Defects in sperm capacitation/fertilizing ability are equally prevalent across ages in men seeking fertility assistance.

RESEARCH QUESTION: How do capacitation ability, measured by Cap-Score™, and traditional semen analysis measures (volume, concentration, motility) change with age in men questioning their fertility (MQF)? DESIGN: Cap-Score and semen analysis measures were obtained from MQF (n = 2652; multicentric design: 35 reproductive endocrinologist prescribers, n = 16 clinics). Morphology was not included due to differences among clinics. A Mann-Whitney test was used to compare Cap-Scores between MQF and men with known recent paternity (n = 76). The following age groups were constructed for MQF: 20-24, 25-29, 30-34, 35-39, 40-44, 45-49 and 50+. Associations between semen analysis, Cap-Score and age groups were evaluated using mixed-model analysis of variance to identify possible influence of Cap-Score collection kit type (n = 763 collected at home; n = 1889 collected at clinics). RESULTS: MQF had reduced capacitation ability (mean ± SE; 29.25 ± 0.15 versus 35.34 ± 0.88; P < 0.001). No change in Cap-Score (P = 0.916) or concentration (P = 0.926) was detected with age group. In contrast, both volume (P = 0.008) and % motility (P < 0.001) declined with age. CONCLUSIONS: Men presenting because of difficulties in generating pregnancy showed equivalent reductions in capacitation ability regardless of age. In contrast, motility and volume declined with age. These data suggest that capacitation ability is a more sensitive indicator of male fertility across age groups than traditional semen analysis and should not be reserved for older men. Importantly, these data do not address whether sperm fertilizing ability declines in the general population as men age. Instead, they indicate that if men are having difficulty conceiving, no matter what their age, then defects in sperm fertilizing ability are equally likely to be the cause.

Platelet-rich plasma: inconclusive evidence of reproductive outcomes in menopausal women.

PURPOSE: The use of platelet-rich plasma is being investigated in reproductive medicine and clinically promoted as a fertility treatment for menopause. We aimed to review the literature on the impact of PRP on fertility in menopause. METHODS: A literature search was performed using the PubMed and MEDLINE search engines. The search was limited to the English language. Articles studying PRP use in menopause were selected for the purpose of this review. RESULTS: Limited case reports and case series studied fertility outcomes of PRP in menopause. Randomized controlled trials are lacking. Furthermore, no studies have been conducted to evaluate the effect of different PRP concentrations, injection techniques, or side effects on reproductive outcomes in menopausal women. CONCLUSION: There is a dearth of data to support the routine implementation of intraovarian PRP injections for fertility restoration in menopausal women. Patients considering such therapy need to be well aware of the lack of adequate data for PRP use in menopause and should be counseled accordingly.

The Disparities in ART (DART) Hypothesis of Racial and Ethnic Disparities in Access and Outcomes of IVF Treatment in the USA.

We propose the Disparities in ART (DART) hypothesis which identifies underlining causes that contribute to racial disparities in access and outcomes of ART treatment in the USA. Reasons for disparities in access and outcomes of ART treatment for infertility are derived from some relative contribution of four identified causes. They are simply stated as delays in obtaining treatment, higher dropout during and following unsuccessful ART treatment, provider factors, and differences in patient biological factors. Each of these causes has a subset of 4-6 factors that contribute to each of the 4 broad categorical causes that are discussed. This hypothesis may serve as a platform for better understanding the scope of the challenges and potential research inquiries that may lead to narrowing of racial/ethnic disparities in access and outcomes in ART.

Adenomyosis and infertility.

PURPOSE: Adenomyosis is a poorly understood entity with no unified treatment protocol. It has been thought to only affect the quality of life of older women, but growing evidence is highlighting the increased frequency of adenomyosis in younger patients and its possible effects on fertility outcomes. This can have a great impact on how clinicians screen, diagnose, and treat this condition. The aim of this review is to explore the relationship between adenomyosis and infertility. METHODS: A literature search of the keywords "adenomyosis", "infertility", "pregnancy" and "fertility" was conducted using the PubMed and Medline search engines. The articles selected were observational, systematic reviews, meta-analyses, and randomized controlled trials. The search was limited to English, abstracts were screened, and articles were selected. RESULTS: The literature reports lower clinical pregnancy rates, lower live birth rates, higher miscarriage rates, and higher odds of adverse obstetric outcomes in patients with adenomyosis. Treatment seems to be associated with higher pregnancy rates and live births rates. CONCLUSION: An association between adenomyosis and infertility seems to exist, and treatment could lead to improved fertility outcomes.

Endometrioma and assisted reproductive technology: a review.

PURPOSE: Endometriomas are a common cause of infertility necessitating assisted reproductive technology (ART). It had been previously thought that surgical removal of the endometriomas prior to ART would improve reproductive outcomes, but recent data suggests that surgical cystectomy might affect the ovarian reserve, decreasing the chances of ART success. The aim of this article is to review the literature on the effects of endometrioma surgery on ART outcomes providing an overview of the current evidence and assessing the need for further studies. METHODS: A literature search was performed using PubMed and MEDLINE databases to identify studies that discuss endometriomas and assisted reproductive technology before versus after surgery. RESULTS: In women with an endometrioma requiring ART, growing evidence suggests that surgery might result in damage to the ovarian reserve and further decrease chances of fertility. However, pregnancy rates, implantation rates, fertilization rates, and live birth rates seemed to be consistently similar across both groups. CONCLUSION: The current evidence is inconclusive on whether endometriomas should be surgically removed prior to ART. Further large randomized controlled trials are needed for a definite answer, and until then, management should be individualized.

Current and Prospective Treatment of Adenomyosis.

(1) Background: Adenomyosis is a poorly understood entity which makes it difficult to standardize treatment. In this paper we review and compare the currently approved medical and surgical treatments of adenomyosis and present the evidence behind them. (2) Methods: A PubMed search was conducted to identify papers related to the different treatments of adenomyosis. The search was limited to the English language. Articles were divided into medical and surgical treatments. (3) Results: Several treatment options have been studied and were found to be effective in the treatment of adenomyosis. (4) Conclusions: Further randomized controlled trials are needed to compare treatment modalities and establish a uniform treatment algorithm for adenomyosis.

2008 financial crisis versus 2020 economic fallout: how COVID-19 might influence fertility treatment and live births.

RESEARCH QUESTION: The economic and reproductive medicine response to the coronavirus disease 2019 (COVID-19) pandemic in the USA has reduced the affordability and accessibility of fertility care. What is the impact of the 2008 financial recession and the COVID-19 recession on fertility treatments and cumulative live births? DESIGN: The study examined annual US natality, Centers for Disease Control and Prevention IVF cycle activity and live birth data from 1999 to 2018 encompassing 3,286,349 treatment cycles, to estimate the age-stratified reduction in IVF cycles undertaken after the 2008 financial recession, with forward quantitative modelling of IVF cycle activity and cumulative live births for 2020 to 2023. RESULTS: The financial recession of 2008 caused a 4-year plateau in fertility treatments with a predicted 53,026 (95% confidence interval [CI] 49,581 to 56,471) fewer IVF cycles and 16,872 (95% CI 16,713 to 17,031) fewer live births. A similar scale of economic recession would cause 67,386 (95% CI 61,686 to 73,086) fewer IVF cycles between 2020 and 2023, with women younger than 35 years overall undertaking 22,504 (95% CI 14,320 to 30,690) fewer cycles, compared with 4445 (95% CI 3144 to 5749) fewer cycles in women over the age of 40 years. This equates to overall 25,143 (95% CI 22,408 to 27,877) fewer predicted live births from IVF, of which only 490 (95% CI 381 to 601) are anticipated to occur in women over the age of 40 years. CONCLUSIONS: The COVID-19 recession could have a profound impact on US IVF live birth rates in young women, further aggravating pre-existing declines in total fertility rates.

Current Advancements in Noninvasive Profiling of the Embryo Culture Media Secretome.

There have been over 8 million babies born through in vitro fertilization (IVF) and this number continues to grow. There is a global trend to perform elective single embryo transfers, avoiding risks associated with multiple pregnancies. It is therefore important to understand where current research of noninvasive testing for embryos stands, and what are the most promising techniques currently used. Furthermore, it is important to identify the potential to translate research and development into clinically applicable methods that ultimately improve live birth and reduce time to pregnancy. The current focus in the field of human reproductive medicine is to develop a more rapid, quantitative, and noninvasive test. Some of the most promising fields of research for noninvasive assays comprise cell-free DNA analysis, microscopy techniques coupled with artificial intelligence (AI) and omics analysis of the spent blastocyst media. High-throughput proteomics and metabolomics technologies are valuable tools for noninvasive embryo analysis. The biggest advantages of such technology are that it can differentiate between the embryos that appear morphologically identical and has the potential to identify the ploidy status noninvasively prior to transfer in a fresh cycle or before vitrification for a later frozen embryo transfer.

A narrative review of platelet-rich plasma (PRP) in reproductive medicine.

PURPOSE: Platelet-rich plasma (PRP) has become a novel treatment in various aspects of medicine including orthopedics, cardiothoracic surgery, plastic surgery, dermatology, dentistry, and diabetic wound healing. PRP is now starting to become an area of interest in reproductive medicine more specifically focusing on infertility. Poor ovarian reserve, menopause, premature ovarian failure, and thin endometrium have been the main areas of research. The aim of this article is to review the existing literature on the effects of autologous PRP in reproductive medicine providing a summation of the current studies and assessing the need for additional research. METHODS: A literature search is performed using PubMed, MEDLINE, and CINAHL Plus to identify studies focusing on the use of PRP therapy in reproductive medicine. Articles were divided into 3 categories: PRP in thin lining, PRP in poor ovarian reserve, and PRP in recurrent implantation failure. RESULTS: In women with thin endometrium, the literature shows an increase in endometrial thickness and increase in chemical and clinical pregnancy rates following autologous PRP therapy. In women with poor ovarian reserve, autologous intraovarian PRP therapy increased anti-Mullerian hormone (AMH) levels and decreased follicle-stimulating hormone (FSH), with a trend toward increasing clinical and live birth rates. This trend was also noted in women with recurrent implantation failure. CONCLUSIONS: Limited literature shows promise in increasing endometrial thickness, increasing AMH, and decreasing FSH levels, as well as increasing chemical and clinical pregnancy rates. The lack of standardization of PRP preparation along with the lack of large randomized controlled trials needs to be addressed in future studies. Until definitive large RCTs are available, PRP use should be considered experimental.

Evaluation of an embryology and genetic testing patient counseling education intervention for reproductive endocrinology nurses.

OBJECTIVE: To study the impact of an educational program on the knowledge base of reproductive endocrinology nurses on embryology and genetics topics to determine both improvement in knowledge and confidence in the nurses' ability to counsel patients on such topics. DESIGN: Interventional study. SETTING: Clinics. PATIENT(S): None; subjects were reproductive endocrinology nurses. INTERVENTION(S): Preintervention knowledge self-efficacy test, educational exposure, and 2-week follow-up testing. MAIN OUTCOME MEASURE(S): Knowledge test scores, self-efficacy scores. RESULT(S): Nurses, regardless of educational attainment, demonstrated statistically significant increases in knowledge of both embryology and genetics, which was retained at least 2 weeks after the educational intervention. Furthermore, nurse self-efficacy increased after intervention, and qualitative data support the desire for increased educational opportunities. CONCLUSION(S): Nurses benefit from focused educational efforts, resulting in improved knowledge in embryology and genetics. This improved knowledge base resulted in improved nurse confidence in patient education.

Secretome profile selection of optimal IVF embryos by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

PURPOSE: Selecting an embryo at the transfer stage with the best chance of a successful pregnancy is still largely dependent on preceding subjective evaluation of morphokinetics. Expensive prenatal genomic profiling has been so far proved ineffective. Proteomics and metabolomics are promising new approaches to assess embryo viability, but methodologies are often complex and do not lend themselves to rapid analysis in the critical time between blastocyst formation and embryo transfer. Here, we used matrix-assisted laser desorption ionization time-of-flight (MALDI ToF) mass spectrometry to assess the secretome of blastocysts in the minutes prior to embryo transfer and correlated spectral features with pregnancy outcome. METHODS: Four hundred one samples of spent blastocyst culture media were collected from embryo cultures at the time of embryo transfer, of which 136 were used to construct the predictive model. The media samples were frozen at - 20 °C and stored for analysis. Sample analysis was conducted in batches using 1 µl of spent embryo in direct MALDI ToF mass spectral analysis. Quantitative characteristics within this mass range (2000-17,000 m/z) were used to generate a score for selected mass regions (bins) in order to predict pregnancy outcome for each sample. RESULTS: With a simple algorithm based on nine mass bins within the 2000-10,000 m/z region, it was possible to identify samples with the best chance of becoming an ongoing pregnancy (positive predictive value of 82.9%, p = 0.0018). CONCLUSION: A simple, direct and rapid analysis of spent culture fluid from blastocysts at the point of embryo transfer can quickly identify optimal embryos with the best chance of achieving ongoing pregnancy. Methods like this, which take less than 20 min to perform, could dramatically improve the approach to embryo selection and live births.

Obstetrical complications of thin endometrium in assisted reproductive technologies: a systematic review.

PURPOSE: The aim of the systematic review is to describe the obstetrical complications associated with pregnancies in the context of a thin endometrial lining. METHODS: Systematic review of the literature. RESULTS: Patients who conceive in the setting of a thin endometrium have a significantly increased risk of early pregnancy loss, namely miscarriage and ectopic pregnancy. These patients also have a twofold increase in low birth weight and preterm delivery, as well as a significantly higher risk of intrauterine growth restriction and composite adverse perinatal outcomes. CONCLUSIONS: In addition to the lower probability of conception, a thin endometrium in assisted reproductive technologies appears to be associated with both early and late pregnancy complications. These pregnancies thus warrant special attention and close follow-up from obstetricians.

Projecting the potential impact of the Cap-Score™ on clinical pregnancy, live births, and medical costs in couples with unexplained infertility.

PURPOSE: The Cap-Score™ was developed to assess the capacitation status of men, thereby enabling personalized management of unexplained infertility by choosing timed intrauterine insemination (IUI), versus immediate in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) in individuals with a low Cap-Score™. The objective of this study was to estimate the differences in outcomes and costs comparing the use of the Cap-Score™ with timed IUI (CS-TI) and the standard of care (SOC), which was assumed to be three IUI cycles followed by three IVF-ICSI cycles. METHODS: We developed and parameterized a decision-analytic model of management of unexplained infertility for women based on data from the published literature. We calculated the clinical pregnancy rates, live birth rates, and medical costs comparing CS-TI and SOC. We used Monte Carlo simulation to quantify uncertainty in projected estimates and performed univariate sensitivity analysis. RESULTS: Compared to SOC, CS-TI was projected to increase the pregnancy rate by 1-26%, marginally reduce live birth rates by 1-3% in couples with women below 40 years, increase live birth rates by 3-7% in couples with women over 40 years, reduce mean medical costs by $4000-$19,200, reduce IUI costs by $600-$1370, and reduce IVF costs by $3400-$17,800, depending on the woman's age. CONCLUSION: The Cap-Score™ is a potentially valuable clinical tool for management of unexplained infertility because it is projected to improve clinical pregnancy rates, save money, and, depending on the price of the test, increase access to treatment for infertility.

A prospective, randomized study comparing morning to evening administration of gonadotropins in ART.

OBJECTIVE: We sought to determine whether administering the daily gonadotropin dose in the morning (AM) or in the evening (PM) affects cycle outcome in patients undergoing IVF. DESIGN: This is a prospective randomized study. SETTING: The study is performed in a private assisted reproductive technology (ART) clinic. PATIENT(S): The study included one hundred and twenty-seven women undergoing IVF. INTERVENTION(S): Morning (AM) and evening (PM) administration of gonadotropins (uFSH and hMG) was compared. MAIN OUTCOME MEASURE(S): Live birth rate was the main outcome measured. Secondary outcomes including total IU use, days of stimulation, peak E2, peak P4, endometrial thickness, number of oocytes retrieved, MII oocytes, fertilization rates, #ET, IR, and clinical PR were all assessed. RESULTS: A total of 127 cycles were included, 61 in the AM group and 67 in the PM group. Baseline and stimulation characteristics were similar in both groups. There was a trend for a higher implantation rate in the AM group vs. the PM group (60.3 vs. 47.2%, P = 0.066). The AM group had a higher chemical pregnancy rate compared to the PM group (81.7 vs. 65.6%, P = 0.024) and a higher clinical pregnancy rate (78.3 vs. 62.1%, P = 0.048), but the delivery rates were similar (68.3 vs. 56.1%, P = 0.16). The study was unfortunately prematurely terminated when uFSH (Bravelle©) was pulled out of the US market. CONCLUSIONS: AM administration of gonadotropins may be associated with a better ART outcome compared to PM administration. Larger studies are needed to confirm our findings.

G-CSF and stem cell therapy for the treatment of refractory thin lining in assisted reproductive technology.

PURPOSE: The study aims to describe two promising therapeutic options for resistant "thin" endometrium in fertility treatment: granulocyte colony-stimulating factor (G-CSF) and stem cell therapy. METHODS: A review of the scientific literature related to patients with thin endometrium undergoing fertility treatment. RESULTS: Sufficient endometrial growth is fundamental for embryo implantation. Whether idiopathic or resulting from an underlying pathology, a thin endometrium of <7 mm is associated with lower probability of pregnancy; however, no specific thickness excludes the occurrence of pregnancy. We specifically reviewed two relatively new treatment options for resistant thin lining: intrauterine G-CSF and stem cell therapy. The majority of the reviewed trials showed a significant benefit for intrauterine G-CSF infusion in improving endometrial thickness and pregnancy rates. Early results of stem cell therapy trials seem promising. CONCLUSIONS: EMT <7 mm is linked to lower probability of pregnancy in assisted reproductive technology. Intrauterine G-CSF infusion appears to be a potentially successful treatment option for resistant cases, while stem cell therapy seems to be a promising new treatment modality in severely refractory cases.

Promoting the use of elective single embryo transfer in clinical practice.

BACKGROUND: The transfer of multiple embryos after in vitro fertilization (IVF) increases the risk of twins and higher-order births. Multiple births are associated with significant health risks and maternal and neonatal complications, as well as physical, emotional, and financial stresses that can strain families and increase the incidence of depression and anxiety disorders in parents. Elective single embryo transfer (eSET) is among the most effective methods to reduce the risk of multiple births with IVF. MAIN BODY: Current societal guidelines recommend eSET for patients <35 years of age with a good prognosis, yet even this approach is not widely applied. Many patients and clinicians have been reluctant to adopt eSET due to studies reporting higher live birth rates with the transfer of two or more embryos rather than eSET. Additional barriers to eSET include risk of treatment dropout after embryo transfer failure, patient preference for twins, a lack of knowledge about the risks and complications associated with multiple births, and the high costs of multiple IVF cycles. This review provides a comprehensive summary of strategies to increase the rate of eSET, including personalized counseling, access to educational information regarding the risks of multiple pregnancies and births, financial incentives, and tools to help predict the chances of IVF success. The use of comprehensive chromosomal screening to improve embryo selection has been shown to improve eSET outcomes and may increase acceptance of eSET. CONCLUSIONS: eSET is an effective method for reducing multiple pregnancies resulting from IVF. Although several factors may impede the adoption of eSET, there are a number of strategies and tools that may encourage the more widespread adoption of eSET in clinical practice.

Is there a role for DHEA supplementation in women with diminished ovarian reserve?

PURPOSE: Poor ovarian reserve and poor ovarian response presents a challenge to IVF centers. Dehydroepiandrosterone (DHEA) supplementation is increasingly being used by many IVF centers around the world in poor responders despite the lack of convincing data. We therefore examined the rationale for the use of DHEA in poor responders, address the relevant studies, present new data, and address its potential mechanisms of action. METHODS: All published articles on the role of DHEA in infertile women from 1990 to April 2013 were reviewed. RESULTS: Several studies have suggested an improvement in pregnancy rates with the use of DHEA. Potential mechanisms include improved follicular steroidogenesis, increased IGF-1, acting as a pre-hormone for follicular testosterone, reducing aneuploidy, and increasing AMH and antral follicle count. While the role of DHEA is intriguing, evidence-based recommendations are lacking. CONCLUSIONS: While nearly 25 % of IVF programs use DHEA currently, large randomized prospective trials are sorely needed. Until (and if) such trials are conducted, DHEA may be of benefit in suitable, well informed, and consented women with diminished ovarian reserve.

Managing a solo practice.

Our health care system has been facing significant changes over the past 20 years with the introduction of health maintenance organizations plus the seismic changes associated with the introduction of the Patient Protection and Affordable Health Care Act and accountable care organizations. Lower reimbursements by health plans and the need for significant infrastructure investments in information technology such as electronic medical records have also put major financial and organizational strains on solo practices. Although it is unknown how these changes will have an impact on reproductive endocrinologists, consolidation and mergers seem to be on the rise in anticipation of the coming tsunami. Many solo physicians have cherished the freedom and opportunity of small practices, but it appears that the delivery system of the future will be dramatically different.

Decreased gonadotropin requirements in once daily compared to twice daily administration: a prospective, randomized study.

OBJECTIVE: Despite the lack of any scientific data, many ART programs split the daily gonadotropin dose during ovarian stimulation, while others give the entire dose during a single administration, usually at night. DESIGN: Prospective randomized. PATIENT(S): 213 women undergoing IVF/ICSI cycles at a single private ART center. INTERVENTION(S): Gonadotropin administration once daily compared to twice daily. MAIN OUTCOME MEASURE(S): Gonadotropin usage, clinical and ongoing PR RESULTS: There were 110 women in the once daily compared to 103 in the twice daily arm. All cycles were blastocyst transfers. There was a significantly lower FSH use in the once daily arm compared to the twice daily arm (1507.5 ± 517.5 IU vs. 1702.5 ± 622.5, P = 0.015), and a trend towards lower hMG use in the once daily arm (1342.5 ± 562.5 IU vs. 1462.5 ± 645.0, P = 0.15), without compromising clinical pregnancy rate (PR) (71.8% vs. 70.9%, P = NS) or delivery/ongoing PR (58.2% vs. 62.1%, P = NS). There were no differences in age, body mass index (BMI), peak estradiol, peak progesterone, retrieved oocytes, fertilized oocytes, number of ET, or PR. CONCLUSIONS: Once daily administration is associated with lower gonadotropin usage without compromising success rates.

Incidence of monozygotic twins in blastocyst and cleavage stage assisted reproductive technology cycles.

OBJECTIVE: To study the incidence of monozygotic twins (MZT) in blastocyst and cleavage stage ET. DESIGN: Retrospective review. PATIENT(S): Four hundred ninety-six women undergoing IVF/intracytoplasmic sperm injection cycles at a private assisted reproductive technology (ART) center. INTERVENTION(S): Patients undergoing ART were divided according to the stage of ET into blastocyst transfer (BT) and cleavage stage (CS) ET. MAIN OUTCOME MEASURE(S): Incidence of MZT as noted on vaginal ultrasound at 6 to 8 weeks. RESULT(S): There were 374 (75.4%) BT cycles, and 122 (24.6%) CS cycles. Women in the BT group were significantly younger, had more oocytes retrieved, and had less embryos transferred compared with the CS group. The clinical pregnancy rate was significantly higher in the BT group at 67.9% (254 of 374), compared with 37.7% (46 of 122) among the CS group. There was a significantly higher incidence of multiple gestation in the BT group compared with CS group (37.4% compared with 19.6%). The overall incidence of MZT was 1.3%, but differed with the stage of ET: the incidence of MZT was 1.57% (4 of 254) in the BT group, and 0 (0 of 46) in the CS group. CONCLUSION(S): Contrary to the older published literature on MZT in BT cycles, the incidence of MZT is low. Women undergoing ART therefore should not be discouraged to undergo BT for fear of MZT, especially in light of the higher pregnancy rate and lower number of transferred embryos noted in those cycles compared with cleavage stage transfers.