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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 you!sundaramr2@mail.nih.gov

Day in Cycles

Monitor Peak EndPeak End

Cycle

End Cycle