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Searching for semen phenotypes in impaired male fecundity
Chirag J Patel Raji Sundaram, Germaine Buck Louis
Epi Congress, Miami06/22/16
[email protected]@chiragjp
www.chiragjpgroup.org
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Sperm count, morphology, and motility have been hypothesized to be predictive of fecundity…
However, prognostic utility of semen phenotypes under debate and elusive.
Lack prospective cohorts to examine association between sperm phenotype and male fecundity.
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Semen phenotypes are important for fertility…but clinical use have been debated.
NEJM, 2001
Semen and the curse of cutoffs.Niederberger, J Urol 2011
Fertil Steril, 2013
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What sperm phenotypes have utility of prediction of impaired couple fecundity (> 6 cycles to pregnancy)?
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Longitudinal Investigation of Fertility and the Environment (LIFE): a prospective study of couples
desiring to become pregnant
• Reproductive age (18-40 for females; >18 for males)
• N=501 couples (Michigan and Texas) in 2005-2007
• Data collected in couples’ home
• urine, blood, semen (at baseline and at month 1)
• pregnancy and fertility monitors (ClearBlue)
• monitors and journals used to define menstrual cycle
Buck Louis et al, 2013Buck Louis et al, 2014
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EHP, 2012
Fertility and Sterility, 2014
“male and female persistent pollutants and reduced fecundibility…”
“male phthalates and 20% reduction in fecundity…”
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Fertility and Sterility, 2014
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35 semen phenotypes:5 general, 8 motility, 6 head measures, 12
morphology, 2 chromatin stability
Buck Louis, 2014
general count
volumeconcentration straw distance
hypo-osmotic swollen
motility average path
straight & curvilinear velocityamplitude head displacement
beat cross frequency% motility% straight
% linear movement
% normal (2 criteria) % amorphous
roundpyriform
bichephalictapered
megalo/micro headneck/midpiece abnorm.coiled/other tail abnorm.
immature spermcytoplasmic droplet
morphology head lengthwidth
perimeter % elongation factor
area % acrosome
chromatin % fragmentation
high fragmentation sustain.
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35 semen + 5 risk factors have modest ρ
motility/morphology
head/morphology
chromatin/morphology
head
34 PCs (out of 40)~ 99% of variationEffective number of variables: 38 (vs. 40)
WHO normal and strict criteria
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Impaired fecundity and “traditional” risk factorsTime-to-pregnancy (TTP) > 6 cycles (N=402)
TTP ≤ 6 mean (SE)
TTP > 6 mean (SE) p-value
Age (year) 31.2 (0.3) 33.3 (0.5) 0.0005
BMI (kg/m2) 29.8 (0.3) 29.2 (0.6) 0.6
Lipids (ng/g) 726.8 (12) 713.5 (22) 0.6
Cotinine (mg/dL) 40.9 (6.7) 79.9 (17.3) 0.04
Previous pregnancies (#) 1.3 (0.04) 1.6 (0.13) 0.07
N=302 N=100
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LIFE Study 35 semen and 5 non-semen
Prospective TTP
Time-to-pregnancy IQR: 1-6 N=302 and 100
TTP > 6? = Pi + agePi n=40
age-adjusted logistic regression
False discovery rate < 10%:Px … Pz
TTP > 6? = age + father + BMI + cotinine + Px + … + Pz
TTP > 6? = age + father + BMI + cotinineversus
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OR in time-to-pregnancy > 6 cycles: 5 morphological phenotypes
Age-adjusted
FDR < 10%
head
f(volume, count, concentration, motility)
f(head, neck, tail)
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ROC Curve for TTP > 6, AUC=0.730 [green]/0.673 [red]
False positive rate
True
pos
itive
rate
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
Sperm phenotypes offer modest predictive boost over “traditional” factors (age, smoking, fathered)
p < 0.05
Nagelkerke R2: 0.2 vs 0.1
OR PAge* 1.66 (1.29, 2.15) 0.0001
Fathered? 0.45 (0.26, 0.75) 0.002
BMI* 0.87 (0.67, 1.11) 0.25
Cotinine* 1.27 (1.01, 1.60) 0.04
% Normal* 1.23 (0.73, 2.12) 0.44
% Coiled Tail* 1.52 (1.09, 2.14) 0.02
% Pyriform* 1.46 (1.08, 2.01) 0.01
% Amorphous* 1.57 (1.07, 2.35) 0.03
* per 1 SD
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Conclusions: Semen phenotypes modest prognostics for TTP > 6
cycles
Weak to moderate associations between sperm phenotypes and time to pregnancy greater than 6 cycles.
Little predictive value beyond common risk factors of age, smoking, and history.
Cannot rule out measurement errors and residual confounding.
Larger sample sizes and more measures to describe variance in fecundity.
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Chirag J [email protected]
@chiragjpwww.chiragjpgroup.org
NIH Common FundBig Data to Knowledge
Acknowledgements
RagGroup Chirag Lakhani Adam Brown Danielle RasoolyArjun ManraiErik CoronaNam Pho
Germaine Buck Louis Rajeshwari Sundaram