Early menopause in women with chronic inflammatory disease: a population-based cohort study

Early menopause in women with chronic inflammatory disease: a population-based cohort study


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O-7 Monday, October 17, 2011 12:45 PM METABOLOMIC PROFILING OF CULTURE MEDIA BY NEAR INFRARED SPECTROSCOPY AS AN ADJUNCT TO MORPHOLOGY FOR SELECTION OF A SINGLE DAY 3 EMBRYO TO TRANSFER IN IVF: A DOUBLE BLIND RANDOMISED TRIAL. C. G. Vergouw, D. C. Kieslinger, E. H. Kostelijk, P. G. Hompes, R. Schats, C. B. Lambalk. Reproductive Medicine, VU University Medical Center, Amsterdam, Noord Holland, Netherlands. OBJECTIVE: To investigate if the selection of a single day 3 embryo by metabolomic profiling of culture media with Near Infrared (NIR) spectroscopy as an adjunct to morphology is able to improve pregnancy rates in IVF, compared to embryo selection by morphology alone. DESIGN: Double blind randomised trial. MATERIALS AND METHODS: Patients were included from November 2009-March 2011. Single embryo transfer (SET) was performed on day 3 after ovum pick-up (OPU). Randomisation was performed at OPU. The study was blinded for physician and patient. Patients were randomised into either the control group (embryo selection by morphology only) or the treatment group (embryo selection by morphology plus NIR spectroscopy). Main inclusion criteria before SET was the presence of two or more similar best quality embryos. In the treatment group, a viability score for each embryo was generated using NIR spectroscopy; the embryo with the highest viability score was transferred. The embryo with the best morphology was transferred in the control group. In order to detect a 15% increase in ongoing pregnancy rates (Beta 80%, Alpha 5%), 153 transfers were needed in each group. RESULTS: 417 patients were randomised at OPU, 309 had two or more similar best quality embryos before day 3 SET. 163 patients were randomised in the control group and 146 were randomised in the treatment group. Patient baseline characteristics were equally distributed. The clinical pregnancy rates were 41.7% and 41.8% for the control group and the treatment group respectively. For the treatment group, the laboratory technician’s independent choice (by morphology) of which embryo to transfer was recorded 138 times. In 75.4% (104/138) of the transfers, the embryo with the best morphology did not have the highest viability score. The clinical pregnancy rate of these 104 transferred embryos was 45.2%. CONCLUSION: This double blind randomised trial shows that day 3 embryo selection with a NIR spectrometer as an addition to morphology is not able to improve clinical pregnancy rates.

MENOPAUSE O-8 Monday, October 17, 2011 04:15 PM 17b-ESTRADIOL INHIBITS C-REACTIVE PROTEIN-DRIVEN VASCULAR INFLAMMATION IN MACROPHAGES DERIVED FROM YOUNG BUT NOT AGED MICE. M. R. Bowling, S. Oparil, G. W. Bates, Y.-F. Chen, F. Hage. Division of Reproductive Endocrinology and Infertility, University of Alabama at Birmingham, Birmingham, AL; Division of Cardiolovascular Disease, University of Alabama at Birmingham, Birmingham, AL. OBJECTIVE: 17b-estradiol (E2) protects against acute vascular injury response in rodent models. However, clinical trials show increased coronoary heart disease (CHD) in women treated with hormone replacement therapy (HRT). This discrepancy may be explained by the timing hypothesis, which suggests HRT initiated soon after menopause protects against CHD, while later initiation has a negative effect. Monocyte/macrophages are the first cells recruited to a vascular injury site and initiate the inflammatory cascade. We have shown that C-reactive protein (CRP) drives the inflammatory response in mice macrophages through the Fcg receptor. This study tests the hypothesis that E2-signaling in mouse macrophages is age-dependent. DESIGN: 24 Young (10-wk) and 24 aged (18-mo) mice were randomized into 4 groups: control, E2 only, CRP only, or E2+CRP. MATERIALS AND METHODS: Bone marrow was harvested and grown in culture with M-CSF. After 7 days, cells were >90% positive for the macrophage marker F4/80 and treated with E2 (10-7 M) or vehicle for 24hrs, then incubated with CRP (50 mcg/ml) for 4hrs. RNA was extracted and analyzed using RT-PCR to measure expression of inflammatory mediators. RESULTS: CRP treatment increased expression of Interleukin-1 (IL-1) (24-fold), IL-6 (332-fold), IL-8 (41-fold) and complement 3 (C3) (33-fold) in macrophages of young mice. Pre-treatment with E2 attenuated response to CRP in young mice for expression of C3 (decreased 49%) and IL-1 (de-


creased 35%) (P<0.05 for both) as well as IL-6 and IL-8 (nonsignificant). In macrophages of aged mice, CRP resulted in a similar increase in inflammatory mediator expression, but E2 did not attenuate this effect. CONCLUSION: E2 attenuates the inflammatory response of macrophages in young but not aged mice. This data supports the vasculoprotective effects of E2 in young animals, and may explain the vasculotoxic effects of E2 seen in clinical studies of postmenopausal women. We are now testing this hypothesis in monocytes derived from pre- and postmenopausal women. Supported by: HL 087980.

O-9 Monday, October 17, 2011 04:30 PM IMPACT OF SMOKING ON THE AGE AT NATURAL MENOPAUSE IN BRCA1/2 MUTATION CARRIERS IN NORTHERN CALIFORNIA. W. T. Lin, M. Beattie, S. Crawford, E. Gold, L.-m. Chen, M. Rosen. Obstetrics Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA; Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA; Preventive and Behavioral Medicine, University of Massachusetts, Worcester, MA; Public Health Sciences, University of California, Davis, Davis, CA. OBJECTIVE: Timing of fertility preservation and risk-reducing salpingooophorectomy is of great concern for BRCA1 and BRCA2 mutation (BRCA1/2) carriers. Our preliminary analyses suggested BRCA1/2 carriers may have an earlier age at natural menopause, consistent with findings from a recent study relating BRCA1 to occult primary ovarian insufficiency. The aim of this study was to examine the association of BRCA1/2 and age at natural menopause, and possible effect modification of smoking,a possible exogenous modifiable risk factor. DESIGN: Retrospective study with historical control. MATERIALS AND METHODS: 166 Caucasian BRCA1/2 carriers in Northern California with natural menopause or still menstruating were identified within UCSF Cancer Risk Program registry and compared to 765 Caucasian women in Northern California included in the Study of Women’s Health Across the Nation(SWAN) cohort. We compared median age at natural menopause and any effect modification of smoking,using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses to adjust for confounding factors. RESULTS: The median age at natural menopause in BRCA1/2 carriers was statistically significantly earlier than normal population (48 vs 53years,log-rank p-value <0.0001). The unadjusted hazard ratio of natural menopause was 3.94 (95% confidence interval 2.34,6.65), 4.05 (2.30,7.12) after adjusting for smoking. For BRCA1/2 carriers who were current heavy smokers (R20cigarettes/day), the median age at natural menopause was45.5, significantly earlier than never or past smokers or current light smokers (<10,10-19cigarettes/day) (log-rank p-value ¼ 0.0021). CONCLUSION: BRCA1/2 is associated with significantly earlier age at natural menopause, and heavy smoking poses additional risk for even earlier menopause. As the relationship between menopause and end of natural fertility is considered fixed, this finding of earlier menopause and the impact of smoking is important for counseling BRCA1/2 carriers and is suggestive of the underlying mechanism.

O-10 Monday, October 17, 2011 04:45 PM EARLY MENOPAUSE IN WOMEN WITH CHRONIC INFLAMMATORY DISEASE: A POPULATION-BASED COHORT STUDY. J. F. McLaren, K. Haynes, K. T. Barnhart, M. D. Sammel, B. L. Strom. Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA. OBJECTIVE: Current knowledge is limited on how chronic inflammatory disease or the medications used to treat these conditions affect reproductive senescence. The objective of this study was to determine if early menopause (age<45 years) or premature ovarian failure (POF, age<40 years) is more prevalent in women with psoriasis, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or systemic lupus erythematosus (SLE) compared to the general population. Our hypothesis was that early menopause and POF would be more prevalent in women with chronic inflammatory disease. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: All women of reproductive age (15-45 years old) with research-quality records were identified in The Health Improvement Network (THIN), an electronic medical records database.


Exposure was defined by identifying diagnostic codes for psoriasis, RA, IBD or SLE. Subjects without these conditions comprised the comparator group. The outcomes of early menopause and POF were measured by identifying diagnostic, or lab codes for the conditions. The relative risk (RR) of early menopause and POF in subjects with chronic inflammatory disease was estimated using logistic regression modeling. RESULTS: The cohort contained 1,757,214 women of reproductive age. The unadjusted RR for early menopause was 2.21 (P<0.01, 95%CI 2.02,2.42) for psoriasis, 5.10 (P<0.01, 95%CI 4.34,5.99) for RA, 2.86 (P<0.01, 95%CI 2.46,3.32) for IBD, and 3.91 (P<0.01, 95%CI 2.95,5.20) for SLE. The RRs for POF were 2.35 (P<0.01, 95%CI 2.03,2.72) for psoriasis, 4.12 (P<0.01, 95%CI 3.12,5.46) for RA, 3.16 (P<0.01, 95%CI 2.51,4.02) for IBD, and 5.80 (P<0.01, 95%CI 3.96,8.47) for SLE. CONCLUSION: We provide objective evidence of a 2- to 5-fold increase of both early menopause and premature ovarian failure in women with chronic inflammatory disease. Further research is needed to differentiate if the effect is due to the underlying illness or treatment. Supported by: NIH T32 CA009679, 5UL1RR024134-05.

pause. We evaluated the ability of AFC and other ovarian reserve markers to predict natural menopause (NatMen) in US women ages 34-49. DESIGN: CARDIA is a multicenter (Chicago, IL; Birmingham, AL; Minneapolis, MN; Oakland, CA) observational cohort study begun in 1985-86. In 2002-04, CWS evaluated 1163 women with R1 ovary with transvaginal ultrasound and FSH levels. The exam was targeted to the follicular phase unless irregular cycles or OCP use was present. Subjects were re-examined in 2005-06 and followed-up annually by phone through 2009-10. MATERIALS AND METHODS: AFC (total # of 2-10mm follicles on 2 visualized ovaries) was assessed in 498 CWS subjects with follow-up data and no history of ovarian/uterine surgeries or menopause. We used Cstatistics to determine optimal age, FSH, and AFC cutpoints for NatMen. Cox regression was used to predict NatMen hazard over 7 years’ follow up adjusting for race, smoking, OCP use and menstrual history.

Risk for NatMen over 7 Years of Follow-up

Variable O-11 Monday, October 17, 2011 05:00 PM OVARIAN NON-GROWING FOLLICLE COUNTS ACCORDING TO THE STAGING OF REPRODUCTIVE AGING (STRAW) STAGING SYSTEM. K. R. Hansen, H. R. Burks, L. B. Craig, M. R. Soules, N. A. Klein. Department of Obstetrics and Gynecology, Section of Reproductive Endocrinology and Infertility, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Seattle Reproductive Medicine, Seattle, WA. OBJECTIVE: The development and validation of a staging system of reproductive aging is of considerable interest to clinicians and researchers alike in order to predict the timing and duration of the menopausal transition and to standardize patient populations across studies. Given that the reproductive aging process is essentially due to ovarian non-growing (primordial, intermediate, and primary) follicle depletion, an important step in the validation of a staging system of reproductive aging would be the identification of significant differences in ovarian follicle number between stages. The purpose of this investigation was to examine the differences in ovarian non-growing follicle (NGF) count between the STRAW stages associated with the menopausal transition. DESIGN: Prospective study, university setting. MATERIALS AND METHODS: Normal ovaries were collected from 53 women (age 40-52) undergoing oophorectomy for benign indications. Prior to surgery, each subject completed a detailed questionnaire collecting information regarding menstrual cycle characteristics and were classified by bleeding patterns into STRAW stages -3, -2, and -1. Ovarian NGF number was determined utilizing a validated fractionator/optical disector method. Ovarian NGF counts were compared between the STRAW stages with one-way ANOVA. Post-hoc comparisons between STRAW stages were performed with Fisher’s protected least significant difference test. A p-value of < 0.05 was considered statistically significant. RESULTS: Significant differences were identified in the ovarian NGF count across the STRAW stages (p < 0.005). In post-hoc testing, the differences in NGF counts were significant between each of the STRAW stages. CONCLUSION: Progression through the menopausal transition stages as defined by the STRAW staging system is associated with progressive and significant decreases in ovarian NGF number. This finding represents an important step in the validation of the STRAW staging system. Supported by: HR04-115 (OCAST, K.R.H.) and NIH R29-HD37360-04 (N.A.K.).

O-12 Monday, October 17, 2011 05:15 PM ANTRAL FOLLICLE COUNT (AFC) PREDICTS NATURAL MENOPAUSE IN A POPULATION BASED COHORT: THE CORONARY ARTERY RISK DEVELOPMENT IN YOUNG ADULTS (CARDIA) AND CARDIA WOMEN’S STUDY (CWS). M. Wellons, C. Lewis, P. Schreiner, W. Bates, B. Sternfeld, D. Siscovick. University of Alabama, Birmingham, AL; University of Minnesota, Minneapolis, MN; Kaiser Permanente Division of Research, Oakland, CA; University of Washington, Seattle, WA. OBJECTIVE: Tools to predict future fertility are needed for contraceptive decision-making as large numbers of women are approaching perimeno-



Hazard Ratio

95% CI

1.72 4.91 0.63 1.68 2.39 0.59

(1.10-2.68) (3.13-7.69) (0.42-0.95) (1.09-2.59) (1.56-3.65) (0.38-0.85)

AFC £4 vs. >4 Age >45 vs. £ 45 Black vs. White Current Smoker vs. Not FSH >13 vs. £13 Regular vs. Irregular Menses OCP use P>0.05

RESULTS: Median(Q1-Q3) AFC and FSH were 5(2-9) and 8(6-11) at a mean age of 42 (range 34-49). 107 women reported NatMen by 2009-10. Cutpoints at Age>45, FSH>13, and AFC%4 yielded the highest c-statistic for NatMen with a PPV ¼ 63% (29/47) and a NPV ¼ 83% (373/451) through 2010. In Cox models, age, race, AFC, and FSH were independent predictors of NatMen. CONCLUSION: AFC is an independent predictor of natural menopause over 7 years of follow-up after controlling for the more established markers of age, race, and FSH in our community-based sample. Supported by: The NHLBI supports CARDIA (N01-HC-95095/4804748050/05187), CWS (R01HL065611) and Dr. Wellons (K23-HL-87114).

O-13 Monday, October 17, 2011 05:30 PM TOLERABILITY OF DESVENLAFAXINE 100 MG IN WOMEN WITH VASOMOTOR SYMPTOMS (VMS) ASSOCIATED WITH MENOPAUSE: A POOLED ANALYSIS OF 5 TRIALS. D. F. Archer, J. L. Shifren, R.-f. J. Cheng, W. Bao, C. J. Guico-Pabia. Eastern Virginia Medical School, Norfolk, VA; Massachusetts General Hospital, Boston, MA; Pfizer Inc, Collegeville, PA. OBJECTIVE: To assess safety and tolerability of desvenlafaxine 100 mg/ d (administered as desvenlafaxine succinate) in women with menopausal VMS. DESIGN: A pooled analysis of all double-blind, randomized, placebocontrolled Phase III clinical desvenlafaxine trials for VMS. MATERIALS AND METHODS: Postmenopausal women with R50 moderate to severe hot flushes/wk (4 studies) or bothersome hot flushes (Greene Climactic Scale total score R12 and question 19 score >2,1 study) at baseline received desvenlafaxine or placebo in 5 trials. All studies included a desvenlafaxine 100-mg arm; 2 used dose titration. Pooled data from desvenlafaxine 100 mg/d or placebo groups were analyzed Study durations were 12 (2 studies), 26 (1 study), or 52 (2 studies) weeks.Adverse events (AEs), laboratory evaluations, and vital signs were assessed. RESULTS: The safety population included 3323 women (desvenlafaxine, 1711; placebo, 1612).The most common treatment-emergent AEs (TEAEs; >5% and 2x placebo) for desvenlafaxine were nausea, dizziness, constipation, dry mouth, fatigue, and somnolence. During week 1, overall TEAE rates were lower in studies with titration (desvenlafaxine, 42%; placebo, 20%) vs no titration (desvenlafaxine, 80%; placebo, 58%). In all, 589/1711 (34%) desvenlafaxine-treated women discontinued early, 324/1711 (19%) due to AE; rates were 440/1612 (27%) and 155/1612 (10%), respectively, for placebo. Small but statistically significant changes compared with placebo

Vol. 96., No. 3, Supplement, September 2011