Publications by authors named "Geralyn Lambert-Messerlian"

104 Publications

Human chorionic gonadotropin-mediated modulation of pregnancy-compatible peripheral blood natural killer cells in frozen embryo transfer cycles.

Am J Reprod Immunol 2021 01 2;85(1):e13324. Epub 2020 Sep 2.

Department of Pediatrics, Women & Infants Hospital, Alpert Medical School of Brown University, Providence, RI, USA.

Problem: To evaluate pregnancy-compatible phenotypic and functional changes in peripheral blood natural killer (pNK) cells during frozen embryo transfer (FET) cycles.

Method Of Study: Peripheral blood was collected from patients undergoing frozen embryo transfer cycles at three separate time points in the cycle. pNK cell phenotype was analyzed by flow cytometry. Impact of pregnancy status on pNK cell cytotoxicity was characterized by two methods: (1) a three-dimensional endovascular tube formation approach and (2) a NK cell-specific K562 cell kill assay.

Results: A total of 35 patients were enrolled, 15 with clinical pregnancies and 20 with negative serum β-hCG levels. Overall percentage of CD45 CD3 CD56 pNK cell did not change during the FET cycle. Pregnancy resulted in an increase in CD45 CD3 CD56 pNK cell population on the day of serum β-hCG. pNK cells from non-pregnant patients caused significant tube disruption when compared to pregnant patients. Addition of serum from pregnant women reduced the tube disruption by pNK cells from non-pregnant patients. pNK cells from pregnant patients showed significantly lower cytotoxicity toward K562 cells in serum-free conditions. The addition of pregnancy serum decreased non-pregnant pNK cell cytotoxicity. Pregnancy status had no impact on VEGF-A and VEGF-C serum levels. Recombinant hCG added to non-pregnant serum resulted in a significant reduction in non-pregnant pNK cell-mediated K562 cell kill.

Conclusion: There was no difference in pNK cell populations based on timing of the FET cycle. However, pregnancy increased the percentage of CD45 CD3 CD56 pNK cells. Additionally, pNK cells from pregnant women have reduced cytotoxicity and this is possibly mediated by hCG.
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http://dx.doi.org/10.1111/aji.13324DOI Listing
January 2021

Factors associated with worse cerebrovascular function in aging women with and at risk for HIV.

AIDS 2021 02;35(2):257-266

Department of Medicine, Division of Infectious Diseases, University of California, San Francisco.

Objective: Women may be disproportionately impacted by the negative effect of HIV on cerebrovascular risk. We examined the association of HIV, sex, menopause, and immune activation with cerebrovascular function among women with HIV (WWH) and at risk for HIV from the Women's Interagency HIV Study and men with HIV.

Design: Cross-sectional.

Methods: Participants were aged at least 40 years with coronary heart disease or at least one cardiometabolic risk factor. All persons with HIV were on antiretroviral therapy with undetectable viral load. Cerebral vasoreactivity was assessed by the transcranial Doppler breath-holding test, with lower vasoreactivity corresponding to worse cerebrovascular function. Menopausal status was determined by anti-Müllerian hormone level. We used mixed effects linear regression to identify factors associated with cerebral vasoreactivity.

Results: Mean cerebral vasoreactivity was similar in WWH (n = 33) and women at risk for HIV (n = 16). A trend toward higher cerebral vasoreactivity in WWH compared with men with HIV (n = 37) was no longer present after excluding women on estrogen replacement therapy (n = 3). In women, menopausal status was not significantly associated with cerebral vasoreactivity. WWH with higher cardiovascular risk (-0.14 for each additional cardiometabolic risk factor, P = 0.038), sCD163 (-0.20 per doubling, P = 0.033), and proportion of CD4+CX3CR1+ T cells (-0.14 per doubling, P = 0.028) had lower cerebral vasoreactivity.

Conclusion: Among older women at high cardiovascular risk, women with virologically suppressed HIV and women at risk for HIV had similar cerebrovascular function. Our findings, which must be interpreted in the context of the small sample, highlight the contribution of traditional cardiometabolic risk factors and immune activation to cerebrovascular risk in WWH.
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http://dx.doi.org/10.1097/QAD.0000000000002755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789911PMC
February 2021

Association between a history of depression and anti-müllerian hormone among late-reproductive aged women: the Harvard study of moods and cycles.

Womens Midlife Health 2020 1;6. Epub 2020 Sep 1.

Department of Epidemiology, Boston University School of Public Health, 715 Albany St, Boston, MA 02118 USA.

Background: There is conflicting evidence regarding the association between a history of depression and risk of early menopause. In a cohort of premenopausal women, we investigated the association between depression history and ovarian reserve, as measured by anti-müllerian hormone (AMH).

Methods: The Harvard Study of Moods and Cycles (HSMC) was a prospective cohort study of women living in the Boston, MA metropolitan-area (1995-1999). Women aged 36-45 years at cohort entry (1995) were sampled from seven Boston metropolitan-area communities using census directories. We measured serum AMH in early-follicular phase venous blood specimens from 141 women with a Structured Clinical Interview for DSM-IV (SCID)-confirmed history of depression and 228 without such a history. We calculated prevalence ratios (PR) for the association between characteristics of depression history and low AMH (≤1.4 ng/mL), adjusting for several potential confounders.

Results: The prevalence of low AMH was similar among depressed (57.5%) and non-depressed (57.9%) women (Adjusted [Adj] PR = 0.90, 95% CI: 0.75, 1.08). Among depressed women, results were not appreciably different among those who had ever used antidepressants and those with comorbid anxiety. Modest inverse associations between depression and low AMH were seen among women aged 36-40 years (Adj PR = 0.75, 95% CI: 0.52, 1.09) and nulliparous women (Adj PR = 0.77, 95% CI: 0.59, 1.00). No dose-response association with greater duration or length of depressive symptoms was observed.

Conclusions: Overall, the prevalence of low AMH was similar for depressed and non-depressed women 36-45 years of age. Surprisingly, among younger and nulliparous women, those with a history of depression had a slightly reduced prevalence of low AMH relative to those without such a history. These results do not indicate reduced ovarian reserve among women with a history of depression.
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http://dx.doi.org/10.1186/s40695-020-00056-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461252PMC
September 2020

Serum Decorin, Biglycan, and Extracellular Matrix Component Expression in Preterm Birth.

Reprod Sci 2021 Jan 17;28(1):228-236. Epub 2020 Aug 17.

Warren Alpert Medical School at Brown University, Providence, RI, USA.

Preterm birth is a leading cause of infant morbidity and mortality. Decorin and biglycan are proteoglycans that play key roles in maintaining the connective tissue matrix and tensile strength of human fetal membranes and have been previously linked to PPROM. Extracellular matrix proteins, such as matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), TIMP metallopeptidase inhibitor 1 (TIMP-1), TIMP metallopeptidase inhibitor 2 (TIMP-2), and collagen VI (COL-6), have also been linked to PPROM and may have utility in a serum-based screening model for this condition. To define the natural course of serum decorin and biglycan expression throughout the duration of healthy pregnancy, to explore patterns of serum decorin and biglycan expression in serum of asymptomatic women who go on to develop spontaneous preterm labor, and to investigate the potential role for matrix metalloproteinases, their inhibitors, and collagen VI in a serum-based screening model to predict PPROM. Serum decorin level decreases less than 1% per week, and serum biglycan decreases by 2.9% per week over the duration of healthy pregnancy. Serum decorin and biglycan concentrations do not differ in spontaneous preterm labor cases compared with those in controls. Mean concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, and COL-6 do not differ in PPROM cases compared with those in controls. We have demonstrated that serum decorin and biglycan concentrations remain stable throughout the duration of normal pregnancy and are not early indicators of preterm labor, while common MMPs, TIMPs, and collagen VI are not early indicators of PPROM.
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http://dx.doi.org/10.1007/s43032-020-00251-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782456PMC
January 2021

Adjusting antimüllerian hormone levels for age and body mass index improves detection of polycystic ovary syndrome.

Fertil Steril 2020 04 5;113(4):876-884.e2. Epub 2020 Mar 5.

Ansh Labs, Webster, Texas.

Objective: To examine whether accounting for a woman's age and body mass index (BMI) would improve the ability of antimüllerian hormone (AMH) to distinguish between women with (cases) and without (controls) polycystic ovarian syndrome (PCOS).

Design: An opportunistic case-control dataset of reproductive age women having evaluations for PCOS as defined by National Institutes of Health criteria.

Setting: Two medical centers in the United States enrolled women. Serum samples were analyzed for relevant analytes.

Patients: Women were between 18 and 39 years of age when samples and clinical information were collected. Residual samples had been stored for 2-17 years. AMH was measured via immunoassay.

Interventions: None; this was an observational study.

Main Outcome Measures: Detection and false-positive rates for PCOS were computed for AMH results expressed as multiples of the median (MoM) both before and after adjustment for the woman's age and BMI.

Results: Using unadjusted AMH MoM results, 168 cases (78%) cases were at or beyond the 90 centile of controls (2.47 MoM). After accounting for each woman's age and BMI, 188 (87%) of those women were beyond the 90 centile of controls (2.20 MoM), a significant increase (P = .015). The adjusted AMH MoM levels fitted logarithmic normal distributions well (mean, standard deviation for controls and cases of 0.0000, 0.2765 and 0.6884, 0.2874, respectively) and this allowed for computation of patient-specific PCOS risks.

Conclusions: Accounting for the woman's age and BMI resulted in significantly higher AMH-based detection rates for PCOS at a 10% false-positive rate, and patient-specific PCOS risks could be computed.
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http://dx.doi.org/10.1016/j.fertnstert.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583345PMC
April 2020

AMH is Higher Across the Menstrual Cycle in Early Postmenarchal Girls than in Ovulatory Women.

J Clin Endocrinol Metab 2020 04;105(4)

Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.

Context: Adolescents have more small, growing follicles and larger ovaries than normal women and are prone to anovulatory cycles (ANOV). It is unknown if a higher antral follicle count (AFC) per se contributes to ANOV in early postmenarchal girls.

Objective: To determine the relationship between AMH (an AFC biomarker), other reproductive hormones, and ANOV in postmenarchal girls and to compare AMH in girls and regularly cycling adults.

Methods: A total of 23 girls (1.7 ± 0.2 years postmenarche) and 32 historic adult controls (≤34 years) underwent serial hormone measurements during 1 to 2 menstrual cycles. Girls also had pelvic ultrasounds. AMH was measured 5 times/subject using the Ansh ultrasensitive ELISA.

Results: Girls had higher AMH than women (5.2 ± 0.3 vs. 3.3 ± 0.4 ng/mL; P < 0.01) and girls with more ovulatory (OV) cycles tended to have lower AMH than those with ANOV (2 OV 4.5 ± 0.2, 1 OV 5.7 ± 1.1, 0 OV 6.8 ± 1.1 ng/mL; P = 0.1). In girls, AMH correlated with natural-log (ln) transformed LH (r = 0.5, P = 0.01), ln_androstenedione (r = 0.6, P = 0.003), ln_testosterone (r = 0.5, P = 0.02), and ovarian volume (r = 0.7, P < 0.01) but not with FSH, estradiol, P4, or body mass index. In women, AMH correlated with estradiol and P4 (both r = -0.4, P ≤ 0.03) but not with ln_LH or body mass index.

Conclusions: In postmenarchal girls, AMH is higher than in ovulatory women and is associated with LH, androgens, and a propensity for anovulatory cycles. The cause of the transient increase in AMH and AFC during late puberty and the steps underlying the transition to a mature ovary deserve further study.
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http://dx.doi.org/10.1210/clinem/dgaa059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082083PMC
April 2020

Levels of angiogenic markers in second-trimester maternal serum from in vitro fertilization pregnancies with oocyte donation.

Fertil Steril 2019 12;112(6):1112-1117

Department of Pathology and Laboratory Medicine, Women and Infants Hospital and Alpert Medical School, Brown University, Providence, Rhode Island.

Objective: To determine whether differences exist in angiogenic placental growth factor (PlGF) and antiangiogenic soluble vascular endothelial growth factor receptor 1 (sVEGFR-1; both being early markers of placental ischemic disease) in oocyte-donation (OD) pregnancies, compared with autologous in vitro fertilization (aIVF) and spontaneous pregnancies.

Design: Case-control study of residual second-trimester serum samples from women undergoing prenatal screening.

Setting: Academic medical center.

Patient(s): Fifty-seven OD pregnancies were identified. Each OD pregnancy was matched to two spontaneous pregnancies (n = 114) and one aIVF pregnancy (n = 57).

Interventions(s): None.

Main Outcome Measure(s): Second-trimester serum PlGF and sVEGFR-1 levels.

Result(s): sVEGFR-1, PlGF, and unconjugated E levels were similar among the three study groups. The ratio of sVEGFR-1 to PlGF was significantly higher in the OD group. Consistently with previous studies, alpha-fetoprotein (AFP) in the OD group was significantly elevated compared with spontaneous pregnancy. Both aIVF and OD groups had greater levels of inhibin A than the spontaneous pregnancy group, and the OD group had significantly higher levels of inhibin A than the aIVF group. hCG levels were significantly elevated in aIVF compared with spontaneous pregnancy; however, levels were not different between aIVF and OD.

Conclusion(s): Second-trimester serum sVEGFR-1 and PlGF levels were not significantly altered in OD pregnancies. Our data support previous findings that OD pregnancies have uniquely increased second-trimester AFP, hCG, and inhibin A levels compared with aIVF. However, the biologic basis of these marker elevations in OD may not be related to placental angiogenesis.
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http://dx.doi.org/10.1016/j.fertnstert.2019.07.017DOI Listing
December 2019

Anthropometric Measures and Prediction of Maternal Sleep-Disordered Breathing.

J Clin Sleep Med 2019 06 15;15(6):849-856. Epub 2019 Jun 15.

Warren Alpert Medical School at Brown University, Providence, Rhode Island.

Study Objectives: Pregnant women are at risk for sleep-disordered breathing (SDB); however, screening methods in this dynamic population are not well studied. The aim of this study was to examine whether anthropometric measures can accurately predict SDB in pregnant women.

Methods: Pregnant women with snoring and overweight/obesity were recruited in the first trimester. Anthropometric measures were performed according to the International Standards for Anthropometric Assessment, including a seated neutral and extended neck Mallampati class. Home sleep apnea monitoring was performed using a level III device after completion of anthropometric assessment. SDB was defined as an apnea-hypopnea index ≥ 5 events/h of sleep. Pearson and Spearman tests examined correlations between various measures. Generalized linear models, sensitivity, specificity, and area under the curve as well as odds ratios were performed to test the model.

Results: A total of 129 participants were recruited, and 23 had SDB. Average gestational age was 10.6 ± 1.9 weeks. Due to concerns over multicollinearity, the final model included extended Mallampati class and upright neck circumference. Neck circumference was significantly higher in participants with Mallampati classes 2/3 and grade 4 compared to participants with Mallampati class 1 ( = .0005). Increasing neck circumference was associated with higher odds of SDB ( = .0022). In Mallampati class 1, odds ratio for SDB was 2.89 (1.19, 7.03) per unit increase in neck circumference.

Conclusions: Modeling neck circumference while allowing for differences by Mallampati class showed a nearly threefold increase in the risk of SDB with increasing neck circumference in women with Mallampati class 1. Other potential sites of airway obstruction need to be investigated in future research.
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http://dx.doi.org/10.5664/jcsm.7834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557653PMC
June 2019

Maternal BMI, Peripheral Deiodinase Activity, and Plasma Glucose: Relationships Between White Women in the HAPO Study.

J Clin Endocrinol Metab 2019 07;104(7):2593-2600

Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Providence, Rhode Island.

Objectives: Explore the maternal body mass index (BMI) relationship with peripheral deiodinase activity further. Examine associations between deiodinase activity, glucose, and C-peptide. Consider findings in the historical context of related existing literature.

Design: Identify fasting plasma samples and selected demographic, biophysical, and biochemical data from a subset of 600 randomly selected non-Hispanic white women recruited in the Hyperglycemia Adverse Pregnancy Outcomes (HAPO) study, all with glucose tolerance testing [545 samples sufficient to measure TSH, free T4 (fT4), and T3]. Exclude highest and lowest 1% TSH values (535 available for analysis). Assess deiodinase activity by using T3/fT4 ratios. Among women with and without gestational diabetes mellitus (GDM), compare thyroid measurements, C-peptide, and other selected data. Examine relationships independent of GDM status between BMI and thyroid hormones and between thyroid hormones and glucose and C-peptide.

Results: Levels of BMI, T3/fT4 ratio, and T3 were significantly higher among women with GDM (P = 0.01, 0.005, and 0.001, respectively). Irrespective of GDM status, maternal BMI was associated directly with both T3/fT4 ratio (r = 0.40, P < 0.001) and T3 (r = 0.34, P < 0.001) but inversely with fT4 (r = -0.21, P < 0.001). In turn, fasting thyroid hormone levels (most notably T3/fT4 ratio) were directly associated with maternal glucose [z score sum (fasting, 1, 2 hours); r = 0.24, P < 0.001] and with C-peptide [z score sum (fasting, 1 hour); r = 0.27, P < 0.001].

Conclusions: Higher BMI was associated with increased deiodinase activity, consistent with reports from elsewhere. Increased deiodinase activity, in turn, was associated with higher glucose. Deiodinase activity accounts for a small percentage of z score sum glucose.
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http://dx.doi.org/10.1210/jc.2018-02328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453035PMC
July 2019

Fewer women aged 35 and older choose serum screening for Down's syndrome: Impact and implications.

J Med Screen 2019 Jun 25;26(2):59-66. Epub 2018 Sep 25.

1 Department of Pathology and Laboratory Medicine, Women & Infants Hospital and the Alpert Medical School at Brown University, Providence, USA.

Objective: To quantify changes in the proportion of women aged 35 and older choosing serum screening for Down's syndrome over time and the effect on false positive and detection rates.

Methods: From Rhode Island hospital-based laboratory prenatal screening records (2013-2017) we extracted the test performed (Integrated, Combined, Quadruple), maternal age, and Down's syndrome risk; documented observed changes in maternal age distributions and false positive rates, and modelled the impact of varying proportions of older women choosing screening on each test's performance using the 2015 United States birth cohort as baseline.

Results: Over five years, observed false positive rates for Integrated testing declined from 1.9 to 1.3% (-32%). The proportion of older women tested declined from 14.9 to 8.5%, from which modelling predicts a 16% decline in the false positive rate. This is lower than our observed change but consistent with a reduction driven by declining participation by older women. Modelling predicted a detection rate reduction from 89 to 87%. Larger detection rate impacts were predicted for Combined and Quadruple testing.

Conclusions: This study documents, for the first time, the declining proportion of older women choosing Down's syndrome serum screening and subsequent impact on screening performance. The American College of Obstetrics and Gynecology recommends offering cell-free DNA screening for these 'high risk' pregnancies and uptake may increase further. Screening programmes could consider increasing use of Integrated testing over other serum screening tests or lowering risk cut-offs so false positive rates approach those of 2012 to regain lost detection.
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http://dx.doi.org/10.1177/0969141318797961DOI Listing
June 2019

Peripheral deiodinase activity: A potential explanation for the association between maternal weight and gestational hyperglycemia.

Obstet Med 2018 Jun 12;11(2):73-78. Epub 2017 Oct 12.

Department of Pathology and Laboratory Medicine, Division of Medical Screening and Special Testing, Women and Infants Hospital/Alpert Medical School of Brown University, Providence, RI, USA.

Background: High maternal weight is known to associate with both low free thyroxine and gestational diabetes mellitus. We explore a deiodinase-related mechanism that may help explain these associations.

Methods: Among 108 women receiving routine oral glucose tolerance testing for gestational diabetes mellitus, we collected biophysical data and measured free thyroxine and total triiodothyronine, using residual plasma samples.

Results: Fasting triiodothyronine/free thyroxine ratio and triiodothyronine were higher among women with gestational diabetes mellitus ( = 0.02;  = 0.04). The triiodothyronine/free thyroxine ratio and triiodothyronine measurements at 2 h were associated with weight ( = 0.20,  = 0.04;  = 0.22,  = 0.02); free thyroxine showed a non-significant inverse weight relationship ( = -0.06,  = 0.55). Glucose at all four intervals was associated with triiodothyronine/free thyroxine ratios, and triiodothyronine at 2 h. In stepwise regression, triiodothyronine/free thyroxine ratio predicted glucose more strongly than did weight.

Conclusion: These relationships may be explained by higher maternal weight inducing peripheral deiodinase activity, resulting in higher plasma glucose (via triiodothyronine stimulation) and thereby increasing gestational diabetes mellitus risk.
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http://dx.doi.org/10.1177/1753495X17733223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038021PMC
June 2018

Snoring and markers of fetal and placental wellbeing.

Clin Chim Acta 2018 Oct 26;485:139-143. Epub 2018 Jun 26.

The Miriam Hospital, Department of Medicine, United States; Warren Alpert Medical School at Brown University, United States. Electronic address:

Introduction: Snoring, the symptom of partial airway obstruction during sleep, is a common complaint during pregnancy and is associated with adverse perinatal outcomes. Mechanisms underlying this association have not been studied. We investigated the relationship between snoring in pregnancy and maternal serum markers of feto-placental wellbeing.

Methods: We conducted a secondary analysis of a cross sectional study designed to investigate perinatal outcomes of sleep-disordered breathing. Women admitted for delivery were systematically selected and answered a questionnaire about snoring using the Multivariable Apnea Prediction Index. Participants who had screening markers measured were included and divided into snorers and non -snorers. Markers measured included first and second trimester Down syndrome screening markers, reported as multiples of the median (MoM). An additional analysis was performed with snorers categorized as acute or chronic snorers based on duration of snoring in relation to pregnancy.

Results: While significant differences were noted in co-morbid maternal medical conditions between snorers and non-snorers, there were no significant differences in the neonatal outcomes assessed between the two groups. No significant differences were noted in any of the first trimester (PAPP-A) or second trimester (AFP, uE3, hCG, inhibin-A) markers between snorers and non-snorers, p > 0.25. In addition, no significant differences in marker levels were noted between acute and chronic snorers.

Conclusion: Snoring is not associated with alterations in the markers of fetal or placental wellbeing tested here and suggests that there are alternative mechanisms underlying the association between snoring and adverse perinatal outcomes.
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http://dx.doi.org/10.1016/j.cca.2018.06.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113085PMC
October 2018

Current and Emerging Multianalyte Assays with Algorithmic Analyses-Are Laboratories Ready for Clinical Adoption?

Clin Chem 2018 06 17;64(6):885-891. Epub 2018 Jan 17.

Department of Pathology and Laboratory Medicine, Women and Infants' Hospital of Rhode Island, The Warren Alpert Medical School of Brown, Providence, Rhode Island.

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http://dx.doi.org/10.1373/clinchem.2017.275677DOI Listing
June 2018

Ovarian aging is associated with gray matter volume and disability in women with MS.

Neurology 2018 01 22;90(3):e254-e260. Epub 2017 Dec 22.

From the Departments of Neurology (J.S.G., R.G.H., B.A.C.C., E.W., A.Z., S.L.H., J.R.O.), Pharmacology (R.M.G.), Obstetrics, Gynecology and Reproductive Sciences (M.I.C.), and Epidemiology and Biostatistics (P.B.), University of California, San Francisco; and Women and Infants Hospital and the Alpert Medical School at Brown University (G.L.-M.), Providence, RI.

Objective: To determine if ovarian aging as measured by levels of anti-Müllerian hormone (AMH) is associated with pattern of multiple sclerosis (MS) progression in women.

Methods: Women with MS and healthy controls were included from a longitudinal research cohort with up to 10 years follow-up. Plasma AMH levels were measured by ELISA for baseline and years 3, 5, and 8-10. Mixed effects logistic and linear regression models were employed, with adjustments for age, disease duration, and other covariables as appropriate.

Results: AMH levels were similar (0.98-fold difference, 95% confidence interval [CI] 0.69-1.37, = 0.87) in women with MS (n = 412, mean age 42.6 years) and healthy controls (n = 180, mean age 44 years). In a multivariable model of women with MS, including adjustments for age, body mass index, and disease duration, 10-fold lower AMH level was associated with 0.43-higher Expanded Disability Status Scale (EDSS) score (95% CI 0.15-0.70, = 0.003), 0.25-unit worse MS Functional Composite score (95% CI -0.40 to -0.10, = 0.0015), and 7.44 mm lower cortical gray matter volume (95% CI -14.6 to -0.30; = 0.041) at baseline. In a multivariable random-intercept-random-slope model using all observations over time, 10-fold decrease in AMH was associated with a 0.27 increase in EDSS (95% CI 0.11-0.43, = 0.006) and 5.48 mm (95% CI 11.3-0.33, = 0.065) and 4.55 mm (95% CI 9.33-0.23, = 0.062) decreases in total gray and cortical gray matter, respectively.

Conclusion: As a marker of ovarian aging, lower AMH levels were associated with greater disability and gray matter loss in women with MS independent of chronological age and disease duration.
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http://dx.doi.org/10.1212/WNL.0000000000004843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772165PMC
January 2018

Relaxin-2 connecting peptide (pro-RLX2) levels in second trimester serum samples to predict preeclampsia.

Pregnancy Hypertens 2018 Jan 7;11:124-128. Epub 2017 Nov 7.

Women and Infants Hospital, Providence, USA. Electronic address:

Objectives: Preeclampsia is a serious complication of pregnancy, threatening fetal and maternal health. The aim of our study is to examine the association between preeclampsia and the connecting peptide of the pregnancy hormone relaxin (pro-RLX2) as a potential new biochemical marker.

Study Design: This is a nested case/control study derived from the cohort of pregnancies delivering at Women & Infants Hospital. Cases were identified at a clinic or by hospital codes, and individually confirmed by record review. Stored samples were available from 'integrated' Down syndrome screening. Results were expressed as multiples of the median (MoM).

Main Outcome Measures: Preeclampsia was classified as early/severe, late/severe, or mild based on professional guidelines.

Results: Fifty-one cases were each matched with five control pregnancies. Population distribution parameters were derived for cases and controls. As shown previously, discrimination between cases and controls (applying MoM analysis) was possible for PlGF (0.576, p < .05), inhibin A (1.45, p < .05) and endoglin (1.278, p < .05). No association with preeclampsia was found for pro-RLX2. However, pro-RLX2 correlates with Inhibin A and Endoglin.

Conclusions: Endoglin, Inhibin A and PlGF are highly predictive of preeclampsia. Quantification of pro-RLX2 is not able to predict preeclampsia. Nevertheless, the potential involvement of relaxin 2/pro-RLX2 in the pathophysiology of preeclampsia requires further study.
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http://dx.doi.org/10.1016/j.preghy.2017.11.001DOI Listing
January 2018

Antimüllerian Hormone Levels Are Not Altered by Glucose Challenge or a Meal.

J Appl Lab Med 2017 Sep;2(2):238-243

Department of Pathology and Laboratory Medicine, Women and Infants Hospital and Alpert Medical School at Brown University, Providence, RI.

Background: Measurement of antimüllerian hormone (AMH) is used to assess ovarian reserve. Circulating levels of AMH correlate with antral follicle count, with relatively high levels indicating an ample reserve of primary and preantral follicles in the ovary. AMH levels are stable with dilution and freezer storage, and are not altered by hemolysis or menstrual cycle day in young women of reproductive age. We sought to examine whether glucose challenge or food intake modifies AMH levels compared with fasting.

Methods: Residual plasma samples were available from 54 pregnant women under fasting conditions and then 1, 2, and 3 h after ingestion of a 100-g glucose challenge. These samples were collected as part of routine clinical care to identify gestational diabetes (GDM) at 24-28 weeks of gestation. Twelve of these women met criteria for GDM based on an increased glucose level at a minimum of 2 time points. A second set consisted of serum samples collected from 8 nonpregnant women at fasting and 1 h after a meal. Levels of AMH were measured using an ultrasensitive assay (Ansh Labs, Webster, TX). A 2-way ANOVA (sample timing and GDM status) or matched t-test was performed. AMH measurements were subject to a logarithmic transformation before analysis.

Results: Median AMH levels in pregnant women at 1, 2, or 3 h after glucose challenge did not differ compared with AMH levels at fasting or by diagnosis of GDM. Similarly, there was no difference in median AMH levels in nonpregnant women of reproductive age at fasting and after a meal.

Conclusion: AMH levels are not altered by glucose or food intake.
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http://dx.doi.org/10.1373/jalm.2017.023622DOI Listing
September 2017

Correlation between follicular fluid levels of sRAGE and vitamin D in women with PCOS.

J Assist Reprod Genet 2017 Nov 19;34(11):1507-1513. Epub 2017 Aug 19.

Department of Obstetrics and Gynecology, NYU School of Medicine, New York, NY, 11014, USA.

Purpose: The pro-inflammatory advanced glycation end products (AGEs) and their anti-inflammatory soluble receptors, sRAGE, play a role in the pathogenesis of PCOS. There is a correlation between vitamin D (vit D) and sRAGE in the serum, whereby vit D replacement increases serum sRAGE levels in women with PCOS, thus incurring a protective anti-inflammatory role.

Objective: This study aims to compare levels of sRAGE, N-carboxymethyl-lysine (CML; one of the AGEs), and 25-hydroxy-vit D in the follicular fluid (FF) of women with or without PCOS, and to evaluate the correlation between sRAGE and 25-hydroxy-vit D in the FF.

Material And Methods: Women with (n = 12) or without (n = 13) PCOS who underwent IVF were prospectively enrolled.

Results: Women with PCOS had significantly higher anti-Mullerian hormone levels, higher number of total retrieved and mature oocytes, and higher number of day 3 and day 5 embryos formed. Compared to women without PCOS, women with PCOS had significantly lower FF sRAGE levels. In women with PCOS, in women without PCOS, and in all participants together, there was a significant positive correlation between sRAGE and 25-hydroxy-vit D. sRAGE positively correlated with CML in women without PCOS but not in women with PCOS.

Conclusions: In women with PCOS, the low ovarian levels of the anti-inflammatory sRAGE suggest that sRAGE could represent a biomarker and a potential therapeutic target for ovarian dysfunction in PCOS. Whether there is a direct causal relationship between sRAGE and vit D in the ovaries remains to be determined.
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http://dx.doi.org/10.1007/s10815-017-1011-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699991PMC
November 2017

Measuring maternal serum screening markers for Down's syndrome in plasma collected for cell-free DNA testing.

J Med Screen 2017 09 21;24(3):113-119. Epub 2016 Oct 21.

1 Department of Pathology and Laboratory Medicine, Women & Infants Hospital, Providence, RI, USA.

Objectives To determine whether maternal plasma collected in cell-free DNA stabilizing tubes is suitable for measuring prenatal screening 'serum' markers. Methods Matched plasma and serum samples were collected from 41 second trimester and 42 first trimester non-Down's syndrome pregnancies. Second trimester samples were tested for alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin-A (Beckman Coulter DxI immunoassay). First trimester samples were tested for human chorionic gonadotropin and pregnancy-associated plasma protein A. Method comparisons performed for each marker compared plasma and serum results. Down's syndrome likelihood ratios in serum and plasma were compared. Results Plasma and serum results for all markers were highly correlated ( r > 0.983) but for all, plasma results differed, usually by proportional amounts. After conversion to multiples of the median using sample type-specific medians, the logarithmic standard deviations in serum and plasma did not differ (all p > 0.37). Likelihood ratios for the first and second trimester marker combinations were highly correlated and closely agreed (log likelihood ratios range 1.005 to 1.032; 1.000 indicates complete agreement). Conclusions These results using specialized plasma collection tubes are similar to those of our earlier study showing that plasma collected in EDTA tubes is suitable for 'serum' Down's syndrome screening. Laboratories must account for proportional changes by computing new plasma medians or modifying existing serum medians. Using a portion of the plasma from cell-free DNA collection tubes for 'serum screening' may have an advantage in programmes that are reflexively testing cell-free DNA, as only one sample type need be collected.
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http://dx.doi.org/10.1177/0969141316670193DOI Listing
September 2017

Assessment of serum HE4 levels throughout the normal menstrual cycle.

Am J Obstet Gynecol 2017 07 22;217(1):53.e1-53.e9. Epub 2017 Feb 22.

Department of Obstetrics and Gynecology, Women and Infants Hospital, Alpert Medical School at Brown University, Providence RI; Departments of Pathology and Laboratory Medicine and Obstetrics and Gynecology, Center for Biomarkers and Emerging Technologies, Women and Infants Hospital, Alpert Medical School at Brown University, Providence RI.

Background: Human epididymis protein 4 is a serum biomarker to aid in differentiating benign and malignant disease in women with a pelvic mass. Interpretation of human epididymis protein 4 results relies on robust normative data.

Objective: The purpose of this study was to evaluate whether human epididymis protein 4 levels are variable in women during the normal menstrual cycle.

Study Design: Healthy women, 18-45 years old, with regular menstrual cycles were recruited from community gynecologic practices in Rhode Island. Women consented to enroll and to participate by the donation of blood and urine samples at 5 specific times over the course of each cycle. Levels of reproductive hormones and human epididymis protein 4 were determined. Data were analyzed with the use of linear regression after log transformation.

Results: Among 74 enrolled cycles, 53 women had confirmed ovulation during the menstrual cycle and completed all 5 sample collections. Levels of estradiol, progesterone, and luteinizing hormone displayed the expected menstrual cycle patterns. Levels of human epididymis protein 4 in serum were relatively stable across the menstrual cycle, except for a small ovulatory (median, 37.0 pM) increase. Levels of human epididymis protein 4 in urine, after correction for creatinine, displayed the same pattern of secretion observed in serum.

Conclusion: Serum human epididymis protein 4 levels are relatively stable across the menstrual cycle of reproductive-aged women and can be determined on any day to evaluate risk of ovarian malignancy. A slight increase is expected at ovulation; but even with this higher human epididymis protein 4 level, results are well within the healthy reference range for women (<120 pM). Levels of human epididymis protein 4 in urine warrant further investigation for use in clinical practice as a simple and convenient sample.
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http://dx.doi.org/10.1016/j.ajog.2017.02.029DOI Listing
July 2017

Oxidative and carbonyl stress in pregnant women with obstructive sleep apnea.

Sleep Breath 2018 03 24;22(1):233-240. Epub 2017 Feb 24.

Department of Medicine, Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA.

Purpose: Pregnant women are particularly susceptible to sleep-disordered breathing. Obstructive sleep apnea (OSA) in pregnancy is associated with poor pregnancy and fetal outcomes. Oxidative stress caused by intermittent hypoxemia and reoxygenation may impact pregnancy health. We hypothesize that pregnant women with OSA have a pronounced oxidative stress profile.

Methods: A case-control study was performed to study oxidative stress markers in the serum of pregnant women with or without OSA. Patients with OSA were identified between 2003 and 2009. Contemporaneous controls were pregnant subjects without apnea, gasping, or snoring around the time of delivery. Serum markers of oxidative and carbonyl stress were measured by spectrophotometric/fluorometric methods. Multiple linear regression analysis was used with a model including age, body mass index at delivery, history of diabetes, and gestational age.

Results: Serum samples from 23 OSA cases and 41 controls were identified. Advanced oxidation protein products, a marker for oxidative stress, and advanced glycation end products (AGEs), a marker for carbonyl stress, were significantly lower in women with OSA than in controls (p value <0.0001). Total antioxidant capacity was higher in women with OSA in comparison to controls (p value <0.0001). The difference in AGEs remained significant even after adjusting for confounders.

Conclusion: Contrary to our hypothesis, the results of this study suggest that pregnant women with OSA have higher antioxidant capacity and lower oxidative and carbonyl stress markers compared to controls, suggesting a possible protective effect of intermittent hypoxia. Whether OSA in pregnancy impacts oxidative stress differently than OSA in the general population remains to be confirmed.
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http://dx.doi.org/10.1007/s11325-017-1475-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568979PMC
March 2018

Nuchal translucency measurement in the era of prenatal screening for aneuploidy using cell free (cf)DNA.

Prenat Diagn 2017 03 17;37(3):303-305. Epub 2017 Feb 17.

Department of Pathology and Laboratory Medicine, Women and Infants Hospital and the Alpert Medical School at Brown University, Providence, RI, USA.

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http://dx.doi.org/10.1002/pd.5010DOI Listing
March 2017

Serum Progesterone Levels in Pregnant Women with Obstructive Sleep Apnea: A Case Control Study.

J Womens Health (Larchmt) 2017 03 19;26(3):259-265. Epub 2017 Jan 19.

1 Department of Medicine, Warren Alpert Medical School of Brown University , Providence, Rhode Island.

Background: Pregnancy is a risk factor for sleep disordered breathing, including obstructive sleep apnea (OSA). Progesterone, one of the key hormones in pregnancy, a known respiratory drive stimulant, increases ventilation and may protect against OSA. We aimed to examine the relationship between circulating progesterone and OSA, after accounting for body weight and gestational age.

Methods: A case control study was conducted of pregnant women with OSA and those at low risk for the disorder. Cases were identified by ICD-9 code and review of medical record. Controls were identified if they scored zero (never) for snoring, apnea, and gasping on the multivariable apnea prediction index questionnaire immediately following delivery. Subjects with available stored first and/or second trimester residual serum samples were then included in this study and serum analyzed for progesterone. Raw progesterone levels were adjusted for the effects of gestational age and maternal weight.

Results: Twenty-seven cases and 64 controls with available serum were identified. Women with OSA had greater maternal weight and higher rates of related comorbidities, compared to controls. Progesterone levels correlated positively with gestational age and negatively with greater weight. Progesterone levels, adjusted for gestational age and maternal weight and expressed as multiples of median (MoM), were significantly lower in OSA cases compared to controls in both the first trimester (MoM = 0.71, confidence interval [95% CI] 0.60-0.83) relative to the MoM in controls of 1.00. In the second trimester levels were also lower in OSA cases (MoM = 0.84, 95% CI 0.73-0.96) compared to the MoM of 1.00 in controls.

Conclusions: Progesterone levels, after accounting for weight and gestational age, were lower in women with OSA than controls. Progesterone may play a protective role against OSA.
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http://dx.doi.org/10.1089/jwh.2016.5917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361753PMC
March 2017

The clinical utility of DNA-based screening for fetal aneuploidy by primary obstetrical care providers in the general pregnancy population.

Genet Med 2017 07 12;19(7):778-786. Epub 2017 Jan 12.

Department of Pathology and Laboratory Medicine, Women &Infants Hospital, Providence, Rhode Island, USA.

Objective: To assess the clinical utility of cell-free DNA (cfDNA)-based screening for aneuploidies offered through primary obstetrical care providers to a general pregnancy population.

Methods: Patient educational materials were developed and validated and providers were trained. Serum was collected for reflexive testing of cfDNA failures. Providers and patients were surveyed concerning knowledge, decision making, and satisfaction. Pregnancy outcome was determined by active or passive ascertainment.

Results: Between September 2014 and July 2015, 72 providers screened 2,691 women. The five largest participating practices increased uptake by 8 to 40%. Among 2,681 reports, 16 women (0.6%) were screen-positive for trisomy 21, 18, or 13; all saw genetic professionals. Twelve were confirmed (positive predictive value (PPV), 75%; 95% CI, 48-93%) and four were false-positives (0.15%). Of 150 failures (5.6%), 79% had a negative serum or subsequent cfDNA test; no aneuploidies were identified. Of 100 women surveyed, 99 understood that testing was optional, 96 had their questions answered, and 95 received sufficient information. Pretest information was provided by the physician/certified nurse midwife (55) or office nurse/educator (40); none was provided by genetic professionals.

Conclusion: This first clinical utility study of cfDNA screening found higher uptake rates, patient understanding of basic concepts, and easy incorporation into routine obstetrical practices. There were no reported cases of aneuploidy among cfDNA test failures.Genet Med advance online publication 12 January 2017.
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http://dx.doi.org/10.1038/gim.2016.194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532959PMC
July 2017

A First-Trimester Biomarker Panel for Predicting the Development of Gestational Diabetes.

Reprod Sci 2017 06 12;24(6):954-959. Epub 2016 Nov 12.

2 Department of Pathology and Laboratory Medicine, Women and Infants Hospital and the Alpert Medical School at Brown University, Providence, RI, USA.

Objective: Serum markers measured early in pregnancy have been associated with the later diagnosis of gestational diabetes mellitus (GDM). This study aims to explore the performance of a panel of first-trimester biochemical markers for the prediction of GDM.

Methods: A case-control study was performed that included 12 women who developed GDM and 60 controls matched for maternal and gestational age at blood collection. Levels of pregnancy-associated plasma protein A (PAPP-A), soluble endoglin, pregnancy protein 13, and adiponectin (Adipo) were measured on residual sera used in first-trimester screening for Down syndrome. Data were analyzed by nonparametric methods. A receiver operating characteristic curve was used to calculate the detection rate (DR) obtained with a panel of significant predictors for GDM.

Results: Multiples of the median values for Adipo and PAPP-A were significantly reduced in GDM cases versus matched controls. Combination of Adipo and PAPP-A yielded a DR of 63.6% at a false-positive rate of 10%. Addition of body mass index (BMI) to this panel increased DR to 72.7%.

Conclusion: This study suggests that first-trimester screening with Adipo, PAPP-A, and BMI may effectively identify women at high risk for the development of GDM.
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http://dx.doi.org/10.1177/1933719116675057DOI Listing
June 2017

Where have all the trisomies gone?

Am J Obstet Gynecol 2016 Nov;215(5):583-587.e1

Department of Pathology and Laboratory Medicine, Women & Infants Hospital, Providence, RI.

Providing reliable prenatal screening performance estimates is critical for patient counseling and policy-making. Women who choose prenatal screening for aneuploidy are likely to be concerned not only with the common aneuploidies but with all causes of intellectual disability and serious birth defects. Sequential prenatal screening (combined serum and ultrasound testing) for aneuploidy detection commonly is offered as a primary screening test. Among women identified as screen positive, cell-free (cf)DNA has been added recently as a secondary, noninvasive screening option, before the consideration of invasive diagnostic testing (eg, amniocentesis and karyotype). With the anticipation of lower costs in the future, cfDNA might be an alternative to sequential screening in the general population. Sequential and cfDNA tests are both noninvasive, and both identify common aneuploidies. Screening via cfDNA detects more common chromosome abnormalities (eg, trisomy 21, sex trisomies). Sequential screening can identify other aneuploidies (eg, triploidy), as well as chromosome abnormalities associated with fetal structural abnormalities. When the advantages and disadvantages of routine sequential screening with routine cfDNA screening are compared, one important measure is the proportion and severity of chromosome abnormalities identified. When reporting these detection rates, authors need to carefully consider the impact of multiple well-described biases. For women to make informed choices in situations of this type, determining reliable comparative performance estimates is crucial.
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http://dx.doi.org/10.1016/j.ajog.2016.06.046DOI Listing
November 2016

Use of antimüllerian hormone to predict the menopausal transition in HIV-infected women.

Am J Obstet Gynecol 2017 Jan 26;216(1):46.e1-46.e11. Epub 2016 Jul 26.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.

Background: HIV infection has been associated with early menopausal onset, which may have adverse long-term health consequences. Antimüllerian hormone, a biomarker of ovarian reserve and gonadal aging, is reduced in HIV-infected women.

Objective: We sought to assess the relationship of antimüllerian hormone to age of menopause onset in HIV-infected women.

Study Design: We used antimüllerian hormone levels measured in plasma in 2461 HIV-infected participants from the Women's Interagency HIV Study to model the age at final menstrual period. Multivariable normal mixture models for censored data were used to identify factors associated with age at final menstrual period.

Results: Higher antimüllerian hormone at age 40 years was associated with later age at final menstrual period, even after multivariable adjustment for smoking, CD4 cell count, plasma HIV RNA, hepatitis C infection, and history of clinical AIDS. Each doubling of antimüllerian hormone was associated with a 1.5-year increase in the age at final menstrual period. Median age at final menstrual period ranged from 45 years for those in the 10th percentile of antimüllerian hormone to 52 years for those in the 90th percentile. Other factors independently associated with earlier age at final menstrual period included smoking, hepatitis C infection, higher HIV RNA levels, and history of clinical AIDS.

Conclusion: Antimüllerian hormone is highly predictive of age at final menstrual period in HIV-infected women. Measuring antimüllerian hormone in HIV-infected women may enable clinicians to predict risk of early menopause, and potentially implement individualized treatment plans to prevent menopause-related comorbidities and to aid in interpretation of symptoms.
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http://dx.doi.org/10.1016/j.ajog.2016.07.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182170PMC
January 2017

Free Thyroxine During Early Pregnancy and Risk for Gestational Diabetes.

PLoS One 2016 24;11(2):e0149065. Epub 2016 Feb 24.

Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University College of Physicians and Surgeons, New York, New York, United States of America.

Several studies have now reported associations between gestational diabetes mellitus (GDM) and low free thyroxine (fT4) during the second and third trimesters, but not in the first trimester. The present study further examines relationships between low fT4, maternal weight, and GDM among women in the FaSTER (First and Second Trimester Evaluation of Risk) trial, in an effort to determine the extent to which thyroid hormones might contribute to causality. The FaSTER cohort includes 9351 singleton, euthyroid women; 272 of these women were subsequently classified as having GDM. Thyrotropin (TSH), fT4, and thyroid antibodies were measured at 11-14 weeks' gestation (first trimester) and 15-18.9 weeks' gestation (second trimester). An earlier report of this cohort documented an inverse relationship between fT4 in the second trimester and maternal weight. In the current analysis, women with GDM were significantly older (32 vs. 28 years) and weighed more (75 vs. 64.5 kg). Maternal weight and age (but not TSH) were significantly associated univariately with fT4 (dependent variable), in the order listed. Second trimester fT4 odds ratios (OR) for GDM were 2.06 [95% CI 1.37-3.09] (unadjusted); and 1.89 [95% CI 1.26-2.84] (adjusted). First trimester odds ratios were not significant: OR 1.45 [95%CI 0.97-2.16] (unadjusted) and 1.11 [95% CI 0.74-1.62] (adjusted). The second trimester fT4/GDM relationship thus appeared to strengthen as gestation progressed. In FaSTER, high maternal weight was associated with both low fT4 and a higher GDM rate in the second trimester. Peripheral deiodinase activity is known to increase with high caloric intake (represented by high weight). We speculate that weight-related low fT4 (the metabolically inactive prohormone) is a marker for deiodinase activity, serving as a substrate for conversion of fT4 to free triiodothyronine (fT3), the active hormone responsible for glucose-related metabolic activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766100PMC
August 2016

Cut-off levels for hyperandrogenemia among Samoan women: An improved methodology for deriving normative data in an obese population.

Clin Biochem 2016 Jul 18;49(10-11):782-6. Epub 2016 Feb 18.

Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI 02912, USA.

Objective: To define biochemical hyperandrogenemia (HA) among a population-based sample of reproductive-aged Samoan women, taking into consideration their high BMI levels.

Design And Methods: A secondary analysis was performed among a cross-sectional sample of Samoan women aged 25-39years (n=494) who were part of a larger genome-wide association study (GWAS) of adiposity. Women indicating pregnancy/lactation, hysterectomy, oophorectomy, cancer treatment, or use of contraceptive injections were excluded from the study. We analyzed the distribution of free androgen index (FAI) values to establish normative androgen data among Samoan women of reproductive age. Using the lowest tertile of body mass index (BMI), we defined HA as free androgen index (FAI) values >95(th) FAI percentile in that subsample. We compared the anthropometric and metabolic characteristics of women with HA to women with normal androgen levels.

Results: HA was defined as FAI>8.5. Using this definition, 14% of women were classified as hyperandrogenemic. Women with HA had significantly higher average BMI values, abdominal circumferences, fasting triglycerides, and insulin levels as well as significantly lower adiponectin levels.

Conclusion: This study is the first to define normative androgen values among Samoan women with a quantitative assessment of the relationship between adiposity and androgen levels. The uniquely high BMI levels in the population not only provide important clinical insight into normative androgen values among Samoan women, but they also serve as references for the clinical assessment of HA, taking into consideration BMI, in other populations.
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http://dx.doi.org/10.1016/j.clinbiochem.2016.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915982PMC
July 2016

Vitamin D Supplementation Decreases TGF-β1 Bioavailability in PCOS: A Randomized Placebo-Controlled Trial.

J Clin Endocrinol Metab 2015 Nov 20;100(11):4307-14. Epub 2015 Oct 20.

Departments of Obstetrics and Gynecology (M.I., N.J., D.B., B.K., S.I.) and Genesis Fertility and Reproductive Medicine (R.V.G.), Maimonides Medical Center, Brooklyn, New York 11219; Department of Reproductive Endocrinology and Infertility (D.B.S.), Oregon Health & Science University, Portland, Oregon 97239; School of Business and Hospitality (O.T.), Conestoga College, Kitchener, Ontario, Canada N2G 4M4; Division of Medical Screening and Special Testing (G.L.-M.), Women and Infants Hospital, Providence, Rhode Island 02905; and Division of Reproductive Endocrinology and Infertility (R.T.), Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520.

Context: There is an abnormal increase in TGF-β1 bioavailability in women with polycystic ovary syndrome (PCOS), which might play a role in the pathophysiology of this syndrome. Vitamin D (VD) supplementation improves various clinical manifestations of PCOS and decreases TGF-β1 levels in several diseases including myelofibrosis.

Objective: The objective of the study was to determine the effect of VD supplementation on TGF-β1 bioavailability in VD-deficient women with PCOS and assess whether changes in TGF-β1/soluble endoglin (sENG) levels correlate with an improvement in PCOS clinical manifestations.

Design: This was a prospective, randomized, placebo-controlled trial.

Setting: The study was conducted at an academic-affiliated medical center.

Participants: Sixty-eight VD-deficient women with PCOS who were not pregnant or taking any exogenous hormones were recruited between October 2013 and January 2015.

Interventions: Forty-five women received 50 000 IU of oral vitamin D3 and 23 women received oral placebo once weekly for 8 weeks.

Main Outcomes Measures: Serum TGF-β1, sENG, lipid profile, testosterone, dehydroepiandrosterone sulfate, and insulin resistance were measured. The clinical parameters were evaluated before and 2 months after treatment.

Results: The VD level significantly increased and normalized after VD supplementation (16.3 ± 0.9 [SEM] to 43.2 ± 2.4 ng/mL; P < .01), whereas it did not significantly change after placebo. After the VD supplementation, there was a significant decrease in the following: the interval between menstrual periods (80 ± 9 to 60 ± 6 d; P = .04), Ferriman-Gallwey score (9.8 ± 1.5 to 8.1 ± 1.5; P < .01), triglycerides (138 ± 22 to 117 ± 20 mg/dL; P = .03), and TGF-β1 to sENG ratio (6.7 ± 0.4 to 5.9 ± 0.4; P = .04). In addition, the ΔTGF-β1 to sENG ratio was positively correlated with Δtriglycerides (r = 0.59; P = .03).

Conclusions: VD supplementation in VD-deficient women with PCOS significantly decreases the bioavailability of TGF-β1, which correlates with an improvement in some abnormal clinical parameters associated with PCOS. This is a novel mechanism that could explain the beneficial effects of VD supplementation in women with PCOS. These findings may support new treatment modalities for PCOS, such as the development of anti-TGF-β drugs.
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http://dx.doi.org/10.1210/jc.2015-2580DOI Listing
November 2015

Levels of antimüllerian hormone in serum during the normal menstrual cycle.

Fertil Steril 2016 Jan 23;105(1):208-13.e1. Epub 2015 Oct 23.

Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infant's Hospital, Alpert Medical School at Brown University, Providence, Rhode Island; Center for Biomarkers and Emerging Technology, Department of Obstetrics and Gynecology, Women and Infant's Hospital, Alpert Medical School at Brown University, Providence, Rhode Island.

Objective: To determine whether levels of antimüllerian hormone (AMH) in serum vary during the normal menstrual cycle, using the most recently developed immunoassay method.

Design: Prospective cohort study.

Setting: Local community.

Patient(s): Women with normal menstrual cycles and between the ages of 18 and 45 years were recruited (n = 45). Blood samples were collected on 5 days within each cycle: two in the follicular phase and three after confirmed ovulation. Exclusion criteria were anovulatory cycles, incomplete sample collection, insufficient blood volume, or non-Caucasian ethnicity.

Intervention(s): None.

Main Outcome Measure(s): Serum samples were tested for levels of AMH using a new immunoassay method (Ansh Labs). The effects of body mass index (BMI) and smoking on serum AMH levels were considered.

Result(s): Serum AMH levels varied significantly during the menstrual cycle, with the highest levels in the follicular phase. When the analysis was stratified by age, AMH variation during the menstrual cycle was significant only for women older than 30 years. Serum AMH levels were not significantly altered by BMI or smoking.

Conclusion(s): The new AMH immunoassay revealed a follicular phase rise in serum levels, particularly in women over the age of 30 years. This is consistent with other reports finding an interaction of menstrual cycle variation in AMH and chronological age. Nonetheless, the extent of variation is small, and sampling on any day of the menstrual cycle is expected to adequately reflect ovarian reserve.

Clinical Trial Registration Number: NCT01337999.
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http://dx.doi.org/10.1016/j.fertnstert.2015.09.033DOI Listing
January 2016