Mark D Hornstein’s research while affiliated with Harvard Medical School and other places

Introduction Prior studies have investigated the diagnostic potential of microRNA (miRNA) expression profiles for endometriosis. However, the vast majority of previous studies have only included adult women. Therefore, we sought to investigate differential expression of miRNAs among adolescents and young adults with endometriosis. Methods The Women's Health Study: from Adolescence to Adulthood (A2A) is an ongoing WERF EPHect compliant longitudinal cohort. Our analysis included 64 patients with surgically-confirmed endometriosis (96% rASRM stage I/II) and 118 females never diagnosed with endometriosis frequency matched on age (median = 21 years) and hormone use at blood draw. MicroRNA measurement was separated into discovery (10 cases and 10 controls) and internal replication (54 cases and 108 controls) phases. The levels of 754 plasma miRNAs were assayed in the discovery phase using PCR with rigorous internal control measures, with the relative expression of miRNA among cases vs. controls calculated using the 2−ΔΔCt method. miRNAs that were significant in univariate analyses stratified by hormone use were included in the internal replication phase. The internal replication phase was split 2:1 into a training and testing set and utilized FirePlex miRNA assay to assess 63 miRNAs in neural network analyses. The testing set of the validation phase was utilized to calculate the area under the curve (AUC) of the best fit models from the training set including hormone use as a covariate. Results In the discovery phase, 49 miRNAs were differentially expressed between endometriosis cases and controls. The associations of the 49 miRNAs differed by hormone use at the time of blood draw. Neural network analysis in the testing set of the internal replication phase determined a final model comprising 5 miRNAs (miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p), yielding AUC = 0.77 (95% CI: 0.67–0.87, p < 0.001). Sensitivity in the testing dataset improved (83.3% vs. 72.2%) while the specificity decreased (58.3% vs. 72.2%) compared to the training set. Conclusion The results suggest that miR-542-3p, let-7b-3p, miR-548i, miR-769-5p, miR-30c-1-3p may be dysregulated among adolescent and young adults with endometriosis. Hormone use was a significant modifier of miRNA dysregulation and should be considered rigorously in miRNA diagnostic studies.

Endometriosis is now widely considered to be a disease characterized by chronic inflammation. The purpose of this review is to summarize the literature regarding the immunologic aspects of endometriosis and highlight recent advances in the field. The microenvironment of the endometrium and peritoneal cavity form the foundation for development of endometriosis. Each is structurally comprised of an assortment of immunologic components, including immune cells, signaling factors, and the microbiome, in an estrogen-dependent, pro-inflammatory setting, fueling endometriotic disease. This leads to the angiogenesis and neuroinflammation seen in disease progression. Recent findings center on translational studies that build on years of research on the interplay of the immune system, steroidogenic hormones, and endometriosis to develop new biomarkers for early detection and therapeutics for prevention and treatment of disease.

Purpose The objective of this study was to assess if very-low–dose Lupron (VLDL) and ultra-low–dose Lupron (ULDL) protocols can have comparable cycle outcomes when compared to other “poor responder” stimulation protocols based on POSEIDON classification groups 3 (PG3) and 4 (PG4). Methods A retrospective cohort study at a single, large academic center was performed. Women in PG3 (age < 35, AMH < 1.2 ng/mL) or PG4 (age ≥ 35, AMH < 1.2 ng/mL) undergoing in vitro fertilization using an ULDL (Lupron 0.1 to 0.05 mg daily), VLDL (Lupron 0.2 to 0.1 mg daily), microflare (Lupron 0.05 mg twice a day), estradiol priming/antagonist, antagonist, or minimal stimulation protocols from 2012 to 2021 were included. The primary outcome was the number of mature oocytes (MII) obtained. The secondary outcome was live birth rate (LBR). Results The cohort included 3601 cycles. The mean age was 38.1 ± 3.8 years. In the PG3 group, ULDL and VLDL protocols produced a comparable number of MIIs (5.8 ± 4.3 and 5.9 ± 5.4, respectively) and live births (33.3% and 33.3%, respectively) when compared to other protocols. In the PG4 group, ULDL and VLDL protocols resulted in a higher percentage of MIIs when compared to microflare or minimal stimulation (Microflare/ULDL: adjusted relative risk (aRR) 0.78 (95% CI 0.65, 0.95); min stim/ULDL: aRR 0.47 (95% CI 0.38, 0.58); microflare/VLDL: aRR 0.77 (95% CI 0.63, 0.95); min stim/VLDL: aRR 0.47 (95% CI 0.38, 0.95)). There were no significant differences in LBR. Conclusion Dilute Lupron downregulation protocols have comparable outcomes to other poor responder protocols and are reasonable to use.

Purpose The purpose of this study is to clarify which pre-wash total motile count are associated with improved clinical pregnancy rate (CPR) and live birth rate (LBR) based on maternal age, AMH level, stimulation regimen, and infertility diagnosis. Methods This was a retrospective cohort study of first completed IUI cycles at two academic fertility centers from 5/2015 to 9/2019. Cycles were stratified by pre-wash TMC, maternal age, AMH level, stimulation regimen, and infertility diagnosis. The primary outcome was CPR and secondary outcomes were live birth and miscarriage. Results One thousand one hundred fifty-four cycles were analyzed. Of the 162 cycles that resulted in a CPR (14.0%), most had an insemination TMC > 20 million. Compared to TMC > 20 million, there was no difference in CPR or LBR for lower TMC categories, excluding the TMC < 2 million group, in which there were no pregnancies. When TMC was stratified by deciles, there was also no difference in CPR and LBR, including within the lowest decile (TMC 0.09–8.6 million). Younger age and higher ovarian reserve parameters were associated with higher pregnancy and LBR when stratified by TMC. There was no difference in pregnancy and LBR when considering different stimulation protocols. Conclusions Our data suggest that pregnancy and LBR are equivalent above a TMC of 2 million. Data stratified by TMC and patient parameters can be used to counsel patients pursuing ART.

Purpose Supraphysiologic serum estradiol levels may negatively impact the likelihood of conception and live birth following IVF. The purpose of this study is to determine if there is an association between serum estradiol level on the day of progesterone start and clinical outcomes following programmed frozen blastocyst transfer cycles utilizing oral estradiol. Methods This is a retrospective cohort study at an academic fertility center analyzing 363 patients who underwent their first autologous single (SET) or double frozen embryo transfer (DET) utilizing oral estradiol and resulting in blastocyst transfer from June 1, 2012, to June 30, 2018. Main outcome measures included implantation, clinical pregnancy, live birth, and miscarriage rates. Cycles were stratified by quartile of serum estradiol on the day of progesterone start and separately analyzed for SET cycles only. Poisson and Log binomial regression were used to calculate relative risks (RR) with 95% confidence intervals (CI) for implantation, clinical pregnancy, live birth, and miscarriage with adjustments made for age and BMI. Results Cycles with the highest quartile of estradiol (mean 528 pg/mL) were associated with lower risks of implantation (RR 0.66, CI 0.50–0.86), ongoing pregnancy (RR 0.66, CI 0.49–0.88), and live birth (RR 0.70, CI 0.52–0.94) compared with those with the lowest estradiol quartile (mean 212 pg/mL). Similar findings were seen for analyses limited to SETs. There was no significant difference in miscarriage rate or endometrial thickness between groups. Conclusion High levels of serum estradiol on the day of progesterone start may be detrimental to implantation, pregnancy, and live birth following frozen blastocyst transfer.

Objective To estimate the efficacy and safety of a novel non-hormonal therapeutic agent, cabergoline, compared to a clinical standard therapy, norethindrone acetate (NETA), for the treatment of endometriosis-associated pain in young women with endometriosis. Design Randomized, double-blind, placebo-controlled pilot study Setting Tertiary care center Patients Females (n=9) with surgically-confirmed endometriosis Intervention A random, double-blind assignment to 1) NETA (5 mg/d) + placebo twice weekly or 2) cabergoline 0.5 mg twice weekly + placebo daily for 6 months. Outcomes We collected measures of pelvic pain and laboratory studies every 3 months. Results We observed a decrease in pain scores and increase in pain relief in women randomized to cabergoline that appear similar to or exceed improvements in women treated with NETA. Serum measures of VEGF-Receptor 1 declined over 6 months in those receiving cabergoline. Cabergoline was well tolerated, and no serious adverse events occurred. Conclusions Safe, effective adjunct treatments are lacking for patients with endometriosis who do not respond to standard of care. Because growth of endometriosis requires angiogenesis, blood vessel growth is an attractive therapeutic target. This pilot study suggests that cabergoline, a VEGF pathway inhibitor, may be an effective therapeutic option for women suffering from chronic pain due to endometriosis. Building upon this investigation, we will conduct larger randomized trials of cabergoline, advancing research on the best treatments for endometriosis—particularly disease resistant to hormonal therapies.

Background More than 67% of all embryos transferred in the United States involve frozen-thawed embryos. Progesterone supplementation is necessary in medicated cycles to luteinize the endometrium and prepare it for implantation, but little data is available to show if this is beneficial in true natural cycles. We evaluated the use of luteal phase progesterone supplementation for cryopreserved/warmed blastocyst transfers in true natural cycles not using an ovulatory trigger. Methods Retrospective cohort study in a single academic medical center. We studied the use of luteal phase progesterone supplementation in patients undergoing true natural cycle cryopreserved blastocyst embryo transfers. Our primary outcome measure was ongoing pregnancy rate, with other pregnancy outcomes being evaluated (i.e. implantation rate, miscarriage rate, ectopic rate, and multifetal gestation). Categorical data were analyzed utilizing Fisher’s exact test and all binary variables were analyzed using log-binomial regression to produce a risk ratio. Results Two hundred twenty-nine patients were included in the analysis with 149 receiving luteal phase progesterone supplementation and 80 receiving no luteal phase support. Patient demographic and cycle characteristics, and embryo quality were similar between the two groups. No difference was seen in ongoing pregnancy rate (49.0% vs. 47.5%, p = 0.8738), clinical pregnancy rate (50.3% vs. 47.5%, p = 0.7483), positive HCG rate (62.4% vs. 57.5%, p = 0.5965), miscarriage/abortion rate (5.4% vs. 2.5%, p = 0.2622), ectopic pregnancy rate (0% vs. 1.3%, p = 0.3493), or multifetal gestations (7.4% vs. 3.8%, p = 0.3166). Conclusion(s) The addition of luteal phase progesterone support in true natural cycle cryopreserved blastocyst embryo transfers did not improve pregnancy outcomes and therefore the routine use in practice cannot be recommended based on this study, but the utilization should not be discouraged without further studies. Capsule Progesterone supplementation as luteal phase support in true natural cycle cryopreserved blastocyst transfers does not improve ongoing pregnancies.

Background A controversial and unresolved question in reproductive medicine is the utility of preimplantation genetic testing for aneuploidy (PGT-A) as an adjunct to in vitro fertilization (IVF). Infertility is prevalent, but its treatment is notoriously expensive and typically not covered by insurance. Therefore, cost-effectiveness is critical to consider in this context. Objective To analyze the cost-effectiveness of PGT-A for the treatment of infertility in the United States Study design IVF cycles occurring between 2014 and 2016 in the United States, as reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System, a national data registry, were analyzed. A probabilistic decision tree was developed using empiric outputs to simulate the events and outcomes associated with IVF with and without PGT-A. The treatment strategies were (1) IVF with intended PGT-A, and (2) IVF with transfer(s) of untested embryo(s). Patients progressed through the treatment model until they achieved a live birth or twelve months after ovarian stimulation. Clinical costs related to both treatment strategies were extracted from the literature and considered from both the patient and payer perspectives. Outcome metrics included incremental cost (measured in 2018 US dollars), live birth outcomes, incremental cost-effectiveness ratio (ICER) and incremental cost per live birth between treatment strategies. Results The study population included 114,157 first fresh IVF stimulations and 44,508 linked frozen embryo transfer cycles. 16.2% intended PGT-A and 83.8% did not. In patients younger than 35, PGT-A was associated with worse clinical outcomes and higher costs. At age 35 and older, PGT-A led to more cumulative births, but was associated with higher costs from both perspectives. From a patient perspective, the incremental cost per live birth favored the no PGT-A strategy from <35 until age 38, and beginning at age 39 favored PGT-A. From a payer perspective, the incremental cost per live birth favored PGT-A regardless of patient age. Conclusions The cost-effectiveness of PGT-A is dependent on patient age and perspective. From an economic perspective, routine PGT-A should not be universally adopted, but may be cost-effective in certain scenarios.