Erica T. Wang

BRCA1 germline mutations may be associated with reduced ovarian reserve

OBJECTIVE To determine whether BRCA carriers have a decreased ovarian reserve compared with women without BRCA mutations, because BRCA mutations may lead to accelerated oocyte apoptosis due to accumulation of damaged DNA. DESIGN Cross-sectional study. SETTING Academic tertiary care center. PATIENT(S) A total of 143 women, aged 18-45 years, who underwent clinical genetic testing for BRCA deleterious mutations because of a family history of cancer, were included. The cohort was classified into three groups: BRCA1 carriers, BRCA2 carriers, and women without BRCA mutations (controls). None had a personal history of breast or ovarian cancer. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The main outcome was serum antimüllerian hormone (AMH) level. Linear and logistic regression models adjusting for age and body mass index (BMI) were performed to determine the association between BRCA mutations and AMH. RESULT(S) BRCA1 mutation carriers had a significant decrease in AMH levels compared with controls after adjusting for age and BMI (0.53 ng/mL [95% confidence interval (CI) 0.33-0.77 ng/mL] vs. 1.05 ng/mL [95% CI 0.76-1.40 ng/mL]). Logistic regression confirmed that BRCA1 carriers had a fourfold greater odds of having AMH <1 ng/mL compared with controls (odds ratio 4.22, 95% CI 1.48-12.0). There was no difference in AMH levels between BRCA2 carriers and controls. CONCLUSION(S) BRCA1 carriers have lower age- and BMI-adjusted serum AMH levels compared with women without BRCA mutations. Our results contribute to the current body of literature regarding BRCA carriers and their reproductive outcomes. Larger prospective studies with clinical outcomes such as infertility and age at menopause in this population are needed to further substantiate our findings.

Pregnancy outcomes in very advanced maternal age pregnancies: the impact of assisted reproductive technology

OBJECTIVE To determine whether there are differences in adverse pregnancy outcomes in very advanced maternal age (vAMA) women who conceived with assisted reproductive technologies (ART) compared with spontaneous conceptions. DESIGN Retrospective cohort study. SETTING Academic tertiary care medical center. PATIENT(S) A total of 472 women aged ≥45 years who delivered at one institution. INTERVENTION(S) Mode of conception. MAIN OUTCOME MEASURE(S) Maternal and neonatal outcomes. RESULT(S) For singleton pregnancies, vAMA women who conceived with ART were significantly older (47.0 ± 2.3 vs. 45.6 ± 0.1 years), more likely to be white (88.1% vs. 75.6%), and less parous (0.4 ± 0.9 vs. 1.2 ± 1.8) than vAMA women who conceived spontaneously. They were at significantly increased risk for cesarean delivery (CD) (75.1% vs. 49.7%) and were more likely to undergo elective primary CD without labor (25.4% vs. 9.4%). Risk of retained placenta was also significantly higher (2.7% vs. 0%). Rates of other maternal complications and neonatal outcomes were similar. Subgroup analysis of ART singleton pregnancies did not demonstrate differences in women using autologous oocytes versus donor oocytes. CONCLUSION(S) Very advanced maternal age women who conceive after ART are more likely to be white, older, primiparous, and are more likely to proceed with an elective CD compared with vAMA women who conceive spontaneously. The increased risk of retained placenta in women who conceive with ART may indicate an underlying risk for placentation defects.

Predisposing Factors to Abnormal First Trimester Placentation and the Impact on Fetal Outcomes

Normal placentation during the first trimester sets the stage for the rest of pregnancy and involves a finely orchestrated cellular and molecular interplay of maternal and fetal tissues. The resulting intrauterine environment plays an important role in fetal programming and the future health of the fetus, and is impacted by multiple genetic and epigenetic factors. Abnormalities in placentation and spiral artery invasion can lead to ischemia, placental disease, and adverse obstetrical outcomes including preeclampsia, intrauterine growth restriction, and placental abruption. Although first trimester placentation is affected by multiple factors, preconception environmental influences such as mode of conception, including assisted reproductive technologies which result in fertilization in vitro and intrauterine influences due to sex differences, are emerging as potential significant factors impacting first trimester placentation.

Phenotypic comparison of Caucasian and Asian women with polycystic ovary syndrome: a cross-sectional study

OBJECTIVE To determine whether manifestations of polycystic ovary syndrome (PCOS), particularly androgen excess, differ between Caucasian and Asian women in the San Francisco Bay Area. DESIGN Cross-sectional study. SETTING Multidisciplinary PCOS clinic at a tertiary academic center. PATIENT(S) 121 Caucasian and 28 Asian women, aged 18-44, examined between 2006 and 2011 with PCOS verified by a reproductive endocrinologist and dermatologist according to the Rotterdam criteria. INTERVENTION(S) Transvaginal ultrasounds, comprehensive dermatologic exams, and serum testing. MAIN OUTCOME MEASURE(S) Hirsutism defined as a modified Ferriman-Gallwey (mFG) score ≥ 8, acne, androgenic alopecia, and biochemical hyperandrogenism. RESULT(S) Caucasian and Asian women had a similar prevalence of all measures of androgen excess. Both groups had similar total mFG scores and site-specific mFG scores, except Asian women had a lower site-specific mFG score for the chest. Although Asian women were more likely to use laser hair removal, the results were unchanged when the women with a history of laser hair removal were excluded. CONCLUSION(S) Caucasian and Asian women with PCOS living in the same geographic region had a similar prevalence of hirsutism as well as other markers for androgen excess. Further studies are necessary to evaluate the need for ethnic-specific mFG scores in women with PCOS.

Cutaneous Findings and Systemic Associations in Women With Polycystic Ovary Syndrome

IMPORTANCE Understanding of the associations among cutaneous findings, systemic abnormalities, and fulfillment of the diagnostic criteria in women suspected of having polycystic ovary syndrome (PCOS) is incomplete. OBJECTIVE To identify cutaneous and systemic features of PCOS that help distinguish women who do and do not meet the diagnostic criteria. DESIGN, SETTING, AND PARTICIPANTS Retrospective cross-sectional study of a racially diverse referred sample of women seen at the University of California, San Francisco, Polycystic Ovary Syndrome Multidisciplinary Clinic over a 6-year period between May 18, 2006, and October 25, 2012. Participants were 401 women referred for suspected PCOS. In total, 68.8% (276 of 401) met the Rotterdam PCOS diagnostic criteria, while 12.0% (48 of 401) did not. Overall, 11.5% (46 of 401) had insufficient data to render a diagnosis, 1.7% (7 of 401) were excluded from the study, and 6.0% (24 of 401) refused to participate in the study. EXPOSURE Comprehensive skin examination and transvaginal ultrasonography. All patients were tested for levels of total testosterone, free testosterone, dehydroepiandrosterone (DHEAS), androstenedione, luteinizing hormone, and follicle-stimulating hormone. Levels of serum cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides were obtained, in addition to 0-hour and 2-hour oral glucose tolerance test (OGTT) results, with measurement of glucose and insulin levels. MAIN OUTCOMES AND MEASURES Findings from comprehensive skin examination, laboratory testing, and transvaginal ultrasonography. RESULTS In total, 401 women with suspected PCOS were included in the study. The median patient age was 28 years. Compared with women who did not meet the diagnostic criteria for PCOS, women who met the criteria had higher rates of hirsutism (53.3% [144 of 270] vs 31.2% [15 of 48], P = .005) (with higher mean modified Ferriman-Gallwey scores of 8.6 vs 5.6, P = .001), acne (61.2% [164 of 268] vs 40.4% [19 of 47], P = .004), and acanthosis nigricans (AN) (36.9% [89 of 241] vs 20.0% [9 of 45], P = .03). Cutaneous distributions also varied. Women who met the PCOS criteria demonstrated more severe truncal hirsutism and higher rates of axillary AN. Women who met the PCOS criteria had elevated total testosterone levels (40.7% [105 of 258] vs 4.3% [2 of 47], P < .001). Among women with PCOS, the presence of hirsutism (43.9% [54 of 123] vs 30.9% [34 of 110], P = .04) or AN (53.3% [40 of 75] vs 27.0% [40 of 148], P < .001) was associated with higher rates of elevated free testosterone levels as well as several metabolic abnormalities, including insulin resistance, dyslipidemia, and increased body mass index. Although the prevalence of acne was increased among women with PCOS, there were minimal differences in acne types and distribution between the women meeting vs not meeting the PCOS criteria. CONCLUSIONS AND RELEVANCE Hirsutism and AN are the most reliable cutaneous markers of PCOS and require a comprehensive skin examination to diagnose. When present, hirsutism and AN should raise clinical concern that warrants further diagnostic evaluation for metabolic comorbidities that may lead to long-term complications. Acne and androgenic alopecia are prevalent but unreliable markers of biochemical hyperandrogenism among this population.

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation.

ABSTRACT Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3. Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.

The Role of Inflammatory Pathways in Implantation Failure: Chronic Endometritis and Hydrosalpinges

The process of implantation is highly complex and involves a delicate interplay between the embryo and the appropriate maternal environment. The failure to implant is thought to be due to maternal factors or embryonic factors. Inflammation can be a part of the normal physiologic process during implantation; however, there are also pathologic entities that adversely affect uterine receptivity. This review will focus on chronic endometritis and hydrosalpinges as two specific inflammatory processes that contribute to implantation failure. For both chronic endometritis and hydrosalpinges, we will review the diagnosis, pathophysiology, and effect on implantation following treatment. The existing literature conclusively demonstrates that hydrosalpinges should be addressed by either laparoscopic salpingectomy or proximal tubal occlusion prior to in vitro fertilization. The picture for chronic endometritis is less clear since the diagnosis and treatment of chronic endometritis are not standardized, and there are no available randomized controlled trials on this topic. Future studies may target gene expression arrays as a method for further elucidating the role of inflammatory markers in normal and abnormal implantation processes.

Irregular menses predicts ovarian cancer: Prospective evidence from the Child Health and Development Studies.

We tested the hypothesis that irregular menstruation predicts lower risk for ovarian cancer, possibly due to less frequent ovulation. We conducted a 50‐year prospective study of 15,528 mothers in the Child Health and Development Studies cohort recruited from the Kaiser Foundation Health Plan from 1959 to 1966. Irregular menstruation was classified via medical record and self‐report at age 26. We identified 116 cases and 84 deaths due to ovarian cancer through 2011 via linkage to the California Cancer Registry and Vital Statistics. Contrary to expectation, women with irregular menstrual cycles had a higher risk of ovarian cancer incidence and mortality over the 50‐year follow‐up. Associations increased with age (p <0.05). We observed a 2‐fold increased incidence and mortality by age 70 (95% confidence interval [CI] = 1.1, 3.4) rising to a 3‐fold increase by age 77 (95% CI = 1.5, 6.7 for incidence; 95% CI = 1.4, 5.9 for mortality). We also found a 3‐fold higher risk of mortality for high‐grade serous tumors (95% CI = 1.3, 7.6) that did not vary by age. This is the first prospective study to show an association between irregular menstruation and ovarian cancer—we unexpectedly found higher risk for women with irregular cycles. These women are easy to identify and many may have polycystic ovarian syndrome. Classifying high‐risk phenotypes such as irregular menstruation creates opportunities to find novel early biomarkers, refine clinical screening protocols and potentially develop new risk reduction strategies. These efforts can lead to earlier detection and better survival for ovarian cancer.

Oncofertility for women with gynecologic malignancies

The emerging field of oncofertility addresses fertility and the reproductive health needs for cancer patients, a key topic in cancer survivorship. Given that the standard treatment for gynecologic malignancies involves removal of reproductive organs, pelvic radiation, or chemotherapy, the effect of such treatment on fertility and options for fertility preservation are even more relevant than for other malignancies. In young women with new diagnoses of cervical, endometrial, or ovarian cancers, viable strategies for fertility preservation without compromising oncological outcome exist and should be considered. We present here a comprehensive review of the literature as it pertains to gynecologic malignancies on 1) the effects of radiation and chemotherapy on fertility, 2) fertility-sparing surgeries and the role of assisted reproductive technology, and 3) fertility preservation in adolescent girls and women with BRCA germline mutations.

Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First-Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments.

Background: Assisted reproductive technologies are associated with altered methylation in term placenta. However, it is unclear whether methylation patterns are the result of fertility treatments or intrauterine environment. Thus, we set out to determine whether there are differences in the first-trimester placenta that may be altered by the underlying fertility treatments. Genome-wide DNA methylation analyses from chorionic villus sampling (CVS) from matched singleton pregnancies conceived using in vitro fertilization (IVF), non-IVF fertility treatment (NIFT), or those conceived spontaneously were performed using Illumina Infinium HumanMethylation450 BeadChip from 15 matched CVS samples. Nanofluidic quantitative polymerase chain reaction (qPCR) of differently methylated genes was performed in a confirmatory cohort of 23 IVF conceptions and 24 NIFT conceptions. Results: Global methylation was similar among the IVF, NIFT, and spontaneous conceptions. However, differential methylation from IVF and NIFT pregnancies was present at 34 CpG sites, which was significantly different. Of those, 14 corresponded to known genes, with methylation changes detected at multiple loci in 3 genes, anaphase-promoting complex subunit 2 (ANAPC2), C-X-C motif chemokine ligand 14 (CXCL14), and regulating synaptic membrane exocytosis 1 (RIMS1). Nanofluidic qPCR of differentially methylated genes identified pre T-cell antigen receptor alpha (PTCRA) to be significantly downregulated in IVF versus NIFT conceptions. Conclusion: Although global methylation patterns are similar, there are differences in methylation of specific genes in IVF compared to NIFT conceptions, leading to altered gene expression. PTCRA was differentially methylated and downregulated in IVF conceptions, warranting further investigation. It remains to be determined whether these changes affect placentation and whether it is due to the more profound underlying infertility requiring IVF, yet these data provide unique insight into the first-trimester placental epigenome.