health issues for women. Despite the widespread health impact of this process, the molecular mechanisms underlying the aging-specific decline in ovarian function are almost completely unknown. To provide the first gene-protein analysis of the ovarian transition to menopause, we have established and contrasted RNA gene expression profiles and protein localization and content patterns in healthy young and perimenopausal mouse ovaries. We report a clear distinction in specific mRNA and protein levels that are noted prior to molecular evidence of steroidogenic failure. In this model, ovarian reproductive aging displays similarities with chronic inflammation and increased sensitivity to environmental cues. Overall, our results indicate the presence of mouse climacteric genes that are likely to be major players in aging-dependent changes in ovarian function.

National survey of the Society for Assisted Reproductive Technology membership regarding insurance coverage for assisted reproductive technologies.

OBJECTIVE: To assess the attitudes of Society for Assisted Reproductive Technology (SART) members regarding expanding insurance coverage for patients seeking assisted reproductive technologies (ART) and identify some of the factors that may influence such attitudes. DESIGN: An anonymous online 14-question survey of SART membership; 1,556 surveys were sent through the SART Research Portal from June to December 2017. Questions were incremental in scope, beginning with expanding insurance coverage for ART for vulnerable populations (e.g., fertility preservation for cancer, couples with same recessive gene, fertility preservation for transgender individuals) to extending coverage to include patients who were uninsured for ART. Additional questions assessed attitudes about assuming some fiscal responsibility if mandated insurance were contingent on elective single-embryo transfer (eSET) and lower charges in anticipation of increased number of cases. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Specific response to 14 survey questions. RESULT(S): The overall response rate was 43.4% (675/1,556). A large majority (>95%) favored insurance for fertility preservation for cancer patients and for avoidance of genetic disorders; 62.3% were supportive of infertility insurance coverage for transgender patients; 78% supported expanding insurance for the broadest segment of the general uninsured population; 76.7% supported expanding insurance contingent on eSET; and 51.3% would consider expanding insurance contingent on lowering charge per cycle in general, but only 23% responded as to what lower charge would be acceptable. Three of four factors were shown by multivariable logistic regression to be predictive of attitudes willing to expand insurance: practice setting (academic > hybrid > private), practicing in a mandated state, and higher annual volume of cases (>500 cycles); these had significant increased adjusted odds ratios ranging from 1.7 to 2.9. A fourth factor, the professional role one had in the practice, was not found to be of significant predictive value. CONCLUSION(S): The great majority of respondents were supportive of expanding insurance for specific segments of vulnerable populations with special needs and for the population who are presently uninsured. Furthermore, the majority of respondents would consider expanding insurance coverage contingent on age-appropriate eSET but have concerns about reduced reimbursement. Those most likely to be willing to expand insurance are those who practice in an academic setting or a mandated state and/or have a high annual volume of cases.

A mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadism.

CONTEXT: Kallmann syndrome (KS) consists of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia/hyposmia. Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis. OBJECTIVE: Mutations in FGFR1 typically demonstrate reduced penetrance, variable expressivity, and until recently have been exclusively identified in families with anosmia. The purpose of this study was to determine whether FGFR1 mutations were present in a unique family with autosomal dominant, fully penetrant, normosmic IHH. DESIGN: The study is a review of detailed clinical findings, dynamic endocrine studies, and performance of a molecular analysis of the FGFR1 gene. SETTING: The study was carried out in an academic medical center. PATIENTS: All four affected individuals have complete IHH with full penetrance but no anosmia/hyposmia, and they have none of the FGFR1-associated anomalies. In addition, no other family member has anosmia. Inverventions: Interventions included detailed phenotype characterization including history, physical exam, smell testing, dynamic pituitary testing, brain imaging, and molecular analysis. MAIN OUTCOME MEASURES: Outcome was measured by the determination of the severity of IHH, olfactory function, and sequence of the FGFR1 gene. RESULTS: The same heterozygous nonsense mutation, Arg622X, was present in all four affected members, but not in three unaffected members or 100 controls. The mutation is predicted to encode a truncated protein or result in nonsense-mediated decay. CONCLUSIONS: Our findings indicate that mutations in the FGFR1 gene can cause normosmic, fully penetrant, complete IHH with little or no variable expressivity, and without the other FGFR1-associated anomalies typically found in KS.

Embryo transfer techniques: an American Society for Reproductive Medicine survey of current Society for Assisted Reproductive Technology practices.

OBJECTIVE: To better understand practice patterns and opportunities for standardization of ET. DESIGN: Cross-sectional survey. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): An anonymous 82-question survey was emailed to the medical directors of 286 Society for Assisted Reproductive Technology member IVF practices. A follow-up survey composed of three questions specific to ET technique was emailed to the same medical directors. Descriptive statistics of the results were compiled. MAIN OUTCOME MEASURE(S): The survey assessed policies, protocols, restrictions, and specifics pertinent to the technique of ET. RESULT(S): There were 117 (41%) responses; 32% practice in academic settings and 68% in private practice. Responders were experienced clinicians, half of whom had performed <10 procedures during training. Ninety-eight percent of practices allowed all practitioners to perform ET; half did not follow a standardized ET technique. Multiple steps in the ET process were identified as "highly conserved;" others demonstrated discordance. ET technique is divided among [1] trial transfer followed immediately with ET (40%); [2] afterload transfer (30%); and [3] direct transfer without prior trial or afterload (27%). Embryos are discharged in the upper (66%) and middle thirds (29%) of the endometrial cavity and not closer than 1-1.5 cm from fundus (87%). Details of each step were reported and allowed the development of a "common" practice ET procedure. CONCLUSION(S): ET training and practices vary widely. Improved training and standardization based on outcomes data and best practices are warranted. A common practice procedure is suggested for validation by a systematic literature review.

A balanced chromosomal translocation involving chromosomes 3 and 16 in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome reveals new candidate genes at 3p22.3 and 16p13.3.

BACKGROUND: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, or the congenital absence of uterus and vagina, is the most severe anomaly of the female reproductive tract. It affects 1 in 5,000 females, and is the second most common cause of primary amenorrhea. The etiology remains unknown in most patients, although four single gene defects and some repetitive copy number variants (CNVs) have been identified. Translocations in MRKH patients are very rare, and reported only in three patients previously without breakpoint mapping. We have identified the fourth MRKH translocation patient and are the first to characterize the breakpoints mapped by molecular methods. RESULTS: The proband is a 17- year old white female with agenesis of the uterus and vagina who had a peripheral blood karyotype revealing a de novo balanced translocation 46,XX,t(3;16)(p22.3;p13.3)dn. There were no known related anomalies present in the proband or her family. No CNVs were found by chromosomal microarray analysis, and no genes were directly disrupted by the translocation. DNA sequencing of six nearby candidate genes-TRIM71, CNOT10, ZNF200, OR1F1, ZNF205, and ZNF213-did not reveal any mutations. RT-qPCR of proband lymphoblast RNA for 20 genes near the breakpoints of 3p22.3 and 16p13.3 showed significantly altered expression levels for four genes in the proband compared to three white female controls, after correction for multiple comparisons. Reduced expression was seen for CMTM7 and CCR4 on 3p22.3, while increased expression was observed for IL32 and MEFV on 16p13.3. CONCLUSION: We have mapped the breakpoints of our t(3;16)(p22.3;p13.3) translocation patient using molecular methods to within 13.6 kb at 3p22.3 and within 1.9 kb for 16p13.3 and have suggested 10 nearby genes that become plausible candidate genes for future study.

Surfing the waves of change in reproductive medicine: past, present and future. A presentation of the 2014 ASRM Strategic Plan.

A presentation at the Opening Ceremony of the ASRM Seventieth Annual Meeting reviews advances in reproductive medicine and presents an overview of the 2014 Strategic Plan: "Global Impact Through Dynamic Engagement."

Initiation of the gonadotropin-releasing hormone antagonist ganirelix for in vitro fertilization cycles in which the lead follicle is >14 mm.

The initiation of GnRH antagonists when the lead follicle is >14 mm does not adversely affect IVF success rates and leads to a shortened duration of GnRH antagonist administration.

Variations in individual physician success rates within an in vitro fertilization program might be due to patient demographics.

OBJECTIVE: To determine whether there are variations in individual physician success rates in an IVF program, even with uniform laboratory and treatment protocols. DESIGN: Retrospective analysis. SETTING: Boston IVF, a private practice. PATIENT(S): Patients <38 and 38-40 years of age who underwent non-donor egg, fresh embryo transfer (ET). INTERVENTION(S): Retrospective analysis of IVF success rates for Boston IVF for the year 1999, as reported to the Society of Assisted Reproductive Technology. MAIN OUTCOME MEASURE(S): Each individual physician's clinical pregnancy and live birth rates for patients aged <38 and 38-40 years for the year 1999. Pregnancy rates were also obtained for an "ideal patient group." RESULT(S): Among 13 physicians, the clinical pregnancy rate in the <38-year age group ranged from 20.5% to 35.1% and the live birth rates from 17.8% to 31.1%. For the 38-40-year age group, the clinical pregnancy rate ranged from 10.6% to 29.8% and live birth rates from 7.0% to 25.5%. There was no statistical difference in the clinical pregnancy rate for the ideal patient group. CONCLUSION(S): In the ideal patient group, in which patient demographics are uniform, there are no statistical differences in individual physician performance within the same IVF program. Variation exists in the success rates between the physicians in the <38- and 38-40-year age groups. Possibly this is owing to patient demographics.

Subcutaneous versus intramuscular administration of human chorionic gonadotropin during an in vitro fertilization cycle.

OBJECTIVE: To confirm that hCG levels in follicular fluid and serum would be comparable between i.m. and s.c. administration of purified hCG. DESIGN: In a prospective study, serum and follicular fluid levels of hCG after an i.m. or s.c. injection of 10,000 IU of hCG were evaluated 36 hours after injection, that is, at the time of oocyte retrieval. SETTING: This study was carried out in a university-affiliated IVF program. PATIENT(S): Forty women undergoing oocyte retrieval were entered into the study at the time of egg retrieval, that is, 36 hours after hCG administration. INTERVENTION(S): S.c. or i.m. injection of hCG. MAIN OUTCOME MEASURE(S): Serum and follicular fluid concentrations of hCG were evaluated 36 hours after injection at the time of oocyte retrieval. RESULT(S): There was a significantly higher serum hCG level in the s.c. group (348.6 +/- 98 IU/L) vs. the i.m. group (259.0 +/- 115 IU/L) and a significantly higher follicular fluid hCG level in the s.c. vs. the i.m. group (233.5 +/- 85 vs. 143.4 +/- 134 IU/L). CONCLUSION(S): After purified hCG administration via the s.c. route, both serum and follicular fluid levels are greater compared with the i.m. route.

Contemporary issues in primary amenorrhea.

Reproductive medicine has changed dramatically since the 1981 publication of the study of patients presenting with pubertal amenorrhea. The breakdown of causes likely remains unchanged, with the four most common causes of primary amenorrhea being ovarian failure (48.5%), congenital absence of the uterus and vagina (16.2%), GnRH deficiency (8.3%), and constitutional delay of puberty (6.0%). In the study of patients reported by Reindollar, 60% of patients had barriers to reproduction. Since its publication over 15 years ago, developments in assisted reproductive technologies have enabled pregnancy in many of these patients. Women with ovarian failure may gestate pregnancies from donated oocytes. Women with congenital absence of the uterus and vagina may have their fetuses carried in a surrogate uterus. During this period, the advances of molecular medicine have provided a better understanding of the etiologies of many of these disorders, including Turner's syndrome; 46,XY gonadal dysgenesis; 46,XX gonadal dysgenesis; hypogonadotropic hypogonadism; enzyme-deficient states; gonadotropin resistance; and androgen insensitivity. Contemporary issues related to these disorders involve information about molecular defects and outcome of pregnancies for patients previously considered sterile. Largely, this information has been extremely helpful and reassuring. However, the reported deaths of patients with Turner's syndrome who become pregnant by donor oocyte should remind us to proceed cautiously as new reproductive avenues are opened for these patients.

Turner syndrome in adolescence.

The management of a patient with Turner syndrome is complex and multi-faceted. It is best accomplished by an interdisciplinary approach. Initial diagnosis is generally prenatal or suggested by physical characteristics. Diagnosis should include karyotype analysis and potentially a probe for Y-chromosome centromeric material to assess the risk for the development of germ cell tumors. At the time of initial diagnosis, the patient should be thoroughly investigated for associated medical conditions. Ongoing surveillance for the development of complications is of paramount importance. The interdisciplinary team should include an endocrinologist; cardiologist; nephrologist; reproductive endocrinologist; audiological physician; ear, nose and throat surgeon; plastic surgeon; dentist; and psychologist . It is important to provide to girls and women with Turner syndrome, and their families, comprehensive information about the syndrome and to advise them about the availability of Turner syndrome societies that can provide information and support.

Normal onset of puberty have definitions of onset changed?

Puberty is the sequence of events that culminates in the ability to procreate. It is widely accepted that the onset of puberty in girls occurs on average at 8 years of age and that onset prior to 8 years of age is precocious puberty. As a result of the cross-sectional study by the American Association of Pediatrics, a movement exists to change the age limit of the onset of puberty to 6 years of age in black girls and 7 years of age in white girls. We should be cautious in adhering to strict age limits when diagnosing precocious puberty. Also the rapidity and progression of puberty should be evaluated, and if appropriate, therapy to suppress pubertal development considered.

When is clomiphene or gonadotropin intrauterine insemination futile? Results of the Fast Track and Standard Treatment Trial and the Forty and Over Treatment Trial, two prospective randomized controlled trials.

OBJECTIVE: To determine whether day 3 FSH and E2 levels at the upper limits of normal affect live-birth rates and treatment trajectory in a conventional versus "fast track" treatment program for IVF. DESIGN: Secondary analysis of two randomized controlled trials, FASTT and FORT-T. SETTING: Not applicable. PATIENT(S): Infertile women ages 21-42 years randomized to conventional or accelerated treatment with controlled ovarian hyperstimulation (COH)-IUI and/or IVF (n=603 patients contributing 2,717 total cycles). INTERVENTION(S): Patients were stratified according to basal FSH and E2: FSH<10 mIU/mL and E2<40 pg/mL (group 1A), FSH<10 mIU/mL and E2≥40 pg/mL (group 1B), FSH, 10-15 mIU/mL and E2<40 pg/mL (group 2A), and FSH, 10-15 mIU/mL and E2≥40 pg/mL (group 2B). MAIN OUTCOME MEASURE(S): Number of cancelled cycles, disenrollment for poor response, and cumulative live-birth rates per couple. RESULT(S): Women in groups 2A and 2B were more likely to have cancelled cycles and be disenrolled for poor response. While no live births occurred in group 2B during COH-IUI (0/19 couples, 0/58 cycles), IVF still afforded these patients a reasonable chance of success (6/18 couples, 6/40 cycles, 33.3% live-birth rate per couple). The specificity and positive predictive value of basal FSH of 10-15 mIU/mL and E2≥40 pg/mL for no live birth during COH-IUI treatment were both 100%. CONCLUSION(S): Women who initiated infertility treatment with FSH of 10-15 mIU/mL and E2≥40 pg/mL on day 3 testing were unlikely to achieve live birth after COH-IUI treatment.

Female dietary antioxidant intake and time to pregnancy among couples treated for unexplained infertility.

OBJECTIVE: To determine whether increased antioxidant intake in women is associated with shorter time to pregnancy (TTP) among a cohort of couples being treated for unexplained infertility. DESIGN: Secondary data analysis of a randomized controlled trial. SETTING: Academic medical center associated with a private infertility center. PATIENTS: Females with unexplained infertility. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): The time it took to establish a pregnancy that led to a live birth. RESULT(S): Mean nutrient intake exceeded the estimated average requirement (EAR) for vitamins C and E. No differences in mean intake of any of the antioxidants were noted between women who delivered a live-born infant during the study period vs. those who did not. In multivariable models, intake of ß-carotene from dietary supplements was associated with shorter TTP among women with body mass index (BMI) ≥25 kg/m(2) (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.09-1.53) and women <35 y (HR 1.19, 95% CI 1.01-1.41). Intake of vitamin C from dietary supplements was associated with shorter TTP among women with BMI <25 kg/m(2) (HR 1.09, 95% CI 1.03-1.15) and women <35 y (HR 1.10, 95% CI 1.02-1.18). Intake of vitamin E from dietary supplements among women ≥35 y also was associated with shorter TTP (HR 1.07, 95% CI 1.01-1.13). CONCLUSION(S): Shorter TTP was observed among women with BMI <25 kg/m(2) with increasing vitamin C, women with BMI ≥25 kg/m(2) with increasing ß-carotene, women <35 y with increasing ß-carotene and vitamin C, and women ≥35 y with increasing vitamin E. CLINICAL TRIAL REGISTRATION NUMBER: NCT00260091.

A randomized clinical trial to determine optimal infertility treatment in older couples: the Forty and Over Treatment Trial (FORT-T).

OBJECTIVE: To determine the optimal infertility therapy for women at the end of their reproductive potential. DESIGN: Randomized clinical trial. SETTING: Academic medical centers and private infertility center in a state with mandated insurance coverage. PATIENT(S): Couples with ≥ 6 months of unexplained infertility; female partner aged 38-42 years. INTERVENTION(S): Randomized to treatment with two cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. MAIN OUTCOME MEASURE(S): Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after two treatment cycles and at the end of treatment. RESULT(S): We randomized 154 couples to receive CC/IUI (N = 51), FSH/IUI (N = 52), or immediate IVF (N = 51); 140 (90.9%) couples initiated treatment. The cumulative clinical pregnancy rates per couple after the first two cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatments, 110 (71.4%) of 154 couples had conceived a clinically recognized pregnancy, and 46.1% had delivered at least one live-born baby; 84.2% of all live-born infants resulting from treatment were achieved via IVF. There were 36% fewer treatment cycles in the IVF arm compared with either COH/IUI arm, and the couples conceived a pregnancy leading to a live birth after fewer treatment cycles. CONCLUSION(S): A randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group. CLINICAL TRIAL REGISTRATION NUMBER: NCT00246506.