Identification of Anovulation and Transient Luteal Function Using a Urinary Pregnanediol-3-Glucuronide Ratio Algorithm

Article (PDF Available)inEnvironmental Health Perspectives 104(4):408-13 · April 1996with12 Reads
DOI: 10.1289/ehp.96104408 · Source: PubMed
Abstract
The sensitivity and specificity of a urinary pregnanediol-3-glucuronide (PdG) ratio algorithm to identify anovulatory cycles was studied prospectively in two independent populations of women. Urinary hormone data from the first group was used to develop the algorithm, and data from the second group was used for its validation. PdG ratios were calculated by a cycles method in which daily PdG concentrations indexed by creatinine (CR) from cycle day 11 onward were divided by a baseline PdG (average PdG/Cr concentration for cycle days 6-10). In the interval method, daily PdG/CR concentrations from day 1 onward were divided by baseline PdG (lowest 5-day average of PdG/CR values throughout the collection period). Evaluation of the first study population (n = 6) resulted in cycles with PdG ratios > or = 3 for > or = 3 consecutive days being classified as ovulatory; otherwise they were anovulatory. The sensitivity and specificity of the PdG ratio algorithm to identify anovulatory cycles in the second population were 75% and 89.5%, respectively, for all cycles (n = 88); 50% and 88.3% for first cycles (n = 40) using the cycles method; 75% and 92.2%, respectively, for all cycles (n = 89); and 50% and 94.1% for first cycles (n = 40) using the interval method. The "gold standard" for anovulation was weekly serum samples < or = 2 ng/ml progesterone. The sensitivity values for all cycles and for the first cycle using both methods were underestimated because of apparent misclassification of cycles using serum progesterone due to infrequent blood collection. Blood collection more than once a week would have greatly improved the sensitivity and modestly improved the specificity of the algorithm. The PdG ratio algorithm provides an efficient approach for screening urine samples collected in epidemiologic studies of reproductive health in women.
Identification
of
Anovulation
and
Transient
Luteal
Function
Using
a
Urinary
Pregnanediol-3-Glucuronide
Ratio
Algorithm
Amir
Kassam,1
James
W
Overstreet,1
Christine
Snow-Harter,2
Mary
Jane
De
Souza,3
Ellen
B.
Gold,1
and
Bill
L.
Lasley1
1lnstitute
of
Toxicology
and
Environmental
Health,
University
of
California,
Davis,
CA
95616
USA;
2Department
of
Exercise
and
Sports
Science,
Oregon
State
University,
Corvallis,
OR
97331
USA;
3Center
for
Fertility
and
Reproductive
Endocrinology,
New
Britain
General
Hospital,
New
Britain,
CT
06050
USA
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Anovulation
is
a
common
cause
of
female
infertility
(1),
and
its
frequency
is
reported
to
increase
when
women
are
exposed
to
reproductive
toxicants
(2).
Environmental
exposures
associated
with
anovulation
in
women
may
occur
in
the
home
or
the
workplace
(3).
A
number
of
studies
in
labo-
ratory
animals
have
suggested
that
environ-
mental
chemicals
may
have
adverse
effects
on
ovarian
function
that
result
in
anovula-
tion
and/or
menstrual
dysfunction
(4).
The
consequences
of
these
perturbations
are
not
limited
to
infertility.
For
example,
estrogen
deficiency
may
contribute
to
risk
of
cardio-
vascular
disease
and/or
bone
loss
(5,6).
Anovulation
is
also
associated
with
an
increased
risk
of
breast
cancer
(7)
and
endometrial
cancer
(8).
Menstrual
dysfunc-
tion,
such
as
irregular
uterine
bleeding,
can
result
from
causes
other
than
ovarian
dys-
function
and
also
can
be
associated
with
infertility
(9,1Q).
Epidemiologic
studies
that
rely
solely
on
menstrual
calendars
to
detect
adverse
reproductive
outcomes
associated
with
environmental
exposures
cannot
dis-
tinguish
between
endocrine
abnormalities
that
may
result
from
toxicity
to
reproduc-
tive
organs
and
menstrual
bleeding
disor-
ders
that
may
result
from
toxicity
to
other
organ
systems
(11).
the
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Although
the
occurrence
of
anovula-
tion
in
clinic
populations
can
be
docu-
mented
by
standard
diagnostic
procedures
including
daily
basal
body
temperature
assessments,
daily
measurements
of
serum
progesterone
(Po),
and
ultrasound
evalua-
tions
(12),
these
methods
are
not
feasible
for
monitoring
the
reproductive
function
of
large
groups
of
women
in
population-
based
studies.
Thus,
urinary
metabolites
of
reproductive
hormones
are
now
being
measured
as
biomarkers
of
ovarian
func-
tion
and
implantation
in
epidemiologic
studies
(13,14).
Methods
have
been
devel-
oped
to
use
the
daily
urinary
levels
of
estrogen
and
P
metabolites
for
identifica-
tion
of
the
approximate
day
of
ovulation
in
ovulatory
menstrual
cycles
(15),
but
no
method
is
currently
available
for
classifying
cycles
as
anovulatory
on
the
basis
of
uri-
nary
hormone
measurements
alone.
The
present
study
was
undertaken
to
devise
a
simple
algorithm,
based
on
urinary
hormone
assays,
for
identifying
anovulato-
ry
cycles,
which
may
occur
between
episodes
of
vaginal
bleeding
or
which
may
be
associated
with
prolonged
intervals
of
amenorrhea.
The
method
described
here
can
be
used
to
identify
periods
of
anovula-
tion
or
to
screen
cycles
for
evidence
of
ovu-
lation
before
the
application
of
existing
algorithms
for
determining
the
approximate
day
of
ovulation
and/or
the
occurrence
of
early
pregnancy
loss
in
ovulatory
cycles.
Methods
To
develop
the
algorithm,
six
women
who
had
a
recent
history
of
exercise-induced
amenorrhea
(absence
of
menstruation
dur-
ing
the
preceding
three
months)
were
recruited
at
Oregon
State
University.
These
women
provided
daily
urine
samples,
week-
ly
blood
samples,
and
completed
a
daily
menstrual
calendar
for
a
40-day
study
peri-
od.
These
women
exercised
for
an
average
of
8.0
hr
(SD
3.5)
per
week.
Their
mean
age
was
23.3
years
(SD
4.0),
with
a
range
of
19-29
years,
and
they
were
in
good
general
health.
Each
woman
collected
first-void
morning
urine
samples
every
day
for
40
consecutive
days
and
stored
them
in
a
freezer
(-20°C)
until
analyzed.
In
addition,
4
weekly
blood
samples
were
collected,
beginning
on
day
17
of
the
40-day
study
period.
The
blood
sam-
ples
were
allowed
to
clot,
and
serum
was
removed
and
stored
frozen
until
analyzed.
The
weekly
blood
samples
were
used
to
veri-
fy
that
there
was
no
significant
rise
in
P
pro-
duction
(i.e.,
P
<2
ng/ml)
during
the
study
interval.
Although
such
anovulatory
inter-
vals
during
periods
of
amenorrhea
cannot
be
considered
menstrual
cycles,
we
use
the
term
"