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1.  Self-Reported Menopausal Symptoms, Coronary Artery Calcification and Carotid Intima-Media Thickness in Recently Menopausal Women Screened for the Kronos Early Estrogen Prevention Study (KEEPS) 
Fertility and sterility  2013;99(5):1385-1391.
Objective
To determine whether self-reported menopausal symptoms are associated with measures of subclinical atherosclerosis.
Setting
Multi-center, randomized controlled trial.
Patients
Recently menopausal women (n=868) screened for the Kronos Early Estrogen Prevention Study (KEEPS).
Design
Cross sectional analysis.
Interventions
None
Main Outcome Measures
Baseline menopausal symptoms (hot flashes, dyspareunia, vaginal dryness, night sweats, palpitations, mood swings, depression, insomnia, irritability), serum estradiol (E2) levels and measures of atherosclerosis were assessed. Atherosclerosis was quantified using Coronary Artery Calcium (CAC) Agatston scores (n=771) and Carotid Intima-Media Thickness (CIMT). Logistic regression model of menopausal symptoms and E2 was used to predict CAC. Linear regression model of menopausal symptoms and E2 was used to predict CIMT. Correlation between length of time in menopause with menopausal symptoms, estradiol (E2), CAC, and CIMT were assessed.
Results
In early menopausal women screened for KEEPS, neither E2 nor climacteric symptoms predicted the extent of subclinical atherosclerosis. Palpitations (p=0.09) and depression (p=0.07) approached significance as predictors of CAC. Other symptoms of insomnia, irritability, dyspareunia, hot flashes, mood swings, night sweats, and vaginal dryness were not associated with CAC. Women with significantly elevated CAC scores were excluded from further participation in KEEPS; in women meeting inclusion criteria, neither baseline menopausal symptoms nor E2 predicted CIMT. Years since menopause onset correlated with CIMT, dyspareunia, vaginal dryness and E2.
Conclusions
Self-reported symptoms in recently menopausal women are not strong predictors of subclinical atherosclerosis. Continued follow-up of this population will be performed to determine if baseline or persistent symptoms in the early menopause are associated with progression of cardiovascular disease.
doi:10.1016/j.fertnstert.2012.11.053
PMCID: PMC3615128  PMID: 23312232
KEEPS; estrogen; cardiovascular; menopause; CAC; CIMT; palpitations; depression
2.  Proactively Establishing a Biologic Specimens Repository for Large Clinical Trials: An Idea Whose Time has Come 
Systems biology in reproductive medicine  2011;57(5):10.3109/19396368.2011.604818.
Large randomized clinical trials are becoming more costly, and resources to support them increasingly scarce. Biologic materials, such as blood, DNA, body fluids, or tissue samples collected and stored as a component of these studies represent an invaluable resource, to answer immediate secondary hypotheses, but also as archived material, linked to the study data, for the use of investigators long into the future. The regulatory climate surrounding the storage and future unconstrained utilization of biologic materials is evolving quickly. It is no longer acceptable simply to store samples and use them in an unbridled and unregulated fashion. Thus, to fully utilize the tremendous potential of biologic samples generated from large clinical trials and their related databases, investigators should consider proactively creating a biologic specimen repository, or biorepository. A repository likely assures appropriate subject consent, sample provenance, secure storage, and codified procedures for sample and data retrieval and sharing that protect the subject’s confidentiality, the investigator’s need for accurate data, and the limited resource. Importantly, the biorepository specimens/samples are typically collected in addition to local and core specimens obtained for the parent study that provide baseline assessments for safety and efficacy outcomes.
doi:10.3109/19396368.2011.604818
PMCID: PMC3848250  PMID: 21951166
Biorepository; Repository; Reproductive Medicine Network
3.  Are vasomotor symptoms associated with sleep characteristics among symptomatic midlife women? Comparisons of self-report and objective measures 
Menopause (New York, N.Y.)  2012;19(7):742-748.
Objective
Many women report vasomotor symptoms (VMS) and sleep problems during the menopausal transition. Although reported VMS are consistently related to reported sleep disturbance, findings using physiologic measures of VMS or sleep have been more mixed. Our objective was to examine whether more VMS during sleep are associated with poorer sleep among midlife women with VMS using physiologic measures of both VMS and sleep.
Methods
A subcohort of participants (N = 52) with VMS, a uterus and both ovaries, and free of medications affecting VMS from the Pittsburgh site of the Study of Women’s Health Across the Nation underwent four 24-hour periods of in-home ambulatory VMS and sleep measurement. Measures included sternal skin conductance for the measurement of VMS, actigraphy for assessing sleep, a VMS diary, and a sleep diary completed before bed and upon waking. Associations between VMS and sleep were evaluated using generalized estimating equations with covariates age, body mass index, medications affecting sleep, race, financial strain, and depressive symptoms.
Results
More VMS recalled upon waking were associated with significantly lower actigraphy-assessed sleep efficiency, significantly higher wakefulness after sleep onset, and somewhat longer sleep latency. Conversely, physiologically measured VMS and VMS reported during the night were largely unrelated to sleep characteristics.
Conclusions
Associations between VMS and sleep may depend more on the awareness of and recall of VMS rather than solely on their physiologic occurrence.
doi:10.1097/gme.0b013e3182422973
PMCID: PMC3551537  PMID: 22415568
Hot flashes; Night sweats; Vasomotor symptoms; Sleep; Actigraphy; Menopause
4.  THE PREGNANCY IN POLYCYSTIC OVARY SYNDROME II (PPCOS II) TRIAL: RATIONALE AND DESIGN OF A DOUBLE-BLIND RANDOMIZED TRIAL OF CLOMIPHENE CITRATE AND LETROZOLE FOR THE TREATMENT OF INFERTILITY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME 
Contemporary Clinical Trials  2012;33(3):470-481.
Polycystic Ovary Syndrome (PCOS) is a common cause of female infertility and first line treatment is currently oral clomiphene citrate, a selective estrogen receptor modulator, which results in both a high nonresponse rate and multiple pregnancy rate. Aromatase inhibitors such as letrozole may have more favorable ovarian and endometrial effects. The goal of the Pregnancy in Polycystic Ovary Syndrome II (PPCOSII) study is to determine the safety and efficacy of clomiphene citrate (CC) compared to letrozole, in achieving live birth in infertile women with PCOS. The population will consist of 750 infertile women with PCOS. Additionally, the couple will have no other major infertility factor. This will be a multi-center, prospective, double-blind clinical trial of CC vs. letrozole for 5 treatment cycles (or approximately up to 25 weeks). The randomization scheme will be coordinated through the central data coordinating center (DCC) and the randomization is stratified by each participating site. After progestin withdrawal as needed, 750 women will be equally randomized to two different treatment arms: A) CC 50 mg every day for 5 days (day 3–7 of cycle), or B) letrozole 2.5 mg every day for 5 days (day 3–7 of cycle), for a total of 5 cycles or 25 weeks. The dose will be increased in subsequent cycles in both treatment groups for non-response or poor ovulatory response up to a maximum of 150 mg of CC a day (× 5 days) or 7.5 mg of letrozole a day (× 5 days). The primary analysis will use an intent-to-treat approach to examine differences in the live birth rate in the two treatment arms.
doi:10.1016/j.cct.2011.12.005
PMCID: PMC3312939  PMID: 22265923
Polycystic Ovary Syndrome; Infertility; Ovulation Induction; Hyperandrogenism; Clomiphene Citrate; Letrozole
5.  Predictors of Pregnancy and Live Birth in Couples with Unexplained or Male-factor Infertility after Insemination 
Fertility and Sterility  2012;97(4):959-967.e5.
Objective
To identify risk factors for pregnancy outcomes in couples treated with intracervical or intrauterine insemination, with or without superovulation for unexplained or male-factor infertility. The treatment continued for four cycles unless pregnancy was achieved.
Design
Secondary analysis of data from a randomized superovulation and intrauterine insemination trial.
Setting
Academic medical centers.
Intervention(s)
None.
Patients
Out of 932 couples randomized to four treatment groups, 664 couples who had completed the lifestyle questionnaires were assessed for occurrence of pregnancy and live birth.
Main outcome measure(s)
pregnancy and live birth.
Results
The pregnancy and live birth rates were significantly higher in couples in which the female partners reported that they had consumed coffee or tea in the past or drank alcoholic beverages in the past (past users) when compared to those who had never consumed coffee or tea (4.0, 1.6–10.2 for pregnancy; 3.1, 1.2–8.1 for live birth) or alcoholic beverages (1.9, 1.1–3.3 for pregnancy; 2.1, 1.2–3.7 for live birth) (data are adjusted odds ratio and 95% confidence interval). Past users also had significantly higher pregnancy and live birth rates than those who were currently consuming coffee or tea or alcoholic beverages. Demographic, occupational exposures and other lifestyle factors were not significant.
Conclusion(s)
Couples in which the female partners drank coffee, tea, or alcoholic beverages in the past had higher pregnancy and live birth rates when compared to never or current users. When discontinuing these habits, they might have made other lifestyle changes to improve the pregnancy outcome.
doi:10.1016/j.fertnstert.2012.01.090
PMCID: PMC3319287  PMID: 22270557
Infertility; lifestyle; pregnancy; live birth; insemination; superovulation
6.  Intra-Thoracic Fat, Cardiometabolic Risk Factors, and Subclinical Cardiovascular Disease in Healthy, Recently Menopausal Women Screened for the Kronos Early Estrogen Prevention Study (KEEPS) 
Atherosclerosis  2011;221(1):198-205.
Objective
To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women.
Methods
Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n= 650).
Results
Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r= 0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides= −0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4–1.6], 1.5 [0.8–2.9], and 1.8 [1.0–3.4]; P for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat.
Conclusion
While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.
doi:10.1016/j.atherosclerosis.2011.12.004
PMCID: PMC3288598  PMID: 22209479
coronary calcification; ectopic fat; cardiac fat; hepatic fat; risk factors; women
7.  Impaired Gremlin 1 (GREM1) expression in cumulus cells in young women with diminished ovarian reserve (DOR) 
Purpose
A symbiotic relationship between ovarian granulosa cells (GC) and the developing oocyte is critical. Genetic modulations in GC’s can lead to reproductive insufficiency, highlighting the role of GC’s in reproductive competence. Utilizing gene expression analyses in cumulus GC’s, we attempt to enhance our understanding of mechanisms that may contribute to poor reproductive capacity in young women with diminished ovarian reserve (DOR).
Methods
We measured gremlin 1 (GREM1) gene expression in GC’s from infertile women <38 years undergoing in vitro fertilization in the context of DOR.
Results
GREM1, a member of the differential screening-selected gene aberrative in neuroblastoma (DAN) family of genes known for its highly regulated expression pattern during folliculogenesis and a downstream effecter of oocyte-derived growth and differentiation factor 9, was down-regulated 3-fold (−3.08) in women with DOR versus control; down-regulation was confirmed by qRT-PCR (−4.02).
Conclusion
This is the first demonstration linking differential expression of Gremlin with etiology of infertility in women.
doi:10.1007/s10815-011-9684-8
PMCID: PMC3270130  PMID: 22160428
Cumulus granulosa cell; Gremlin 1; Diminished ovarian reserve; GDF9; Gene expression
8.  Recruitment Challenges of a Multicenter Randomized Controlled Varicocelectomy Trial 
Fertility and sterility  2011;96(6):1299-1305.
Study Objective
To review reasons for suboptimal recruitment for a randomized controlled trial (RCT) of varicocelectomy vs. intrauterine insemination for treatment of male infertility, and suggest means to improve future study recruitment.
Design
A survey of RMN participating sites.
Setting
The Reproductive Medicine Network.
Patients
N/A
Interventions
N/A
Main Outcome Measures
Ascertain reasons for inadequate recruitment and suggest improvements for future varicocelectomy trails.
Results
This study screened 7 and enrolled 3 couples with the first couple randomized on 6/30/2010. The study was subsequently stopped on 03/30/2011. The following themes were cited most frequently by sites and therefore determined to be most likely to have played a role in suboptimal recruitment: (1) men must be screened at the beginning of a couple's infertility evaluation, (2) inclusion of infertile women who have failed previous fertility interventions appeared to be associated with couple intolerance of a placebo arm, and (3) there appeared to be bias against the use of unstimulated IUI cycles, indicating a prejudicial preference for surgical intervention in the male partner.
Conclusions
Improved recruitment may be realized through screening infertile men as early as possible while minimizing study-related time commitments. Focused patient education may promote improved ‘equipoise’ and acceptance of a placebo arm in male infertility studies. Lastly, creative approaches to implementing varicocelectomy trials must be considered in addition to having a network of motivated researchers who carry a high volume of possible study participants, as screening of very large numbers may be needed to complete clinical trial enrollment. Clinicaltrials.gov: NCT00767338.
doi:10.1016/j.fertnstert.2011.10.025
PMCID: PMC3243664  PMID: 22130101
Recruitment; consent; randomization; accrual; enrollment; prospective; varicocele; varicocelectomy
9.  Prospective Evaluation of Bone Mineral Density among Middle-Aged HIV-Infected and Uninfected Women: Association between Methadone Use and Bone Loss 
Maturitas  2011;70(3):295-301.
Objective
We undertook a prospective study to assess the impact of HIV infection on BMD in a cohort of HIV-infected and uninfected women that included illicit drug users, and to measure the contribution of traditional risk factors as well as HIV-related factors to loss of BMD over time.
Methods
We analyzed BMD at baseline and after ≥18 months in 245 middle-aged HIV-infected and 219 uninfected women, and conducted linear regression analysis to determine factors associated with annual BMD change at the femoral neck, total hip and lumbar spine.
Results
HIV-infected women had lower baseline BMD at the femoral neck and total hip compared with controls; unadjusted rates of BMD change did not differ by HIV status at any site. In multivariable analyses, we found that HIV seropositivity without protease inhibitor (PI) use was associated with BMD decline at the lumbar spine (−.009 gm/cm2 per year, p=.03.) Additional factors associated with BMD decline were: postmenopausal status, lower BMI, and methadone use at the lumbar spine; postmenopausal status and hepatitis C seropositivity at the femoral neck; and postmenopausal status, age, smoking, and lower BMI at the total hip (all p<.05). Among HIV-infected women, ≥3 years of PI use was associated with an increase in lumbar spine BMD (.013 gm/cm2 per year, p=.008.)
Conclusions
Bone loss among HIV–infected middle-aged women was modest, and possibly mitigated by PI use. Methadone use was associated with BMD decline, and should be considered when evaluating women for osteoporosis risk.
doi:10.1016/j.maturitas.2011.08.003
PMCID: PMC3189307  PMID: 21944566
osteopenia; osteoporosis; bone mineral density; HIV; women
10.  Association of Ethnicity with Involuntary Childlessness and Perceived Reasons for Infertility: Baseline Data from the Study of Women’s Health Across the Nation (SWAN) 
Fertility and Sterility  2011;96(5):1200-5.e1.
Objective
To evaluate whether ethnicity is associated with involuntary childlessness and perceived reasons for difficulties in becoming pregnant .
Design
Cross-sectional analysis of baseline data from a longitudinal cohort
Setting
Multiethnic, community-based observational study of US women
Patient(s)
3149 midlife women, aged 42-52
Main Outcome Measure(s)
Involuntary childlessness and perceived etiology of infertility
Result(s)
One hundred and thirty-three subjects (4.2%) were involuntarily childless, defined by a reported history of infertility and nulliparity. Ethnicity was significantly associated with self-reported involuntary childlessness. After controlling for economic and other risk factors, African-American (OR 0.30; 95% CI 0.15 – 0.59) and Chinese women (OR 0.36; 95% CI 0.14 – 0.90) were less likely to suffer from involuntary childlessness as compared to non-Hispanic Caucasian women.
Additionally, 302 subjects reported a perceived etiology of infertility. An unexpectedly large proportion of these women (24.5%, 74 out of 302) reported etiologies not known to cause infertility (i.e. tipped uterus, ligaments for tubes were stretched), with African-American women having been most likely to report these etiologies (OR 2.81; 95% CI 1.26 – 6.28) as the reason for not becoming pregnant.
Conclusion(s)
Ethnicity is significantly associated with involuntary childlessness and perceived etiology of infertility. Misattribution of causes of infertility is common and merits further consideration with respect to language or cultural barriers as well as possible physician misattribution.
doi:10.1016/j.fertnstert.2011.08.039
PMCID: PMC3278161  PMID: 21958690
childlessness; infertility; ethnicity
11.  Establishing a Biologic Specimens Repository for Reproductive Clinical Trials: Technical Aspects 
The individual research group or independent investigator often requires access to samples from a unique well characterized subject population. Cohorts of such samples from a well-defined comparative population are rare and limited access can impede progress. This bottleneck can be removed by accessing the samples provided by biorepositories such as the NIH/NICHD Cooperative Reproductive Medicine Network (RMN) Biorepository (detailed in the accompanying manuscript in this issue. In those cases where the individual research group or independent investigator already has access to a unique population, comparisons between well-defined groups are often sought to contextualize the data. In both cases seamless integration of data resources associated with the samples is required to ensure optimal comparisons. At the most basic level this requires standardization of sample collection and storage, as well as a de-identified data base containing demographic, clinical, and laboratory values. To facilitate such interoperability, the reagents and protocols that have been adopted by the RMN Biorepository for the collection and storage of serum, blood, saliva and sperm are described.
doi:10.3109/19396368.2011.604819
PMCID: PMC3183133  PMID: 21899384
biorepository; repository; Reproductive Medicine Network
12.  Increased Incident Hip Fractures in Postmenopausal Women with Moderate-to-Severe Pelvic Organ Prolapse 
Menopause (New York, N.Y.)  2011;18(9):967-973.
Objective
To examine the association between fracture and pelvic organ prolapse (POP) in postmenopausal women enrolled in the Women’s Health Initiative Estrogen plus Progestin (WHI-EP) trial.
Methods
POP was assessed as cystocele, rectocele or uterine prolapse, and was graded as “absent-to- mild” or “moderate-to-severe”. Cox proportional hazard analyses (adjusting for age, BMI, race, asthma, emphysema, thyroid disease, family history of fracture, regular menses, age at menopause, nulliparity, history of hormone therapy [HT], history of falls, SES, calcium and vitamin D supplementation and physical activity) explored relationships between moderate-to-severe POP and incident bone fractures.
Results
Moderate-to-severe grade POP was identified in almost 8% of women (n=1,192). Over a follow up duration of 7.41 ± 2.18 years (mean ± SD), 2,156 incident fractures were observed; the most common fracture site was lower arm (n=615, 28.51%) followed by hip (n=205, 9.51%). Adjusted analyses confirmed moderate-to-severe POP (of any type) as an independent risk factor for incident hip fractures (HR 1.83, 95% CI 1.16–2.89, p=0.010). On analyses stratified by assigned treatment (HT versus placebo) moderate-to-severe rectocele emerged as an independent predictor of incident spine (HR 2.61, 95% CI 1.04–6.56, p=0.042) and lower arm fractures (HR 1.87, 95% CI 1.06–3.29, p=0.030) in the placebo group.
Conclusion
We identify moderate-to-severe POP (any type) in postmenopausal women as a risk factor for hip fracture; moderate-to-severe rectocele holds additional risk for spine and lower arm fractures in women not on HT.
doi:10.1097/gme.0b013e31821b8484
PMCID: PMC3181050  PMID: 21738078
Prolapse; Fracture; WHI; Estrogen; Progesterone; Rectocele; Hip
13.  The SWAN Song: Study of Women’s Health Across the Nation’s Recurring Themes 
SYNOPSIS
There is a belief that reproductive health is a reflection of whole-body health. It then follows that abnormalities of reproductive milestones may be a manifestation of aberrant or unhealthy aging. In order to assess how menopause per se and the process of the menopause transition may affect future health risks and outcomes, the Study of Women’s Health Across the Nation was begun in 1994. SWAN, now in its 14th follow-up year, has characterized the life experience of a multi-ethnic cohort of mid-life US women in an unprecedented level of detail. Several enduring themes have emerged from SWAN that have associated certain patterns of hormones and symptoms with metabolic status. Moreover, the nature of relationships between hormones, body size, ethnicity, metabolic status and cardiovascular disease symptoms risk vary as women traverse the menopause and ovarian hormone production eventually ceases. This review will describe these cross-cutting themes and their possible meaning for the health of the mid-life woman.
doi:10.1016/j.ogc.2011.05.001
PMCID: PMC3185240  PMID: 21961710
Menopause; menopause transition; metabolic syndrome; hot flashes; estrogen; progesterone
14.  Reproductive Hormones and the Menopause Transition 
The hormonal correlates of reproductive aging and the menopause transition reflect an initial loss of the follicle cohort, while a responsive ovary remains, and an eventual complete loss of follicle response, with persistent hypergonadotropic amenorrhea. The physiology of the process is described, along with key findings of relevant studies, with an emphasis on SWAN, the Study of Women’s Health Across the Nation. A clinical framework is provided to help clinicians forecast the major milestones of the menopausal transition and to predict potential symptoms or disease.
doi:10.1016/j.ogc.2011.05.004
PMCID: PMC3197715  PMID: 21961713
Menopause; menopause transition; inhibin; AMH; LH; FSH; estrogen; progesterone
15.  Differential Granulosa Cell Gene Expression in Young Women with Diminished Ovarian Reserve 
Reproductive Sciences  2011;18(9):892-899.
Objective: To investigate if a diagnosis of diminished ovarian reserve (DOR) is associated with a differential gene profile of ovarian granulosa cells (GCs) in infertile women undergoing in vitro fertilization (IVF). Design: Prospective Cohort Study. Setting: Academic IVF Program. Patients: Infertile women <38 years were prospectively enrolled into 2 groups: normal ovarian reserve (NOR, follicle-stimulating hormone [FSH] < 10 mIU/mL, n = 4) and DOR (FSH ≥ 10.0 mIU/mL, n = 4). Interventions: Cumulus (C) and mural (M) GCs were isolated at egg retrieval; messenger RNA was extracted and transcribed. Main Outcome Measure(s): Differential gene expression in cerebellar granule cells (CGCs) in the 2 groups was assessed by cDNA microarray. Microarray findings were validated by quantitative real-time polymerase chain reaction (qRTPCR) in CGCs and explored in multinucleated giant cells (MGCs). Results: Of the 1256 differentially regulated genes identified in CGCs of women with DOR, the insulin-like growth factor (IGF) family was a biologically relevant gene family of a priori interest. Downregulation of IGF1 and IGF2 ligands (−3.28- and −2.54–fold, respectively), and their receptors, (−3.53- and −1.32-fold downregulation of IGF1R and IGF2R, respectively) was identified in luteinized CGCs in women with DOR compared to those with NOR. Downregulation of both IGF1 and IGF 2 ligands (−4.35- and 3.89-fold, respectively) was furthermore observed in MGCs in women with DOR compared to those with NOR; no differences in the expression of respective receptors were however observed in MGCs in the 2 groups. Conclusions: Components of the IGF gene family are downregulated in GCs of women with DOR. These findings maybe contributory to the reproductive compromise observed in women with DOR, and merit further exploration.
doi:10.1177/1933719111398502
PMCID: PMC3343125  PMID: 21846690
granulosa cell; cumulus; mural; diminished ovarian reserve; microarray; insulin-like growth factor; gene expression; ovary
16.  Reduced Neurotrophin Receptor TrkA Expression in Human Granulosa Cells: A Novel Marker of Diminishing Ovarian Reserve 
Fertility and sterility  2011;96(2):474-478.e4.
Structured Abstract
Objective
To determine whether human mural and cumulus granulosa cell neurotrophin and neurotrophin receptor content correlate to ovarian reserve markers.
Design
Prospective, laboratory based study
Setting
Academic assisted reproductive technology (ART) program
Patients
Twenty three women undergoing ART
Interventions
Mural and cumulus granulosa cells were collected from women undergoing oocyte retrieval during ART cycle. Relative mRNA levels of neurotrophins and their receptors were measured by qRT-PCR and correlated to serum anti-mullerian hormone (AMH) levels and the number of oocytes retrieved.
Results
Mural and cumulus granulosa cell nerve growth factor receptor TrkA mRNA correlated strongly to the number of oocytes retrieved. Similarly, higher serum AMH was associated with higher cumulus granulosa cell TrkA mRNA. Both mural and cumulus granulosa cell p75NTR/TrkA ratios were lower in women with higher serum AMH and the number of oocytes retrieved were greater among women with low p75NTR/TrkA ratio. No significant associations were found between brain derived neurotrophic factor (BDNF) and its specific receptor TrkB and ovarian reserve markers. While BDNF and TrkB expression were higher in cumulus compared to mural granulosa cells, no such association was found between TrkA and granulosa cells. AMH and cumulus TrkA mRNA, in a model incorporating both, correlated strongly to the number of oocytes retrieved (R2=0.84, p=0.001).
Conclusions
Cumulus TrkA and p75NTR mRNA correlate to ovarian reserve while BDNF and TrkB are associated with the type of granulosa cell.
doi:10.1016/j.fertnstert.2011.05.017
PMCID: PMC3143233  PMID: 21645891
17.  Increasing Burden of Institutional Review in Multicenter Clinical Trials of Infertility: the Reproductive Medicine Network Experience with Pregnancy in Polycystic Ovary Syndrome (PPCOS) I and II Studies 
Fertility and sterility  2011;96(1):15-18.
Narrative Abstract
Many clinical investigators feel that the burden of institutional review board (IRB) requirements has been consistently increasing over recent years, though there are few objective data describing these trends. Over a period of 7 years the Reproductive Medicine Network observed a significant increase in the size and requirements of IRB submissions, and significant variability of IRB performance in reviewing multicenter trials. These additional regulatory and administrative demands represent substantial burdens to researchers and to the IRBs themselves. It is timely to consider whether these changes better protect the interests and safety of human research participants.
doi:10.1016/j.fertnstert.2011.05.069
PMCID: PMC3151556  PMID: 21645894
multicenter clinical trials; ethical review; institutional review boards; human experimentation
18.  Endogenous Estradiol is Associated with Verbal Memory in Nondemented Older Men 
Brain and cognition  2011;76(1):158-165.
This study examined the relationship between endogenous hormones and cognitive function in nondemented, ethnically-diverse community-dwelling older men enrolled in the Einstein Aging Study (EAS). All eligible participants (185 men, mean age=81 years) received neuropsychological assessment (Free and Cued Selective Reminding Test (FCSRT), Logical Memory (LM), Trail Making Test B (TMTB), Block Design (BD)) and provided blood samples for hormonal assays (total estradiol, total testosterone, calculated free testosterone index). Linear regression analysis adjusted for age, education, body mass index, and cardiovascular comorbidities indicated that men with high levels of total estradiol demonstrated better FCSRT verbal memory performance (β=0.17, p<0.02) compared to men with lower levels of total estradiol. The results remained unchanged when the model was further adjusted for ethnicity. We did not detect an association between testosterone and cognitive performance. These findings indicate that high levels of total estradiol in older men are associated with better performance on a cue-based, controlled learning test of verbal memory that is a sensitive predictor of dementia.
doi:10.1016/j.bandc.2011.01.011
PMCID: PMC3081925  PMID: 21354686
Hormones; Cognition; Memory; Men; Older Adults; Aging; Testosterone; Estradiol
19.  The Reproductive Endocrinology of the Menopausal Transition 
Steroids  2011;76(7):627-635.
doi:10.1016/j.steroids.2011.02.026
PMCID: PMC3100375  PMID: 21419147
20.  Associations between retinol-binding protein 4 and cardiometabolic risk factors and subclinical atherosclerosis in recently postmenopausal women: cross-sectional analyses from the KEEPS study 
Background
The published literature regarding the relationships between retinol-binding protein 4 (RBP4) and cardiometabolic risk factors and subclinical atherosclerosis is conflicting, likely due, in part, to limitations of frequently used RBP4 assays. Prior large studies have not utilized the gold-standard western blot analysis of RBP4 levels.
Methods
Full-length serum RBP4 levels were measured by western blot in 709 postmenopausal women screened for the Kronos Early Estrogen Prevention Study. Cross-sectional analyses related RBP4 levels to cardiometabolic risk factors, carotid artery intima-media thickness (CIMT), and coronary artery calcification (CAC).
Results
The mean age of women was 52.9 (± 2.6) years, and the median RBP4 level was 49.0 (interquartile range 36.9-61.5) μg/mL. Higher RBP4 levels were weakly associated with higher triglycerides (age, race, and smoking-adjusted partial Spearman correlation coefficient = 0.10; P = 0.01), but were unrelated to blood pressure, cholesterol, C-reactive protein, glucose, insulin, and CIMT levels (all partial Spearman correlation coefficients ≤0.06, P > 0.05). Results suggested a curvilinear association between RBP4 levels and CAC, with women in the bottom and upper quartiles of RBP4 having higher odds of CAC (odds ratio [95% confidence interval] 2.10 [1.07-4.09], 2.00 [1.02-3.92], 1.64 [0.82-3.27] for the 1st, 3rd, and 4th RBP4 quartiles vs. the 2nd quartile). However, a squared RBP4 term in regression modeling was non-significant (P = 0.10).
Conclusions
In these healthy, recently postmenopausal women, higher RBP4 levels were weakly associated with elevations in triglycerides and with CAC, but not with other risk factors or CIMT. These data using the gold standard of RBP4 methodology only weakly support the possibility that perturbations in RBP4 homeostasis may be an additional risk factor for subclinical coronary atherosclerosis.
Trial registration
ClinicalTrials.gov number NCT00154180
doi:10.1186/1475-2840-11-52
PMCID: PMC3461442  PMID: 22587616
Retinol-binding protein 4; Subclinical atherosclerosis; Risk factors; Women
21.  The nucleolar channel system reliably marks the midluteal endometrium regardless of fertility status: a fresh look at an old organelle 
Fertility and Sterility  2010;95(4):1385-9.e1.
Objective
To determine if nucleolar channel systems (NCSs) in the midluteal endometrium are associated with overall fertility status and/or with unexplained infertility.
Design
Retrospective and prospective clinical studies.
Setting
Repository of stored specimens from prior multicenter study and private infertility center, respectively.
Patients
Retrospective study: 97 women (49 fertile couples, 48 infertile couples) who had been randomized for endometrial biopsy during the midluteal or late luteal phase. Prospective study: 78 women with a variety of infertility diagnoses.
Intervention
Endometrial biopsies were obtained and assessed for the presence of NCSs by indirect immunofluorescence.
Main Outcome Measures
NCS presence was graded semi-quantitatively and dichotomized as normal versus low or absent.
Results
Normal NCS presence was significantly associated with the midluteal phase compared to the late luteal phase (80% versus 29%). However, there was no association between NCS presence and fertility status or between NCS presence and unexplained infertility.
Conclusions
Midluteal phase endometrium consistently forms NCSs regardless of fertility status, including unexplained infertility. This indicates a possible role for the NCS in initiating the window of endometrial receptivity. However, the consistent presence of NCSs across several different types of infertility challenges the likelihood that inadequate secretory transformation is a cause of infertility.
doi:10.1016/j.fertnstert.2010.10.030
PMCID: PMC3347775  PMID: 21067716
Nucleolar channel system; secretory transformation; receptivity; endometrium; unexplained infertility; immunofluorescence
22.  Aromatase Inhibition Causes Increased Amplitude, but not Frequency, of Hypothalamic-Pituitary Output in Normal Women 
Fertility and sterility  2011;95(6):2063-2066.
Objective
To better understand the site and mode of action of aromatase inhibitors.
Setting
Academic research environment.
Patients and Design
5 eumenorrheic (non-PCOS), early follicular phase women of normal BMI (mean = 20.47 +/− 0.68 kg/m2) and 12 normal weight, mid-reproductive aged, early follicular phase, normal BMI (mean = 20.8 +/− 1.7 kg/m2) historical controls.
Interventions
2.5mg letrozole daily for 7 days. Women were sampled with daily, first morning voided urine collections, thrice weekly blood sampling, and 4 hours of q 10 minute frequent blood sampling
Main outcome measures
Serum LH measured using a well-characterized immunofluorometric assay. LH pulse characteristics were compared between treated and control groups using t tests.
Results
Mean LH and LH pulse amplitude more than doubled in women who had taken letrozole compared to controls, but the LH pulse frequency did not differ between women taking letrozole and controls.
Conclusions
These results indicate that the release of negative feedback inhibition of estradiol on the hypothalamic-pituitary axis in normal women by aromatase inhibitors creates an amplitude-related increase in endogenous hypothalamic-pituitary drive. The finding that mean LH and LH pulse amplitude, but not frequency, increased after letrozole suggests a possible pituitary site of action.
doi:10.1016/j.fertnstert.2011.01.158
PMCID: PMC3080458  PMID: 21353673
Hypothalamic-Pituitary-Gonadal Axis; Luteinizing Hormone; Aromatase Inhibitor; Letrozole; Pituitary; Ovary
23.  Circulating Dehydroepiandrosterone Sulfate Levels in Women with Bilateral Salpingo-Oophorectomy during the Menopausal Transition 
Menopause (New York, N.Y.)  2011;18(5):494-498.
Background
A rise in circulating dehydroepiandrosterone sulfate (DHEAS) concentration occurs during the menopausal transition (MT) that is ovarian-stage but not age-related. The objective of this study was to determine the source of the rise in circulating DHEAS.
Methods
Circulating DS concentrations in women that had undergone bilateral salpingo-oophorectomy (BSO) were compared to the pattern of circulating DHEAS in women that progressed through the MT naturally. Annual serum samples from the Study of Women's Health Across the Nation (SWAN) over a ten year study period were used. From1272 women in the SWAN cohort that were eligible for longitudinal evaluation of DHEAS annual samples, eighty one underwent BSO during the pre- or early-perimenopause stage of the menopausal transition and were potentially available for study. Of these eighty one BSO participants, twenty had sufficient annual samples for evaluation of the post-BSO trajectory of circulating DHEAS. SWAN women not having previous hormone replacement therapy those with intact ovaries were compared to women that underwent a BSO immediately after a pre- or early perimenopausal annual visit. There were no intervention and circulating concentrations of DHEAS was the main outcome.
Results
A detectable rise in DHEAS was observed in fourteen (70%) of the twenty BSO women which is similar to the proportion (85%) of women with intact ovaries that had a detectable DHEAS rise. The mean rise in DHEAS (5-8%) was similar in both BSO and non-BSO women.
Conclusion
The MT rise in DHEAS (5-8%) occurring in the absence of ovaries is largely of adrenal origin.
doi:10.1097/gme.0b013e3181fb53fc
PMCID: PMC3123411  PMID: 21178790
Dehydroepiandrosterone sulfate; menopause; adrenal; ovary
24.  SKIN WRINKLES AND RIGIDITY IN EARLY POSTMENOPAUSAL WOMEN VARY BY RACE/ETHNICITY: BASELINE CHARACTERISTICS OF THE SKIN ANCILLARY STUDY OF THE KEEPS TRIAL 
Fertility and sterility  2010;95(2):658-662.e3.
Objective
To characterize skin wrinkles and rigidity in recently menopausal women.
Design
Baseline assessment of participants prior to randomization to study drug.
Setting
Multicenter trial, university medical centers.
Patients
Recently menopausal participants enrolled in the Kronos Early Estrogen Prevention Study (KEEPS).
Interventions
Skin wrinkles were assessed at 11 locations on the face and neck using the Lemperle wrinkle scale. Skin rigidity was assessed at the forehead and cheek using a durometer.
Outcome
Skin wrinkles and rigidity were compared among race/ethnic groups. Skin wrinkles and rigidity were correlated with age, time since menopause, weight, and BMI.
Results
In early menopausal women, wrinkles, but not skin rigidity, vary significantly among races (p=0.0003), where Black women have the lowest wrinkle scores. In White women, chronological age was significantly correlated with worsening skin wrinkles, but not with rigidity(p<0.001). Skin rigidity correlated with increasing length of time since menopause, however only in the White subgroup (p<0.01). In the combined study group, increasing weight was associated with less skin wrinkling (p<0.05).
Conclusions
Skin characteristics of recently menopausal women are not well studied. Ethnic differences in skin characteristics are widely accepted, but poorly described. In recently menopausal women not using hormone therapy (HT), significant racial differences in skin wrinkling and rigidity exist. Continued study of the KEEPS population will provide evidence of the effects of HT on the skin aging process in early menopausal women.
doi:10.1016/j.fertnstert.2010.09.025
PMCID: PMC3026089  PMID: 20971461
Skin; estrogen; hormone therapy; wrinkles; ridigity; durometer; menopause; race; ethnicity
25.  Decision trees for identifying predictors of treatment effectiveness in clinical trials and its application to ovulation in a study of women with polycystic ovary syndrome 
Human Reproduction (Oxford, England)  2010;25(10):2612-2621.
BACKGROUND
Double-blind, randomized clinical trials are the preferred approach to demonstrating the effectiveness of one treatment against another. The comparison is, however, made on the average group effects. While patients and clinicians have always struggled to understand why patients respond differently to the same treatment, and while much hope has been held for the nascent field of predictive biomarkers (e.g. genetic markers), there is still much utility in exploring whether it is possible to estimate treatment efficacy based on demographic and baseline variables.
METHODS
The pregnancy in polycystic ovary syndrome (PPCOS) study was a prospective, multi-center, randomized clinical trial comparing three ovulation induction regimens: clomiphene citrate (CC), metformin and the combination of the two. There were 446 women who ovulated in response to the treatments among the entire 626 participants. In this report, we focus on the 418 women who received CC (alone or combined with metformin) to determine if readily available baseline physical characteristics and/or easily obtainable baseline measures could be used to distinguish treatment effectiveness in stimulating ovulation. We used a recursive partitioning technique and developed a node-splitting rule to build decision tree models that reflected within-node and within-treatment responses.
RESULTS
Overall, the combination of CC plus metformin resulted in an increased incidence of ovulation compared with CC alone. This is particularly so in women with relatively larger left ovarian volumes (≥19.5 cubic cm), and a left ovarian volume <19.5 cubic cm was related to treatment outcomes for all subsequent nodes. Women who were older, who had higher baseline insulin, higher waist-to-hip circumference ratio or higher sex hormone-binding globulin levels had better ovulatory rates with CC alone than with the combination of CC plus metformin.
CONCLUSIONS
Polycystic ovary syndrome (PCOS) is a phenotypically diverse condition. Both baseline laboratory and clinical parameters can predict the ovulatory response in women with PCOS undergoing ovulation induction. Without a priori hypotheses with regard to any predictors, the observation regarding left ovary volume is novel and worthy of further investigation and validation.
doi:10.1093/humrep/deq210
PMCID: PMC2939757  PMID: 20716558
PCOS; ovulation induction; decision trees; treatment effectiveness

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