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Rajeshwari Sundaram, Ph.D.f d l d hDivision of Epidemiology, Statistics and Prevention Research,
Eunice Kennedy Shriver National Institute of Child Health &Human Development
Growing evidence that endocrine disrupting chemicals affect human reproduction & development, possibly by modulating hormones or their functionhormones or their function
Challenging to study at population level• Need longitudinal measurement of time varying eed o g tud a easu e e t o t e a y g
exposures & outcomes• Many outcomes not readily observable (e.g., ovulation,
conception)conception)
menses & ovulation
semen quality & fertilization
Gilbert SF 2006
Intra- and inter-woman variability Intra and inter woman variability• Inherent variability during menstrual cycles
Methods vary in intensity (as do costs)• Daily collection• Abbreviated collection (on fixed days in cycle)
Research implications Research implications• Potential for mistimed data & biospecimen collection• Considerable costs & logistical issues (e.g., storage
urine in home freezers)• Burden with no immediate feedback for women,
particularly those wishing to become pregnantp y g p g
Commercially available personal fertility monitors that measure & track urinary estrone-3-glucuronide (E3G) & luteinizing hormone (LH)hormone (LH)
• Time biospecimen collection relative to the cycle• Capture hormonal profiles without requiring daily
biospecimens & laboratory analyses• Distinguishes missing data if no test done• Direct uploading data to data systemsp g y• Prompts for timing intercourse relative to the fertile
window (participant incentive)
Ovarian ultrasonology affirms that LH surge occurs 24-36 hours before follicular rupture
WHO i h i E G l d WHO recognizes that urinary E3G correlated with plasma estradiol
Increased pregnancy rate associated with use of fertility monitor (Robinson et al., 2007)of fertility monitor (Robinson et al., 2007)
FSH
LH
ProgesteroneEstradiol
Monitor peak
Howards et al., 2009
100
80
100
ed
Days 12-14
from end 13-15
40
60
nt o
bser
v from end 13-15
Midpoint +/-1
20
40
Perc
en
0
Cycle 1 Cycle 2
Monitor provides software that can be Monitor provides software that can be adapted to collect relevant information (e.g., E3G, LH, date/time stamp, various test diagnostics)
Continuous monitoring of data to identify Continuous monitoring of data to identify irregularities or malfunctions Each upload typically creates duplicate records of
previous tests not yet overwritten by the monitor Repeat records also created due to multiple testing
attempts within the same time framed l d ff l h dl Program developed to efficiently handle
duplications in the LIFE Study
Do persistent environmental chemicalsDo persistent environmental chemicals affect human reproduction & development in the context of couples’ lifestyles?p yStudy outcomes
• 1° Time‐to‐pregnancy; infertility; pregnancy loss, gestation & birth size
2° M l ti d ti fil lit ti• 2° Menses; ovulation; reproductive profiles; semen quality; sex ratios
Chemicals• PCBs, PBDEs, PFCs, pesticides, metals, cotinine, phytoestrogens, BPA,
h h l f lphthalates, & UV filters
Lifestyle• Smoking, alcohol, caffeine, exercise, fish consumption, stress, vitamins
Birth
hCG pregnancy or 12 months
Attempting pregnancy
BaselineDaily
Monthly
Daily
Blood, urine, saliva & semen Urine
HomeHome‐‐Based Data CollectionBased Data Collection
Daily Journals
Number of tests uploaded (n=30,975) Number of failed tests uploaded (n=1,827; 5.9%)
Cycle Characteristic Monitor Based Diary BasedCycle Characteristic(in days)
Monitor Based Diary Based
N 2,567 2,673
R i l l th 11 150 3 135Range in cycle lengths 11-150 3-135
Mean (±SD) cycle length
29.7 (±10.7) 28.6 (±10.9)length Mean (±SD) day of LH peak
15.9 (±3.8) 14.3 (±5.8)
A woman’s hormonal profileA woman’s hormonal profile-- EE33G & LHG & LH
20
30
0
10LH
06 8 10 12 14 6 8 10 12 14 6 8 10 12 14 6 8 10 12 14 6 8 10 12 14
Days within Cycle40
20
30
E3G
0
10
6 8 10 12 14 6 8 10 12 14 6 8 10 12 14 6 8 10 12 14 6 8 10 12 14
D i hi C lDays within Cycle
A woman’s hormonal profileA woman’s hormonal profile-- EE33G & LHG & LH
20
30
H
0
10
20
LH
6 8 10 12 14 16 18 20 22 24 6 8 10 12 14 16 18 20 22 24 6 8 10 12 14 16 18 20 22 24 6 8 10 12 14 6 8 10 12 14 16 18 20 22 24
Days within Cycle40
20
30
E3G
0
10
6 8 10 12 14 16 18 20 22 24 6 8 10 12 14 16 18 20 22 24 6 8 10 12 14 16 18 20 22 24 6 8 10 12 14 6 8 10 12 14 16 18 20 22 24
Days within CycleDays within Cycle
Unanticipated field issues…Unanticipated field issues…
The Texas LIFE Study Proposed County Area, October 2008
Orange
Montgomery
Jefferson
Chambers
Galveston
Harris
Fort Bend
Brazoria
Matagorda
Calhoun
Aransas
Nueces
Hurricanes … Katrina, Rita & Ike
…the dog ate it!
Fertility monitors have utility & are feasible for collecting time varying hormonal datafor collecting time varying hormonal data (also for timing data & biospecimen collection)
Minimal learning curve for participants, despite diverse cohort with varying educational & economic backgroundsW b b d d i l f Web-based data management essential for such data collection
Quantitative assessment of mixtures in Quantitative assessment of mixtures in relation to sensitive interrelated reproductive outcomes possible!outcomes possible!
Buck Louis et al., 2011
LIFE Study – Research TeamNICHD
Dr. Germaine Buck Louis (Study PI)Dr. Zhen ChenDr. Enrique Schisterman Dr. Rajeshwari Sundaram
Texas A&M UniversityDr. Anne Sweeney
RTI InternationalDr. Tim Wilcosky
The EMMES CorporationDr Rob Gore-LangtonDr. Rob Gore LangtonDr. Seth Sherman
Ohio State UniversityDr. Courtney Lynch
Emory UniversityD D B d BDr. Dana Boyd Barr
CDCDr. Steven Schrader
Thank [email protected]
Day in Cycles
Monitor Peak EndPeak End
Cycle
End Cycle