The impact of estradiol supplementation on endometrial thickness and intrauterine insemination outcomes.

The impact of estrogen supplementation during the follicular/proliferative phase on the endometrial lining thickness (EMT) prior to intrauterine insemination (IUI) remains largely unstudied. Our study examined changes in EMT and rates of clinical pregnancy, miscarriage, and live birth for all patients who completed an IUI cycle at Stanford Fertility Center from 2017-2023 (n = 2281 cycles). Cycles with estradiol supplementation (n = 309) were compared to reference cycles without supplementation (n = 1972), with the reference cohort further categorized into cycles with a pre-ovulatory EMT of < 7 mm ("thin-lining", n = 536) and ≥ 7 mm ("normal-lining", n = 1436). The estradiol group had a statistically significant greater change in EMT from baseline to ovulation compared to the thin-lining reference groups (2.4 mm vs 1.9 mm, p < =0.0001). Similar rates of clinical pregnancy and live birth were observed. After adjusting for age, BMI, race/ethnicity, infertility diagnosis, and EMT at trigger, the estradiol cohort had a significantly increased odds of miscarriage versus the entire reference cohort (2.46, 95 % confidence interval [1.18, 5.14], p = 0.02). Thus, although estradiol supplementation had a statistically significant increase in EMT compared to IUI cycles with thin pre-ovulatory EMT (<7 mm), this change did not translate into improved IUI outcomes such as increased rates of clinical pregnancy and live birth or decreased rate of miscarriage. Our study suggests that supplemental estradiol does not appear to improve IUI outcomes.

Platelet-rich plasma infusion as an adjunct treatment for persistent thin lining in frozen embryo transfer cycles: first US experience report.

PURPOSE: To study effect of intrauterine infusion of platelet-rich plasma (PRP) on endometrial growth in the setting of thin endometrial lining in patients with prior cancelled or failed frozen embryo transfer (FET) cycles. MATERIALS AND METHODS: Single-arm cohort study of forty-six patients (51 cycles) with endometrial lining thickness (EMT) < 6 mm in prior cancelled or failed FET cycles requesting intrauterine PRP treatment in upcoming FET cycle. The primary outcomes were final EMT in FET cycle and change in EMT after PRP. The secondary outcomes were overall pregnancy rate, clinical pregnancy rate, miscarriage rate, ongoing pregnancy, and live birth rates. RESULTS: The mean pre-PRP EMT in all FET cycles was 4.0 ± 1.1 mm, and mean post-PRP EMT (final) was 7.1 ± 1.0 mm. Of 51 cycles, 33 (64.7%) reached ≥ 7 mm after PRP administration. There was a significant difference between pre-PRP EMT and post-PRP EMT in all FET cycles, with mean difference of 3.0 ± 1.5 mm. Three cycles were cancelled for failure to reach adequate lining. Total pregnancy rate was 72.9% in our cohort of 48 cycles that proceeded to transfer. Clinical pregnancy rate was 54.2% (26/48 FET cycles); clinical miscarriage rate was 14.3% (5/35 pregnancies). Twenty six women had live birth (18 with EMT ≥ 7 mm and 8 with EMT < 7 mm). Response to PRP was not correlated with any pre-cycle characteristics. CONCLUSION: We demonstrate a significant improvement in lining thickness and pregnancy rates in this challenging cohort of women after PRP infusion, with no adverse events. Cost-effectiveness of PRP with benefits and alternatives should be carefully considered.

Fertility issues in hypopituitarism.

Women with hypopituitarism have lower fertility rates and worse pregnancy outcomes than women with normal pituitary function. These disparities exist despite the use of assisted reproductive technologies and hormone replacement. In women with hypogonadotropic hypogonadism, administration of exogenous gonadotropins can be used to successfully induce ovulation. Growth hormone replacement in the setting of growth hormone deficiency has been suggested to potentiate reproductive function, but its routine use in hypopituitary women remains unclear and warrants further study. In this review, we will discuss the clinical approach to fertility in a woman with hypopituitarism.

Pregnancy and neonatal outcomes of letrozole versus natural cycle frozen embryo transfer of autologous euploid blastocyst.

PURPOSE: To investigate the pregnancy and neonatal outcomes of letrozole-stimulated frozen embryo transfer (LTZ-FET) cycles compared with natural FET cycles (NC-FET). METHODS: Our retrospective cohort included all LTZ-FET (n = 161) and NC-FET (n = 575) cycles that transferred a single euploid autologous blastocyst from 2016 to 2020 at Stanford Fertility Center. The LTZ-FET protocol entailed 5 mg of daily letrozole for 5 days starting on cycle day 2 or 3. Outcomes were compared using absolute standardized differences (ASD), in which a larger ASD signifies a larger difference. Multivariable regression models adjusted for confounders: maternal age, BMI, nulliparity, embryo grade, race, infertility diagnosis, and endometrial thickness. RESULTS: The demographic and clinical characteristics were overall similar. A greater proportion of the letrozole cohort was multiparous, transferred high-graded embryos, and had ovulatory dysfunction. The cohorts had similar pregnancy rates (67.1% LTZ vs 62.1% NC; aOR 1.31, P = 0.21) and live birth rates (60.9% LTZ vs 58.6% NC; aOR 1.17, P = 0.46). LTZ-FET neonates on average were born 5.7 days earlier (P < 0.001) and had higher prevalence of prematurity (18.6% vs. 8.0%NC, ASD = 0.32) and low birth weight (10.4% vs. 5.0%, ASD = 0.20). Both cohorts' median gestational ages (38 weeks and 1 day for LTZ; 39 weeks and 0 day for NC) were full term. CONCLUSION: There were similar rates of pregnancy and live birth between LTZ-FET and NC-FET cycles. However, there was a higher prevalence of prematurity and low birth weight among LTZ-FET neonates. Reassuringly, the median gestational age in both cohorts was full term, and while the difference in gestational length of almost 6 days does not appear to be clinically significant, this warrants larger studies.

The Effect of Human Growth Hormone on Endometrial Growth in Controlled Ovarian Hyperstimulation Cycles.

This study aims to compare endometrial growth before and after the addition of human growth hormone (hGH) in controlled ovarian hyperstimulation (COH) cycles. A 5-year retrospective cohort study of patients treated with hGH to improve oocyte development during COH cycles was conducted. Each patient's cycle without hGH immediately preceding cycle(s) with hGH was used for patients to serve as their own controls. Primary outcome was absolute growth in endometrial thickness from pre-stimulation start to day of hCG trigger. Mixed-model regression analysis controlled for patient correlation over repeat cycles and potential confounders. 80 patients were included. Mean age was 39.7 years; mean BMI was 23.8 kg/m2. Majority of patients were nulliparous, non-smoking, and White or Asian. Most common diagnosis was diminished ovarian reserve. Endometrial growth was compared between 159 COH cycles with hGH and 80 COH control cycles; mean increase was 4.5 mm and 3.9 mm, respectively-an unadjusted difference of 0.6 mm (95% CI: 0.2−1.1, p = 0.01). After adjusting for demographic/clinical factors, hGH was associated with 0.9 mm greater endometrial growth (0.4−1.4, p < 0.01). Absolute increase in endometrial thickness was higher in COH cycles that included hGH. Further prospective studies in embryo transfer cycles are needed.

Public attitudes in the United States toward insurance coverage for in vitro fertilization and the provision of infertility services to lower income patients.

Objective: To assess attitudes and factors that influence public opinion in the general US population toward insurance coverage and provision of infertility care to lower income patients. Design: Cross-sectional survey. Setting: Online. Patients: A nationally representative sample of US residents. Interventions: Questionnaire with multiple choice and open response questions. Main Outcome Measures: Public attitudes toward in vitro fertilization and infertility care coverage for lower income patients. Results: A total of 1,027 (90.2%) participants completed the survey, among whom 620 (60.4%) had private insurance, 275 (26.8%) had Medicare/Medicaid, and 56 (5.5%) were uninsured. The majority (916, 89.2%) did not consider infertility a disease. Over half of the respondents (568, 55.3%) supported private insurance coverage of infertility services, including for in vitro fertilization. Most respondents, 735 (71.6%) believed that the prevalence and psychosocial impact of infertility were equal among the lower and higher income people. The majority of respondents with an opinion (512, 67.6%) believed that doctors should provide infertility treatments regardless of the income level of the patients. Of supporters, 40.1% believed in the right to have a family regardless of income, and 38.2% believed that doctors had a social responsibility to provide infertility services. After adjusting for covariates, age <45 years, noncollege graduates, desiring more children, believing that infertility was a disease, and residence in the Northeast region remained significant predictors for support of private insurance coverage. Conclusions: Public perception of infertility as a disease is one of the strongest predictors of support for insurance coverage for infertility services, underscoring the need for enhanced advocacy and education in the general public.

Provision of infertility care for the underserved in reproductive endocrinology and infertility practices associated with obstetrics and gynecology residency training programs in the United States.

Objective: To survey practice patterns designed to increase access to infertility care and evaluate the exposure of obstetrics and gynecology residents to infertility care for the underserved. Design: Cross-sectional. Setting: Reproductive endocrinology and infertility (REI) practices associated with Accreditation Council for Graduate Medical Education-accredited obstetrics and gynecology residency training programs. Patients: None. Interventions: Questionnaire survey. Main Outcome Measures: Presence of clinical programs designed to improve access to REI care, resident involvement in such programs, and perceived barriers to expanding access to care. Results: Clinical initiatives to expand access included discounted infertility services (38%, n = 30), utilization of a low-cost in vitro fertilization (IVF) program (28%, n = 22), and utilization of a resident- and/or fellow-staffed clinic to provide infertility care (39%, n = 31). The most commonly discounted infertility services were IVF (73%, n = 22), clinical consultation (70%, n = 21), and intrauterine insemination (53%, n = 16). The provision of discounted prices was correlated with the increasing practice size (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.23-4.24) and number of assisted reproductive technology cycles performed annually (OR, 3.65; 95% CI, 1.48-9.02). Academic REI practices (OR, 3.6; 95% CI, 0.98-13.25) were more likely to have a low-cost IVF program. Less than half of obstetrics and gynecology residency programs (39%, n = 31) had an associated REI clinic in which obstetrics and gynecology residents provide direct infertility care to the medically underserved. Frequency and services offered in trainee clinics varied. Multiple barriers to expanding access to care were reported. Conclusions: Reproductive endocrinology and infertility practices associated with obstetrics and gynecology residency programs utilize a diverse range of approaches to provide infertility care to the underserved in the backdrop of considerable challenges and barriers, but significant gaps persist.

Implementation of a comprehensive fertility biobanking initiative.

OBJECTIVE: To present the framework of Stanford Fertility and Reproductive Health's comprehensive reproductive biobanking initiatives and the results of the first year of recruitment. DESIGN: Technical description article. SETTING: Academic fertility center. PATIENT(S): Fertility patients >18 years of age. INTERVENTION(S): Enroll the patients interested in research in biobanking protocols. MAIN OUTCOME MEASURE(S): Patient recruitment and sample inventory from September 2020 to September 2021. RESULT(S): A total of 253 patients have enrolled in the Stanford Fertility and Reproductive Health biobanking initiatives since September 2020. The current inventory consists of 1,176 samples, including serums, plasmas, buffy coats, endometria, maternal deciduae, miscarriage chorionic villi, and human embryos (zygote, cleavage, and blastocyst stages). CONCLUSION(S): This biobanking initiative addresses a critical, unmet need in reproductive health research to make it possible for patients to donate excess embryos and gametes and preserves, for future research, valuable somatic and reproductive tissues that would otherwise be discarded. We present the framework of this biobanking initiative in order to support future efforts of establishing similar biorepositories.

REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies.

PURPOSE: To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing. METHODS: Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children. RESULTS: Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children. CONCLUSION: A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.

Fertility Preservation for Transgender Males: Counseling and Timing of Treatment.

Fertility-preservation counseling in the transgender patient population is recommended by multiple organizations, including the American Society for Reproductive Medicine, the World Professional Association for Transgender Health, and the Endocrine Society. The optimal time to pursue fertility preservation has not been established, and data on potential effects of testosterone therapy on future reproductive potential are limited. This Current Commentary seeks to elucidate the most appropriate time to perform oocyte cryopreservation in relation to time on and off testosterone therapy, age of the individual, and emotional effect of treatment. Although there have been multiple studies that have demonstrated successful oocyte cryopreservation regardless of testosterone exposure, the data on live-birth rates after oocyte cryopreservation are limited. Moreover, the process of oocyte cryopreservation may have a significant negative emotional effect on the transgender male given the feminizing effects of gonadotropin stimulation, as well as the invasiveness of pelvic ultrasonograms and the oocyte-retrieval procedure. With our review, we demonstrate that a comprehensive, individualized approach to fertility-preservation counseling and timing to pursue treatment are essential. Postponing fertility-preservation procedures until patients have reached early adulthood might be considered to avoid the potential effect on mental health, without compromising outcomes.

Fertility Benefits at Top U.S. Medical Schools.

Background: Female physicians have a higher prevalence of infertility compared with the general population. Physician well-being can be significantly impacted by the physical and emotional challenges associated with this, including the high cost of fertility treatments, which are often not covered by health insurance. There are limited data on the current state of fertility coverage available for physicians. This study examines fertility insurance benefits offered for faculty at top U.S. medical schools. Methods: Between March and April 2021, we reviewed fertility benefits at medical schools ranked in the top 14 for research as identified by the US News & World Report 2021. The summary plan descriptions of benefits were collected from each institution's human resources (HR) website and direct phone call to HR representatives. We examined descriptions of coverage for fertility services including evaluation, treatments, medications, maximum lifetime coverage, and whether a formal diagnosis of infertility was required for benefit eligibility. Results: Fourteen institutions offer benefits for fertility evaluation and 13 offer benefits for treatment. Of the 13 institutions that offer treatment coverage, 11 cover in vitro fertilization, with 6 having limits on the number of cycles. Twelve offer medication coverage. Ten institutions specified maximum lifetime coverage for treatments and medications, ranging from $10,000 to $100,000. Only 1 school provided coverage for elective fertility preservation, and none covered surrogacy expenses. Half of the schools are in states where fertility benefits are mandated. Conclusion: There is wide variation in fertility benefits offered at top medical schools across the country. Many schools offered coverage for fertility evaluation and treatments; however, majority had restrictions and limitations to the benefits, suggesting that there is still inadequate coverage provided. This study's selected sample also does not reflect other medical schools across the country, which may not be as well-resourced in their provision of fertility benefits.

Patterns of sex hormone receptor expression in stimulated endometrium from oocyte donors.

In patients with high serum E2 embryo transfer is often postponed, as high E2 levels adversely affect embryo transfer outcome. We aimed to determine if stratified serum oestradiol (E2) and progesterone (P4) levels differentially affect endometrial histology and endometrial oestrogen and progesterone receptor protein levels. Endometrial biopsies were collected from oocyte donors. Samples were divided based on peak serum E2 levels into three groups: (i) low-E2 (n = 33) E2≤2999pg/mL; (ii) mid-E2 (n = 40) E2 3000-4999 pg/mL; and (iii) high-E2 (n = 15) E2≥5000 pg/mL. Oestrogen receptor alpha (ERα) and progesterone receptors A and B (PR) protein levels in endometrial stroma (S), glandular (GE) and luminal (LE) epithelia were assessed by immunohistochemistry. Samples in high-E2 group demonstrated strongest association with accelerated endometrial maturation (2 (1-2); 2 (1-3); and 3 (2.8-3) median days of advancement of endometrial maturation respectively in low, mid, high-E2 groups, p = 0.046). There were significant differences in ERα and PR immunoexpression in S, GE and LE among the groups (p < 0.05). Higher E2 levels were associated with decreased ERα expression (p < 0.017) in GE and LE, and increased PR expression in S and GE (p < 0.011 and p < 0.0001, respectively). Higher serum E2 levels were associated with impaired endometrial steroid hormone receptor expression, higher serum P4 and more advancement of endometrial maturation.

Making More Womb: Clinical Perspectives Supporting the Development and Utilization of Mesenchymal Stem Cell Therapy for Endometrial Regeneration and Infertility.

The uterus is a homeostatic organ, unwavering in the setting of monthly endometrial turnover, placental invasion, and parturition. In response to ovarian steroid hormones, the endometrium autologously prepares for embryo implantation and in its absence will shed and regenerate. Dysfunctional endometrial repair and regeneration may present clinically with infertility and abnormal menses. Asherman's syndrome is characterized by intrauterine adhesions and atrophic endometrium, which often impacts fertility. Clinical management of infertility associated with abnormal endometrium represents a significant challenge. Endometrial mesenchymal stem cells (MSC) occupy a perivascular niche and contain regenerative and immunomodulatory properties. Given these characteristics, mesenchymal stem cells of endometrial and non-endometrial origin (bone marrow, adipose, placental) have been investigated for therapeutic purposes. Local administration of human MSC in animal models of endometrial injury reduces collagen deposition, improves angiogenesis, decreases inflammation, and improves fertility. Small clinical studies of autologous MSC administration in infertile women with Asherman's Syndrome suggested their potential to restore endometrial function as evidenced by increased endometrial thickness, decreased adhesions, and fertility. The objective of this review is to highlight translational and clinical studies investigating the use of MSC for endometrial dysfunction and infertility and to summarize the current state of the art in this promising area.

Autologous platelet-rich plasma treatment for moderate-severe Asherman syndrome: the first experience.

PURPOSE: Treatment of Asherman syndrome (AS) presents a significant clinical challenge. Based on our in vitro data showing that PRP could activate endometrial cell proliferation and migration, we hypothesized that intrauterine infusion of autologous platelet-rich plasma (PRP) may improve endometrial regeneration and fertility outcomes in patients with moderate-severe AS. MATERIALS AND METHODS: Subjects with moderate-severe AS were randomized to PRP or saline control administered following hysteroscopic adhesiolysis. Due to relative inability to randomize patients to the control group, after initial randomization of 10 subjects (6 in PRP and 4 in control groups), the remainder were prospectively enrolled in PRP group (n = 9), with 11 historic controls added to control group, for a total of 30 subjects (PRP n = 15; saline control n = 15). Right after hysteroscopy, 0.5-1 mL of PRP or saline was infused into the uterus via a Wallace catheter, followed by estrogen therapy. The primary outcomes were changes in endometrial thickness (EMT, checked in 3 weeks) and in menstrual flow; secondary outcomes were pregnancy and live birth rates. EMT and menstrual bleeding pattern were assessed before and after the intervention. Pregnancy was assessed over a 6-month period. RESULTS: There were no statistically significant differences in age, gravidity/parity, cause of AS, preoperative menses assessment, AS hysteroscopy score, and intrauterine balloon placement between the groups. There was no statistically significant difference (p = 0.79) in EMT pre-PRP infusion for control (5.7 mm, 4.0-6.0) and study arm (5.3 mm, 4.9-6.0). There was no statistically significant change (p = 0.78) in EMT after PRP infusion (1.4 mm, - 0.5-2.4) vs saline (1.0 mm, 0.0-2.5). Patients tolerated the procedure well, with no adverse effects. There was no difference in the predicted likelihood of pregnancy (p = 0.45) between the control (0.67, 0.41-0.85) and study arm (0.53, 0.29-0.76). CONCLUSIONS: PRP was well accepted and tolerated in AS patients. However, we did not observe any significant EMT increase or improved pregnancy rates after adding PRP infusion, compared to standard treatment only. The use of intrauterine PRP infusion may be a feasible option, and its potential use must be tested on a larger sample size of AS patients.

Pregnancy success rates for lesbian women undergoing intrauterine insemination.

OBJECTIVE: To compare the pregnancy outcomes of lesbian women undergoing donor sperm intrauterine insemination (IUI) with that of heterosexual women undergoing IUI using partner or donor sperm. DESIGN: Retrospective cohort analysis. SETTING: Two academic fertility practices. PATIENTS: All IUI cycles between 2007 and 2016. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Primary outcomes included clinical pregnancy (CP) rates and live birth/ongoing pregnancy (LB) rates. The baseline characteristics and cycle characteristics were compared between the two groups using absolute standardized differences (ASDs). To account for the correlation between cycles per patient, a generalized estimating equation method for multivariable logistic regression was used. RESULTS: A total of 11,870 IUI cycles were included, of which 393 were in lesbian women using donor sperm and 11,477 were in heterosexual women with infertility using either partner or donor sperm. The CP rates were similar between the lesbian and heterosexual groups (13.2% vs. 11.1%, respectively, ASD = 0.06). In addition, the LB rates were similar between the two groups (10.4% vs. 8.3%, respectively, ASD = 0.10). After implementing the generalized estimating equation in a multivariable logistic regression, the lesbian group had an overall higher odds of CP (adjusted odds ratio 1.40, 95% confidence interval: [1.04-1.88]) and LB (adjusted odds ratio 1.59, 95% confidence interval [1.15-2.20]) compared with the heterosexual group. The clinical miscarriage rate was higher in the heterosexual group compared with that in the lesbian group (23.8% vs. 15.4%, respectively, ASD = 0.21). CONCLUSION: Although the unadjusted rates were similar between the two groups, the adjusted CP and LB odds were significantly higher for lesbian women undergoing IUI for procreative management than those for heterosexual women undergoing IUI for infertility.