Unexplained recurrent pregnancy loss and unexplained infertility: twins in disguise.

STUDY QUESTION: Is B-cell CLL/lymphoma 6 (BCL6) endometrial expression, a surrogate biomarker of endometriosis, elevated in women with unexplained recurrent pregnancy loss (uRPL) and unexplained infertility (UI) compared to fertile subjects? SUMMARY ANSWER: Endometrial BCL6 expression is elevated to a similar degree in women with uRPL and UI compared to fertile controls. WHAT IS KNOWN ALREADY: Endometriosis has been linked to the genesis of endometrial progesterone resistance and to specific nuclear proteins, including endometrial BCL6. BCL6 overexpression (immune histologic score > 1.4) has been strongly associated with poor reproductive outcomes in IVF cycles in women with UI. Our previous data have demonstrated an accuracy of 94% for diagnosing endometriosis, and BCL6 protein is elevated in the decidua of women with uRPL. STUDY DESIGN SIZE DURATION: In this case-control study, at a tertiary university teaching hospital, 110 samples (control n = 28; uRPL n = 29; UI n = 53) from pathological archives were analyzed. Timed endometrial biopsies were obtained between 2 January 2002 and 31 December 2016. PARTICIPANTS/MATERIALS SETTING METHOD: LH-timed endometrial biopsies were obtained from women with UI, uRPL (two or more consecutive losses) and normal fertile subjects during the mid-secretory phase of the menstrual cycle. Endometrial BCL6 protein levels were compared in women with UI and uRPL and fertile controls using western blot analysis and immunohistochemistry (HSCORE). MAIN RESULTS AND THE ROLE OF CHANCE: The mean age of the uRPL group was significantly higher than the others [mean (SD)] control = 32.7 (2.6); uRPL = 35.8 (3.7); UI = 32.7 (4.4); P = 0.002, ANOVA]. Seventy-nine percent of women in both subfertile groups (uRPL and UI, 65 out of 82) displayed elevated BCL6 protein levels. From these, a subset of cases with abnormal BCL6 went to laparoscopy and endometriosis was found in 9 out of 11 cases of uRPL and in 20 out of 21 cases of UI. Median BCL6 HSCORE for controls versus uRPL and UI was significantly different [median (interquartile); control = 0.3 (0.02 to 0.5); uRPL = 3 (1.9 to 3.6); UI = 2.9 (1.6 to 3.1); P < 0.0001, Kruskal-Wallis]. A significant trend in the association between the degree of infertility (fertile, uRPL and UI) and the HSCORE level (negative, medium and high) was found (P < 0.001; x 2 for trend). Western blot of representative samples from each group demonstrated similar findings based on protein levels in the whole endometrium. After running ANCOVA analysis for age difference, the BCL6 difference among groups was still significant (P-value < 0.0001). LIMITATIONS REASONS FOR CAUTION: We studied subjects with two consecutive pregnancy losses rather than the definition adopted in Europe of three losses. The findings may lack external validity in other clinical settings (e.g. low prevalence of endometriosis). WIDER IMPLICATIONS OF THE FINDINGS: Based on the data presented here, we postulate that the degree of BCL6 expression may represent a continuum of progesterone resistance and response to inflammation that occurs in women with endometriosis, yielding different degrees of infertility, from uRPL to UI. STUDY FUNDING/COMPETING INTERESTS: This study was supported by NICHD/NIH R01 HD067721 (SLY and BAL), by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior: Grant 99999.003035/2015-08 (BAL) and by CAPES/PROAP (RFS). Two authors (BAL, SLY) have licensed intellectual property for the detection of endometriosis. Dr Bruce Lessey is an unpaid scientific Advisor for CiceroDx. The other authors report no conflict of interest.

A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling.

Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear action. A previously identified mitochondrial progesterone receptor (PR-M) increases cellular respiration in cell models. In these studies, we demonstrated that expression of PR-M in rat H9c2 cardiomyocytes resulted in a ligand-dependent increase in oxidative cellular respiration and beta-oxidation. Cardiac expression in a TET-On transgenic mouse resulted in gene expression of myofibril proteins for remodeling and proteins involved in oxidative phosphorylation and fatty acid metabolism. In a model of increased afterload from constant transverse aortic constriction, mice expressing PR-M showed a ligand-dependent preservation of cardiac function. From these observations, we propose that PR-M is responsible for progesterone-induced increases in cellular energy production and cardiac remodeling to meet the physiological demands of pregnancy.

Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression.

PURPOSE: To evaluate the effect of medical or surgical treatment prior to embryo transfer in women with elevated endometrial BCL6 expression and suspected endometriosis in a prospective, cohort study design at a university-associated infertility clinic. METHODS: All subjects had at least 1 year of unexplained infertility (UI) and each prospectively underwent endometrial biopsy and immunostaining for the oncogene BCL6, prior to embryo transfer during an assisted reproductive technology (ART) cycle. To be included, subjects had to have an abnormal BCL6 result, defined by elevated HSCORE ≥ 1.4. Women that were pre-treated with laparoscopy or medical suppression with GnRH agonist (depot leuprolide acetate; Lupron®, Abbvie, Inc., Chicago, IL) for 2 months were compared to a group that went untreated (controls). Endpoints included implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR), and as well as cycle characteristics. Miscarriage rate were also compared between treatment and control group. RESULTS: Women in each group had similar characteristics. Those treated by medical suppression and those undergoing laparoscopy for endometriosis had a significantly higher LBR, (5/10; 50%; 95%CI 23.7 to 76.3%) and (11/21; 52.4%; 95%CI 32.4 to 71.7), respectively, compared to controls (4/54; 7.4%; 95%CI 2.9 to 17.6). An absolute benefit of 44.2% (16/31; 95%CI 24.6 to 61.2) and a number need to treat of 3 for those that received treatment (medical suppression and laparoscopy), compared to no treatment. Miscarriages were significantly more common in the control group. CONCLUSIONS: Women with suspected endometriosis and aberrant endometrial BCL6 expression have worse reproductive outcomes following embryo transfer, including a high miscarriage rate, poor IR, and low LBR and CPR compared to cycles pre-treated with medical and surgical management.

Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study.

OBJECTIVE: To evaluate endometrial BCL6 expression as a prognostic biomarker for IVF outcome in women with unexplained infertility (UI) before ET. DESIGN: Prospective cohort study. SETTING: University-associated infertility clinic. PATIENT(S): Women with UI for >1 year. INTERVENTION(S): We studied women with UI who underwent testing for endometrial BCL6, in an LH-timed midluteal phase biopsy and completed an IVF cycle and ET. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR) and live birth rate per transfer was compared for women positive or negative for BCL6 expression. An abnormal BCL6 result was defined by an histologic score (>1.4). RESULT(S): Women with normal and abnormal BCL6 and those who conceived or not had similar characteristics. Women with low levels of BCL6 expression had a significantly higher clinical PR (11/17; 64.7%; 95% confidence interval [CI] 41.3-82.6) compared with women with abnormal (high) BCL6 expression (9/52; 17.3%; 95% CI 9.3-30.8). These results yield a relative risk of 0.267 (95% CI 0.13-0.53; P=.0004) for those with normal BCL6 expression, an absolute benefit of 47.4% (95% CI 22.5-72.0). Live birth rate was also significantly higher in women with low BCL6 expression (10/17; 58.8%; 95% CI 36.0-78.4) compared with women with abnormal BCL6 expression (6/52; 11.5%; 95% CI 5.4-23.0). The relative risk was 0.19 (95% CI 0.08-0.45; P=.0002), yielding an absolute benefit of 47.3% (95% CI 21.8-67.8). CONCLUSION(S): Aberrant BCL6 expression (histologic score, >1.4) was strongly associated with poor reproductive outcomes in IVF cycles in women with UI.

Luteal phase HCG support for unexplained recurrent pregnancy loss - a low hanging fruit?

Recurrent pregnancy loss (RPL) is defined by two or more failed pregnancies and accounts for only 1-5% of pregnancy failures. Treatment options for unexplained RPL (uRPL) are limited. Previous studies suggest a link between delayed implantation and pregnancy loss. Based on this, a timely signal for rescue of the corpus luteum (CL) using human chorionic gonadotrophin (HCG) could improve outcomes in women with uRPL. This retrospective cohort study included 98 subjects with uRPL: 45 underwent 135 monitored cycles without HCG support; and 53 underwent 142 cycles with a single mid-luteal HCG injection. Based on Log-rank Mantel-Cox survival curves, miscarriage rate and time to pregnancy decreased in the HCG group (P = 0.0005). Women receiving luteal HCG support had an increased chance of an ongoing pregnancy compared with those not receiving it (RR = 2.4; 95% CI 1.4-3.6; number need to treat (NNT) = 7; 95% CI 4-18). Subjects receiving HCG support had a significant absolute risk reduction (ARR) of miscarriage (P < 0.001; ARR = 11.5%; 95% CI 3.6-19.5; NNT = 9(5-27). These data suggest restoration of synchrony and CL support improves outcomes in women with RPL. Further randomized controlled trials of luteal-phase HCG in women with RPL appears warranted.

Cost analysis of abdominal, laparoscopic, and robotic-assisted myomectomies.

STUDY OBJECTIVE: To perform a cost-minimization analysis of abdominal, traditional laparoscopic and robotic-assisted myomectomy. DESIGN: Cost analysis (Canadian Task Force Classification III). SETTING: Academic medical center. PATIENTS: Women undergoing myomectomy by various surgical approaches. INTERVENTIONS: We developed a decision model to compare the costs ($2009) of different approaches to myomectomy from a healthcare system perspective. The model included operative time, conversion risk, transfusion risk, and length of stay (LOS) for each modality. Baseline estimates and ranges were based on reported values extracted from existing literature. We analyzed two different models: #1) Existing Robot model and #2) Robot Purchase model. MEASUREMENTS AND MAIN RESULTS: In the baseline analysis for the Existing Robot model, abdominal myomectomy (AM) was the least expensive at $4937 compared with laparoscopic myomectomy (LM) at $6219 and robotic-assisted laparoscopic myomectomy (RM) at $7299. The abdominal route remained the least expensive when varying all parameters and costs except for two cases in which LM became least expensive: 1) If AM length of stay was greater than 4.6 days, and 2) If the surgeon's fee for AM was greater than $2410. When comparing LM to RM, the cost of RM was consistently higher unless the robotic disposable equipment costs were less than $1400. In the Robot Purchase model, only the RM costs increased while AM and LM costs remained the same. CONCLUSION: In this cost-minimization analysis, abdominal myomectomy is the least expensive approach when compared to laparoscopy and robotic-assisted laparoscopy.

Early polycystic ovary syndrome as a possible etiology of unexplained premenarcheal ovarian torsion.

STUDY OBJECTIVE: To study evidence of polycystic ovary syndrome (PCOS) in premenarcheal adolescents with unexplained ovarian torsion. DESIGN: Retrospective observational case series. SETTING: Tertiary university clinical center PARTICIPANTS: Six premenarcheal adolescents and six adults with acute ovarian torsion INTERVENTION: A chart review. MAIN OUTCOME MEASURES: Contralateral ovarian size, operative findings, ovarian pathology, hormone testing RESULTS: Five of the six premenarcheal cases had no pathologic explanation for their ovarian torsion. In four of the cases, size measurements of the contralateral ovary were noted to be larger than the criterion of their respective age group. Three of the four cases had either an ovarian volume (28.5 cm(3)) or an area (16.0 cm(2) and 57.6 cm(2)) that was above the size criterion for a polycystic ovary (volume >10 cm(3) or area>5.5 cm(2)). Pathology of a wedge biopsy of one of the contralateral ovaries suggested evidence of polycystic ovary. Finally, hormone testing available in three of the cases revealed elevated testosterone levels in two. Among the adults, half of the cases had a pathologic explanation for ovarian torsion. One out of the five cases had a contralateral ovary that was significantly enlarged and this was noted in a woman with a diagnosis of PCOS. The remaining two cases had extensive necrosis of the torsed ovary and no other diagnosis was made. CONCLUSION: We propose that premenarcheal girls presenting with ovarian torsion, without obvious ovarian pathology, be screened for ultrasound and biochemical evidence of PCOS. In those with evidence of PCOS, treatment with oral contraceptives should be considered taking into account the age and pubertal development, to decrease ovarian volume.

Heterotopic cervical pregnancy treated with transvaginal ultrasound-guided aspiration resulting in cervical site varices within the myometrium.

OBJECTIVE: To report a case of successful treatment of a heterotopic cervical pregnancy from IVF-embryo transfer and intracytoplasmic sperm injection (ICSI) that resulted in uterine varices at the cervical site. DESIGN: Case report. SETTING: Tertiary university clinical center. PATIENT(S): A 34-year-old with a history of infertility associated with oligospermia who developed a heterotopic cervical pregnancy diagnosed at 7 weeks gestation. INTERVENTION(S): Transvaginal ultrasound (TVS)-guided aspiration of the cervical pregnancy; preoperative placement of bilateral hypogastric artery occlusion balloons; cesarean section. MAIN OUTCOME MEASURE(S): Successful delivery of intrauterine pregnancy; conservation of the uterus. RESULT(S): Successful termination of the cervical site pregnancy was achieved with TVS-guided aspiration. However, the pregnancy was then complicated by development of uterine varices at the cervical site noted on serial obstetric ultrasounds and magnetic resonance imaging (MRI). Successful management of the pregnancy required a multidisciplinary approach and preoperative placement of bilateral hypogastric artery occlusion balloons. A scheduled high fundal classic cesarean section at 37 weeks allowed for safe delivery of a healthy infant. Complete spontaneous resolution of the uterine varices was noted after the delivery. CONCLUSION(S): It is unclear whether residual ectopic tissue contributed to this later complication; however, it cannot be ignored that the locations of the aborted site and the prominence of dilated venous vasculature in this same location suggests a correlation. The interventions applied are reasonable conservative treatments of a cervical heterotopic pregnancy and a management strategy for uterine varices.