CONTRACEPTION
EFFECT
AMl
BTE
KULDIP SINGH Senior Lecturer L Consultant WBS, M W!II. WMXIG, MA (Exon).
AM.
OF MIRPLAMT@
IWLARTS
tnr LIVER,
LIPID
0 A C VIERAS Associate Professor 13) (Birmingham), FRCDG,
WTMOLISM
F1D
DA
DIAMAFHLoKE
CLINICALBIOCHEMIST M SC SSRATNAM PEBS, w), FRCS, FRCS (Ed), FACS,
FRCUG,
FRACTX
(Han),
FRCSG, FRACS, FACDG (IIon)
ABSTRACT ---In this study involving 100 women, the metabolic changes seen with Besides a significant increase in serum Norplant@ use were evaluated. liver function to suggest there were no other changes in bilirubin, Even the possible hepatocellular dysfunction at the end of five years. raised mean levels of bilirubin remained within the normal clinical range for the local population. As regards lipid metabolism, total triglycerides, cholesterol and LDL-cholesterol were decreased through the five years of Norplant@ use. The HOL-cholesterol showed a significant increase in the first year: it t.hen decreased over the years to its preinsertion level at the end of five years. As a result, the HDL-cholesterol/Total cholesterol HDL-cholesterol showed a significant increase in the first year and then decreased to almost its preinsertion value at the end of five years. The findings appear to indicate Norplant@ use not to be contributory to cardiovascular risk. The use of Norplant@ was not associated with any significant effect on carbohydrate metabolism.
Address
for
reprints:
Dr Kuldip Singh Department of Obstetrics and National University Hospital 5 Lower Kent Ridge Road Singapore 0511
Gynaecology
Submitted Accepted
for publication for publication
FEBRUARY
1992 VOL. 45 NO. 2
October January
16, 1991 7, 1992
141
CONTRACEPTION IEmMwcTIoN -__-
The
Nor-plant@
implant
progestogen-only recognised altering
contraceptive
that lipid
and
effect
of
Norplant@
South
East
Asian
relatively
were.
healthy,
Singaporean Clinical
obtained to
the
from arm
for
at
least
Glucose
142
the
and
proteins albumin,
were
fasting
in
as
part
hours) half
was
an
used
and the
as
each
hour
prior
globulins
bromocresol
using were green
some
designed in
to
a
been
role
in
long-term
to
study
the
representative surveillance
of
system.
this
study.
These
drinking
non-lactating contraception.
were
6,
the
12, own
the
24,
36,
48
8lood
antecubital
vein
with
at the
done
prior
to
60
months
of
and
controls.
inserted
volunteers
and
study
occasion
has
predisposing
for
were
to
possibly
For
from
on
play
system
their
implants
it
Norplant@
sampling after
reversible,
years,
thus
the
for
the
long-term
function
non-alcohol
and
estimated
was
of
recruited
blood
the
recent
contraceptive
subjects
which
In
and
study
metabolic
chosen
implants
subjects
(0900-1100
For
were
new
contraception
on
non-smoking,
of
day
total
subdermal
assessment
The
This
population
women who had
insertion use.
[l-4].
women
for
a
metabolism
implants
new
One-hundred
used
carbohydrate
disease
is
system.
progestogens
cardiovascular
this
system
the
samples contralateral
same
subjects
were
time
of
having
the
rested
venipuncture.
the
glucose
estimated dye
oxidase using
binding
the
method
FEBRUARY
method Biuret was
1992
[5], method
used
[7].
VOL.
45
while [6]_
NO.
2
CONTRACEPTION Total
bilirubin
was
estimated
Bessey-Lowry-Brock
method
HUL-cholesterol
was
cholesterol
using
enzymatic
hydrolysis
from
was
single
used by
CHOP-PAP
method
determinants Mannheim.
photometry
for
precipitated
the
Boehringer
equation
using
alkaline
magnesium
[13]
[S].
modified
phosphatase
[9].
phosphotungsate
[11,123,
and
were
determined
LDL-cholesterol
The
was
[lo],
triglycerides by
using
kit
calculated
methods
using
the
[14):
LDL-cholesterol=Total
cholesterol-(HDL-cholesterol+Triqlycerides)mnol/litre 2.19
Quality control
control
pools
assay.
For
normal
(about
for
5.5%.
at
Cont.rol
Centre
Chemistry,
paired
‘t’
observing
the test.
the
were
results
statistical
FEBRUARY
1992
of
VOL.
in
were be
using
significance
45
of
NO.
in
assay
8 mnol/l)
was
than
less
2 mmol/l), (about
assessed
Reference
every
at
both
2% while
coefficient 8 mmol/l)
by
(IEQAS)
Scheme
an
of it
was
International
conducted
Services
differences
Further
to
levels)
high
serum
by
in
WHO
Clinical
Kingdom.
changes which
two
between
limit
and
running
variation
was
Assessment
used.
found
high
by
and
(about
control
Research
significance
statistical
the
significance
percent.age levels
level
at
United
was
preinsertion
the
for
Birmingham,
assess
(normal
(about
normal
quality
monitored
of
high
30% and
External
Collborating
To
and the
about
Quality
was
coefficient
3 mmol/l)
was
assay available
cholesterol,
variation
External
lipid
connnercially
triglycerides
about
in
2
from
comparisons
mean
post-insertion
were
as
skewed,
Wilcoxon
signed
distribution
was
the
changes
values, also
levels
designated
median
100%.
mean
In
made
by
compared
to
the
case
rank used
the
where
test to
of
assess
observed.
143
CONTRACEPTION RESULTS
Liver
function -_
The Mean It
most
important
bilirubin
showed
The
levels
a
slight
level
in
total
in
first
in
both
and
alkaline
the
entire
total
It
the
of
third
showed
59%
4.5%
a fall mean
bilirubin in
in
year
preinsertion
use.
factors
and
in of
the
valuefalls
total
years
the the
and
levels. first
year.
second
year.
this
level
in
the
fifth
at
the
end
was
year of
However,
the
In
to
their
preinsertion
showed use
remained
the
total
use.
it
It
then
triglycerides
next
and
5 years
significant
2 years
there
was
means.
The
albumin
changes
during
significant
a
I).
mean
the is
normal
a
no
the
within
showed
the
(Table
seen,
Moreover,
Norplant@
statistically
use.
changes
outside
a
of
general
triglycerides of
showed
Norplant@
globulin
population.
individual
three
years
globulins
years
these
despite
protein
The
three
five
local
and
phosphatase
However,
144
the
mean
by
fall
in
year.
proteins
the
increase
the
the
significantly
further
50% above
in
I).
The fall
seen
non-significant
fourth
significantly
(Table
of
but
the
were
increased
increased
maintained was
changes
levels
normal
important
range
clinical to
bilirubin, range
note
for
that
no
also.
significant
decrease
increased were
of
in still
FEBRUARY
the
in next
the
first.
two
years
significantly
1992
VOL.
lower
45
NO.
2
CONTRACEPTION
TABLE I: EWlCHEHICAL CHANGES IN SINGAWREAN NW’LANW ACCEPTCRS: LIVER FlMTIoN TESTS
AFrRR6 APTRRl mllR2 mRR3 Amu4 AFfRR5 PARAmRRSSmDIRrJ PRRINSRRmU HORTRS OPUSE IBAROFUSE PRARS OFUSR nARs OF USE YRARS OPUSE YRARS OFUSE
n wan f SD (g/d11 P vrltt X difference from preinsertion wan
97 1.24 f 0.37
97 7.17 f 0.44 NS
99 7.68 f 0.69 C 0.05
76 6.87 f 0.43 < 0.001
100
99
98
98
95
n man f SD (gldl) P value X difference from preinsertion mean
97 4.22 + 0.22
97 4.32 f 0.27 < 0.05
% 4.27 f 0.42 < 0.05
76 4.24 f 0.24 NS
65 4.20 f 0.22 NS
100
102
101
97 3.03 f 0.35
97 2.85 f 0.35 < 0.001
96 2.81 f 0.45 < 0.001
76 2.63 f 0.35 C 0.001
65 2.67 f 0.38 C 0.001
101
65 6.87 f 0.33 ( 0.001
100
63 7.17 i 0.42 NS
59 7.31 f 0.51 NS
99
101
63 4.16 + 0.22 NS
59 4.23 t 0.28 NS
99
100
63 3.01 f 0.32 NS
59 3.02 f 0.31 NS
GLOBULIN n mean f SD (gldl) P value X difference frot preinsertion man
loo
94
93
88
89
loo
97 0.55 f 0.19
97 0.81 t 0.38 C 0.001
96 0.87 f 0.31 < O.Wl
76 0.85 ? 0.28 < 0.001
65 0.94 f 0.31 < 0.001
loo -_---
141
1w
BILIRUBIN n meanf SD hgldl) P value X difference from prtinttrtion man
_-
158
150
162
63 0.92 f 0.38 < O.Wl
161 ~______
59 0.84 f 0.32 C 0.001 150
ALMLINR PEOSPRATASB n teat * SD M/l) P value X difference from preinsertion mean
97 61.1 f 17.3
loo
97 % 62.4 t 16.8 60.3 f 15.7 NS NS 102
FEBRUARY 1992 VOL. 45 NO. 2
99
‘76 61.2 ? 14.7 NS 99
65 57.2 f 15.6 NS 95
63 75.1 f 16.7 NS 105
59 61.2 f 15.9 NS 101
145
CONTRACEPTION than
the
preinsertion
cholesterol thereafter next
a
four
end
of
lower
than
as
result
a
showed
a
steady
increase
years. five
reached
It
HDL-cholesterol During to
the
below
and
its
at
the
The an
the end
of
in
and
the in
preinsertion
the
the
the
years
end
of
It
three
to
the
ratio
such
ratio.
first As
The
rat.io, year. ,a
of
of
preinsertion
and
fifth value
at
the
the
ratio
a
highly
it
increased
the
next
in
reach
The end
of
It
has The
first
year.
significantly the
fourth
its
the
first
two
years.
year,
there
was
almost
year
preinsertion
five
in
decreased was years
It
was
a
showed of
signif4cant to an
significant in
significantly
(Table
FEBRUARY
the even
decrease the
next
HDL-cholesterol. significantly
use.
remained
equivalent
progressively
ratio
year
ratio,
encouraging
increase ratio
years.
it
use.
the
LDL-cholesterol/HDL-cholesterol
Therefore
the
ratio
during
fifth
the
LDL-cholesterol/HDL-cholesterol fourth
the
that
showed
result
over
In
year.
at
II).
increase
significantly
the
years,
years.
in
stable
in
However,
subsequent
decreased
increased
(Table
years.
year
remained
and
significantly
two
fifth
HDL-cholesterol
significant
fourth
pertinent
years.
146
in
HDL-cholesterol
decreased
increase
more
increase
and
noted mean
similarly
first
total
year
preinsertion
was
the
first
HDL-cholesterol/Total-cholesterol-HDL-cholesterol
ratio
stable
its
The
was
significantly
mean.
five
below
fourth
years,
the
cholesterol
the
at
years.
total
during
increased
preinsertion
encouraging
The
in
two
thereafter
mean
mean
levels next
the
value
the
five in
LDL-choletserol
preinsertion in
of
decrease
progressive
stable
end
remained
The
a
the
in
preinsertion of
its
at
significant
still
years. its
remained
mean
two the
in below
the its
II).
1992 VOL. 45 NO. 2
CONTRACEPTION
II:
TABLE
BIOCHEMICAL CWNGES IN SILIPID HETABOLISM
AFTBR6 PARANBTBRS STUDIRD PREINSERTIONNURTRSOF USE
mm YRAR OP
1 USE
NoRPLAHT@ACCEPTORS:
AFTBR2 TBARSOF USB
AFTBR3 YRARS OF USE
AFTER4
AFTBR5 USE
YRARS OF USE YBARS OP
TRIGLPCBRIDES n “can f SD (eeolll) P value X difference preinsertion
97 1.21 t 0.74
97 0.86 ?. 0.46 < 0.001
96 0.89 f 0.45 ( 0.001
76 0.90 t 0.52 < 0.001
65 0.m 0.39 < 0.001
63 1.01 f 0.56 < 0.001
59 1.11 k 0.45 c 0.001
100
71
74
76
76
a4
90
97 5.05 f 1.02
97 4.66 ?. 0.81 < 0.001
96
4.64 ? 0.81 ( 0.001
76 4.73 f o.BJ < 0.001
65 4.73 f 1.00 < 0.001
63 4.89 f 0.85 < O.M)l
59 4.92 f 0.97 < 0.05
100
92
92
94
96
97
98
97 1.08 f 0.34
97 1.16 f 0.25 < 0.001
1.13 f 0.24 < 0.091
76 1.08 f 0.23 NS
63 0.96 f 0.20 < 0.01
59 1.08 f 0.06 NS
100
107
105
98
87
98
97 3.38 + 0.99
97 3.10 + 0.73 c 0,001
3.10 f 0.72 ( 0.001
92
92
from mean _
CBOLBSTBROL n mean f SD (mmolll) P value X difference from preinsertion mean EL-CBOLESTEROL n .ean f SD h~Ol/l) P value X difference from preinsertion mean
96
65
f 0.22 < 0.01
1.00
a6
LDL-CROLESTEROL n wan f SD hmolll) P value X difference from preinsertion mean
100
96
76 3.25 f 0.73 *< 0.05 95
64 3.36 + 0.87 NS
63 3.47 f 0.77 NS
IOU
101
59
* 0.87
3.33
NS 99
BDL-CBOLESTBBOL/TGTT CEOLBSTBROL BDLCBOLESTBROL ME
97
97
96.
0.308 t 0.164
0.331 f 0.121 < 0.001
0.342 + 0.111 c 0.001
76 0.311 f 0:098 NS
100
101
111
101
97 3.56 f 1.73
97 2.67 f 0.93 ( 0.001
96 2.85 f 0.90 ( O.Oul
100
75
81
”
mean * SD P value X difference from preinsertion mean
64 63 59 0.285 + 0.090 0.255 t 0.078 0.301 f 0.112 ( 0.05 < 0.05 < 0.05 83
85
98
76 3.17 f 1.13 ( 0.05
64 3.48 f I.12 ( 0.05
63 3.76 f 1.11 < 0.05
59 3.23 t 1.00 G 0.05
91
113
106
93
LDL-CBOLBSTBROLIBDL CEOLESTBROL RATIO n mean f SD P value I difference from preinsertion mean
FEBRUARY 1992 VOL. 45 NO. 2
147
CONTRACEPTION _Carboh&ate -___~ Metabolism
Oral
glucose
tolerance
insertion
before clinically
and
use
using
changes
50-gram
loads
annually
subsequently
significant
Norplant@
tests
were
observed
[15J
showed
were
after
performed NO
insertion.
during
the
five
years
of
III).
(Table
DISCDSSI~
Shaaban
et
bilirubin
in
Similarly the
of
for
our
of
population
The
highly and
the
of
study
other
below fourth
at
end
of
the
study.
in
Total
to
strongly
148
that
a
mean
remained
six
liver
level
1eve.I
within
increase
by
in
raised the
small
normal
change
significantly
function
decrease
its
that
in
seen
in
months.
function of
of
the
in
the
fifth
A rafsed
against a high
this
at
bilirubin.
bilirubln
and
clinical
range
Total
triglycerides, study
The
first
preinsertion and
total
[16-191. in
triglycerides,
be protective believed
to
significant
note
significantly to
reverted
investigators
the
said
to
only
studied.
in
a fall
the
liver
increasing the
only
LDL-cholesterol
increased
significantly
this
significant
cholesterol results
was
important
parameters the
and the
years
is
Egypt
study study,
five
it
However,
from
his
in
end
other
al,
to
reach
It
the
cardiovascular
next
its
HDL-cholesterol cholesterol
comparable
HDL-cholesterol
year.
mean in year
is
total
and disease
HDL-cholesterol/Total
FEBRUARY
in
then
this
decreased
2 years,
before
preinsertion
level
with
value
associated
with
LDL-cholesterol risk.
cholesterol
Thus,
is it
is
- HDL
1992 VOL. 45 NO.
2
CONTRACEPTION III:
TABLE
ORAL GLUOSE
TCXERRNCE
CHANGES IN SINGAPOREAN NORPLANTs
TEST
ACCEPTORS MG/DL
--
1-HOUR
FASTING
--
-----_
Z-HOUR
n = 97 Glucose
0 year(preinsertion) n = 97 1 year P value
Glucose
after
use
89.9
+ 9.9
91.5
89.1
131.3
*
32.1
112.7
f 9.8 NS
144.0 + 34.0 < 0.001
110.4
f 10.4 NS
143.8 f 35.5 < 0.001
112.1 zk29.8
139.7 f 43.0
108.1 + 32.7
NS
NS
135.7 + 38.3 NS
109.9 + 29.9 NS
132.7
108.2
__n = 76 Glucose 2 years P value
after
use
f
27.6
f 28.2 NS ---
NS
n = 65
Glucose 3 years after use
90.7 * 15.9
P value
Glucose
Glucose
n = 63 4 years P value
after
n = 59 5 years P value
after
cholesterol
at
risk
all of
low
In
reaching times
above
complications
the
first
almost
its
0.200
* 38.5 NS
LDL-cholesterol/HDL-cholesterol
cholesterol in
developing
disease
are
a
cardiovascular
increase
before
11.0
* 14.1 NS
88.0
HDL-cholesterol/Total
years
+
84.7
use
and
against
significant
was
use
NS
ratio
protective the
NS
-
coronary
-
year.
It
a value
heart
value
below
diseases
In this study,
HDL,-c:holesterol
preinsertion
which or
showed
in of
are
ratio
[:20,21].
decreased
f 33.6 NS
the
next
0.301.
there
is
progression
The
a.
three ratio
an
increased
of
existing
[ZZ]_
this
minimal
FEBRUARY
study, and
1992
the
are
effects
unlikely
VOL.
45
of
to
NO.
be
2
Norplant@ of
any
on
clinical
carbohydrate
metabolism
significance.
149
CONTRACEPTION _gj.nKLusIoN
It
would
bilirubin, of
appear
there
is
Norplant@
no
at
all, We
treat.ed
effects
could
have
of its
potential
evidence
of
may
be
not
ready
liver of
to
be
however,
to
observed
reversible
and
long-term
to
increasingly
used
in
use
lipid
the
and
absence
of
environmenta
changes.
Thus
contraceptive, the
the
cardiovascular,
extraneous
in
serum
cardiovascular
against
study,
the
he
on to
that
in
with
Norplant@
factor
the
increase
dysfunction
conclude
in
an
contributory
a protective
attributed a
besides
effects
controls
as
appear
that
The
must,
non-steroidal
study
appear
it
complications.
of
other
metabolism
If
implants
this
implants.
carbohydrate risk.
from
by
1
virtue
Norplant@
future
as
a method
contraception.
ACKNMLEDGEMMTS
We are Control The
study
are
also
grateful
Clinic,
to
the
National
was
supported
indebted
to
Medical
University by
Miss
Nursing
Hospital,
a grant Prema
and
from
for
her
staff
for
Family
of
.their
Health
secretarial
the
Fertility
invaluable
help.
International_
We
assistance.
REFWEWCES
1.
Bradley,
(I.D.,
Ramcharan, Women Using Med,
150
299,
Wingred,
S.
(1978).
Oral
J., Serum
Contraceptives,
Petitti, High
D.H., Density Estrogens
Krauss,
R.M.
Lipoprotein and
and Cholesterol
Progestins.
N Engl
in J
17-20.
FEBRUARY
1992 VOL. 45 NO. 2
CONTRACEPTION
2.
Brlggs,
M.
and
Effects
of
Four
Knopp,
R-H.,
Effect
of
4.
Oral
Oral
23,
V.
142,
and
Reference
Wahl,
to
and
Results
after
and
J.J.
Hoover,
Lipoprotein,
Estrogen
R.
6
(1982).
Triglycerides
Progestin
Density
The
(1982).
Contraceptives
High
Metabolic
and
Therapy.
Am J
725.
Oral
to
P.W.
on
Niththyananthan,
Combined
I.
of
463.
C-E.,
Relationship
Study
Contraceptives:
Contraceptives
Gynecol,
Wynn, in
Low-Estrogen
Walden,
Cholesterol: Obstet
(1981). A Randomised
M.
Contraception,
Cycles.
3.
Briggs,
Serum
on
Lipoproteins.
Effects
of
Lipids
wit.h
Am J
Obstet
Progestins Special
Gynecol,
142,
766.
5.
Cramp,
D.G.
Glucose
6.
7.
J Clin
Oxidase.
Weichselbaum,
T.E.
Determination
of
Plasma.
Am J Clin
Spencer,
K.
Reaction
Conditions
Bromocresol
New Automated
(1967).
and
Pathol,
Proteins
in
Pathol,
Price,
16,
C.P. on
Green-Dye
20,
An
(1946).
Method
Small
and
Rapid
Amounts
Glucose
by
Method
of
Blood
for
the
Serum
and
40-49.
Influence
Determination
B-inding
Measuring
910-912.
Accurate
(1977).
the
for
of of
Method.
Ann
Reagent
Serum Clin
Quality
Albumin
by
Biochenm,
and The 14,
105-115.
8.
Jendrassik, for
the
L.
and
Grof,
Determination
P. of
(1938). the
Blood
Simplified
Photometric
Bilirubin.
Biochem
Methods Z.,
297,
81-89.
FEBRUARY
1992
VOL.
45
NO.
2
151
CONTRACEPTION 9.
Bessey, Rapid
Lowry,
F.K.,
Determination
Millimetres
10.
the
with
11.
12.
of
Burstein, for
Isolation
Glucose
Oxidase
Biochem,
6,
Stahler,
F.,
with
Five
the
Cubic
R.
for
(1970).
Human
Rapid
Serum
by
Method
Precipitation
583-595.
of
Glucose
Alternative
in
Oxygen
Blood
Using C lin
Ann
Acceptor.
24-27.
Gruber,
Wahfield,
A.W.
W.
and
(1974).
H.U.
and
Stinohoff,
K.
(1977).
Eine
Cholesterin-Bestimrmng.
of
Cholesterol
Med
Lab
(Stuttg),
the
M.M.,
(1984).
Effect
Elwan,
on Liver
Function.
of
Analysis.
Weinheim
R.I.
and
Fredrickson,
Concentration
Clin
Shaaban,
Chemiw
Plasma,
Ultracentrifuge.
Enzymatic
and
In:
Academic
Press,
New
1831.
Levy,
in
of
Verlag
pp
W-I.,
Friedewald,
Methods
(ed).
London,
Estimation
152
with
for
321-329.
Morfin,
11,
A Method
29-37.
York
15.
and
Res,
an
(1946).
164,
Lipoproteins
Enzymatic
Bergmeyer,
14.
Chem,
Determination
(1969).
M.J.
Phosphatase
H.R.
J Lipid
P.
Brock,
J Biol
of
Polyanions.
and
Alkaline
Scholnik,
M.,
Praxisgerechte
13.
of
Serum.
Trinder,
30,
0-H.
18,
Contraception,
(1982).
Density
Lipoprotein
the
Preparative
of
499-502.
El-Sharkawy,
Levonorgestrel
Low Use
Without
Chem,
S-I.,
of
D.S.
M.M.
and
Contraceptive 30,
Farghaly,
Implants
A.S. (Norplant),
407-412.
FEBRUARY
1992
VOL.
45
NO.
2
CONTRACEPTION 16.
Croxatto,
H-D.,
Clinical
17.
Diaz,
Chemistry
(Norplant)
or
Robertson,
D.N.
Clinical
Effects,
Abdalla,
M.M.,
Effects
of
Norplant,
on Serum
P.
Castelli,
W.P.,
22.
T.,
Dawber,
T.R.
against
Coronary
Hjerman, of
diet
disease.
FEBRUARY
Kagan,
Darwish,
Use
Steroid
H.A.
(1984).
Hames,
in
Subdermal
(Z),
Zukel
Implants,
and of
32
T.,
and
413-419.
Cholesterol
and
Lipids
Other
,
Implants
163-171.
C.G.,
Hjortland,
W. J.
(1977).
Coronary
Heart
HDLDisease.
767-772.
Castell,
W-P.,
(1977).
High
Heart
I.,
Velve
and
smoking
Lancet,
A.
Fertility
127-147.
30,
Contraception,
S.B.,
Human
Rates.
Long-acting
and
During
Gordon,
Release
Contraceptive
(1985).
Human
J.T.,
55,
Gordon,
in
Doyle,
and
S.A.
Rods:
Vivo
pp
Contraception,
D.N.
in
2: USA,
Implants
281-288.
in
Levonorgestrel
Values
Hulley,
Anch,
Lipids.
Levonorgestrel.
Circulation,
S.I.,
Robertson,
Cholesterol
21.
Advances
(1983).
Levonorgestrel
and
New York,
M.
Silastic
Vol
Press,
Releasing
M.C.,
(ed).
Subdermal
and
Pavez,
27,
Effects
Endocrinology,
Shaaban,
with
Contraception,
Jr
Raven
and
Norgestrel-Releasing
D.R.
HDL-Cholesterol
20.
D.N.
Treated
Biochemical
Contraception,
19. Holma,
Women
(X983).
Reproductive
18.
in
Robertson,
TCu-ZOO-IUD.
Mischell,
In:
S.,
Byre,
2,
Hjortland,
M.C.,
Density
Disease.
K.,
intervention
Kannel,
W-B.
as
a Protective
Lipoprotein Am J Med,
Holme. on
I. the
and
62,
and Factor
707-714.
Leren.
incidence
P.
(1981).
of
coronary
Effect heart
1303-1310.
1992 VOL. 45 NO. 2
153
EFFECT
AMl
BTE
KULDIP SINGH Senior Lecturer L Consultant WBS, M W!II. WMXIG, MA (Exon).
AM.
OF MIRPLAMT@
IWLARTS
tnr LIVER,
LIPID
0 A C VIERAS Associate Professor 13) (Birmingham), FRCDG,
WTMOLISM
F1D
DA
DIAMAFHLoKE
CLINICALBIOCHEMIST M SC SSRATNAM PEBS, w), FRCS, FRCS (Ed), FACS,
FRCUG,
FRACTX
(Han),
FRCSG, FRACS, FACDG (IIon)
ABSTRACT ---In this study involving 100 women, the metabolic changes seen with Besides a significant increase in serum Norplant@ use were evaluated. liver function to suggest there were no other changes in bilirubin, Even the possible hepatocellular dysfunction at the end of five years. raised mean levels of bilirubin remained within the normal clinical range for the local population. As regards lipid metabolism, total triglycerides, cholesterol and LDL-cholesterol were decreased through the five years of Norplant@ use. The HOL-cholesterol showed a significant increase in the first year: it t.hen decreased over the years to its preinsertion level at the end of five years. As a result, the HDL-cholesterol/Total cholesterol HDL-cholesterol showed a significant increase in the first year and then decreased to almost its preinsertion value at the end of five years. The findings appear to indicate Norplant@ use not to be contributory to cardiovascular risk. The use of Norplant@ was not associated with any significant effect on carbohydrate metabolism.
Address
for
reprints:
Dr Kuldip Singh Department of Obstetrics and National University Hospital 5 Lower Kent Ridge Road Singapore 0511
Gynaecology
Submitted Accepted
for publication for publication
FEBRUARY
1992 VOL. 45 NO. 2
October January
16, 1991 7, 1992
141
CONTRACEPTION IEmMwcTIoN -__-
The
Nor-plant@
implant
progestogen-only recognised altering
contraceptive
that lipid
and
effect
of
Norplant@
South
East
Asian
relatively
were.
healthy,
Singaporean Clinical
obtained to
the
from arm
for
at
least
Glucose
142
the
and
proteins albumin,
were
fasting
in
as
part
hours) half
was
an
used
and the
as
each
hour
prior
globulins
bromocresol
using were green
some
designed in
to
a
been
role
in
long-term
to
study
the
representative surveillance
of
system.
this
study.
These
drinking
non-lactating contraception.
were
6,
the
12, own
the
24,
36,
48
8lood
antecubital
vein
with
at the
done
prior
to
60
months
of
and
controls.
inserted
volunteers
and
study
occasion
has
predisposing
for
were
to
possibly
For
from
on
play
system
their
implants
it
Norplant@
sampling after
reversible,
years,
thus
the
for
the
long-term
function
non-alcohol
and
estimated
was
of
recruited
blood
the
recent
contraceptive
subjects
which
In
and
study
metabolic
chosen
implants
subjects
(0900-1100
For
were
new
contraception
on
non-smoking,
of
day
total
subdermal
assessment
The
This
population
women who had
insertion use.
[l-4].
women
for
a
metabolism
implants
new
One-hundred
used
carbohydrate
disease
is
system.
progestogens
cardiovascular
this
system
the
samples contralateral
same
subjects
were
time
of
having
the
rested
venipuncture.
the
glucose
estimated dye
oxidase using
binding
the
method
FEBRUARY
method Biuret was
1992
[5], method
used
[7].
VOL.
45
while [6]_
NO.
2
CONTRACEPTION Total
bilirubin
was
estimated
Bessey-Lowry-Brock
method
HUL-cholesterol
was
cholesterol
using
enzymatic
hydrolysis
from
was
single
used by
CHOP-PAP
method
determinants Mannheim.
photometry
for
precipitated
the
Boehringer
equation
using
alkaline
magnesium
[13]
[S].
modified
phosphatase
[9].
phosphotungsate
[11,123,
and
were
determined
LDL-cholesterol
The
was
[lo],
triglycerides by
using
kit
calculated
methods
using
the
[14):
LDL-cholesterol=Total
cholesterol-(HDL-cholesterol+Triqlycerides)mnol/litre 2.19
Quality control
control
pools
assay.
For
normal
(about
for
5.5%.
at
Cont.rol
Centre
Chemistry,
paired
‘t’
observing
the test.
the
were
results
statistical
FEBRUARY
1992
of
VOL.
in
were be
using
significance
45
of
NO.
in
assay
8 mnol/l)
was
than
less
2 mmol/l), (about
assessed
Reference
every
at
both
2% while
coefficient 8 mmol/l)
by
(IEQAS)
Scheme
an
of it
was
International
conducted
Services
differences
Further
to
levels)
high
serum
by
in
WHO
Clinical
Kingdom.
changes which
two
between
limit
and
running
variation
was
Assessment
used.
found
high
by
and
(about
control
Research
significance
statistical
the
significance
percent.age levels
level
at
United
was
preinsertion
the
for
Birmingham,
assess
(normal
(about
normal
quality
monitored
of
high
30% and
External
Collborating
To
and the
about
Quality
was
coefficient
3 mmol/l)
was
assay available
cholesterol,
variation
External
lipid
connnercially
triglycerides
about
in
2
from
comparisons
mean
post-insertion
were
as
skewed,
Wilcoxon
signed
distribution
was
the
changes
values, also
levels
designated
median
100%.
mean
In
made
by
compared
to
the
case
rank used
the
where
test to
of
assess
observed.
143
CONTRACEPTION RESULTS
Liver
function -_
The Mean It
most
important
bilirubin
showed
The
levels
a
slight
level
in
total
in
first
in
both
and
alkaline
the
entire
total
It
the
of
third
showed
59%
4.5%
a fall mean
bilirubin in
in
year
preinsertion
use.
factors
and
in of
the
valuefalls
total
years
the the
and
levels. first
year.
second
year.
this
level
in
the
fifth
at
the
end
was
year of
However,
the
In
to
their
preinsertion
showed use
remained
the
total
use.
it
It
then
triglycerides
next
and
5 years
significant
2 years
there
was
means.
The
albumin
changes
during
significant
a
I).
mean
the is
normal
a
no
the
within
showed
the
(Table
seen,
Moreover,
Norplant@
statistically
use.
changes
outside
a
of
general
triglycerides of
showed
Norplant@
globulin
population.
individual
three
years
globulins
years
these
despite
protein
The
three
five
local
and
phosphatase
However,
144
the
mean
by
fall
in
year.
proteins
the
increase
the
the
significantly
further
50% above
in
I).
The fall
seen
non-significant
fourth
significantly
(Table
of
but
the
were
increased
increased
maintained was
changes
levels
normal
important
range
clinical to
bilirubin, range
note
for
that
no
also.
significant
decrease
increased were
of
in still
FEBRUARY
the
in next
the
first.
two
years
significantly
1992
VOL.
lower
45
NO.
2
CONTRACEPTION
TABLE I: EWlCHEHICAL CHANGES IN SINGAWREAN NW’LANW ACCEPTCRS: LIVER FlMTIoN TESTS
AFrRR6 APTRRl mllR2 mRR3 Amu4 AFfRR5 PARAmRRSSmDIRrJ PRRINSRRmU HORTRS OPUSE IBAROFUSE PRARS OFUSR nARs OF USE YRARS OPUSE YRARS OFUSE
n wan f SD (g/d11 P vrltt X difference from preinsertion wan
97 1.24 f 0.37
97 7.17 f 0.44 NS
99 7.68 f 0.69 C 0.05
76 6.87 f 0.43 < 0.001
100
99
98
98
95
n man f SD (gldl) P value X difference from preinsertion mean
97 4.22 + 0.22
97 4.32 f 0.27 < 0.05
% 4.27 f 0.42 < 0.05
76 4.24 f 0.24 NS
65 4.20 f 0.22 NS
100
102
101
97 3.03 f 0.35
97 2.85 f 0.35 < 0.001
96 2.81 f 0.45 < 0.001
76 2.63 f 0.35 C 0.001
65 2.67 f 0.38 C 0.001
101
65 6.87 f 0.33 ( 0.001
100
63 7.17 i 0.42 NS
59 7.31 f 0.51 NS
99
101
63 4.16 + 0.22 NS
59 4.23 t 0.28 NS
99
100
63 3.01 f 0.32 NS
59 3.02 f 0.31 NS
GLOBULIN n mean f SD (gldl) P value X difference frot preinsertion man
loo
94
93
88
89
loo
97 0.55 f 0.19
97 0.81 t 0.38 C 0.001
96 0.87 f 0.31 < O.Wl
76 0.85 ? 0.28 < 0.001
65 0.94 f 0.31 < 0.001
loo -_---
141
1w
BILIRUBIN n meanf SD hgldl) P value X difference from prtinttrtion man
_-
158
150
162
63 0.92 f 0.38 < O.Wl
161 ~______
59 0.84 f 0.32 C 0.001 150
ALMLINR PEOSPRATASB n teat * SD M/l) P value X difference from preinsertion mean
97 61.1 f 17.3
loo
97 % 62.4 t 16.8 60.3 f 15.7 NS NS 102
FEBRUARY 1992 VOL. 45 NO. 2
99
‘76 61.2 ? 14.7 NS 99
65 57.2 f 15.6 NS 95
63 75.1 f 16.7 NS 105
59 61.2 f 15.9 NS 101
145
CONTRACEPTION than
the
preinsertion
cholesterol thereafter next
a
four
end
of
lower
than
as
result
a
showed
a
steady
increase
years. five
reached
It
HDL-cholesterol During to
the
below
and
its
at
the
The an
the end
of
in
and
the in
preinsertion
the
the
the
years
end
of
It
three
to
the
ratio
such
ratio.
first As
The
rat.io, year. ,a
of
of
preinsertion
and
fifth value
at
the
the
ratio
a
highly
it
increased
the
next
in
reach
The end
of
It
has The
first
year.
significantly the
fourth
its
the
first
two
years.
year,
there
was
almost
year
preinsertion
five
in
decreased was years
It
was
a
showed of
signif4cant to an
significant in
significantly
(Table
FEBRUARY
the even
decrease the
next
HDL-cholesterol. significantly
use.
remained
equivalent
progressively
ratio
year
ratio,
encouraging
increase ratio
years.
it
use.
the
LDL-cholesterol/HDL-cholesterol
Therefore
the
ratio
during
fifth
the
LDL-cholesterol/HDL-cholesterol fourth
the
that
showed
result
over
In
year.
at
II).
increase
significantly
the
years,
years.
in
stable
in
However,
subsequent
decreased
increased
(Table
years.
year
remained
and
significantly
two
fifth
HDL-cholesterol
significant
fourth
pertinent
years.
146
in
HDL-cholesterol
decreased
increase
more
increase
and
noted mean
similarly
first
total
year
preinsertion
was
the
first
HDL-cholesterol/Total-cholesterol-HDL-cholesterol
ratio
stable
its
The
was
significantly
mean.
five
below
fourth
years,
the
cholesterol
the
at
years.
total
during
increased
preinsertion
encouraging
The
in
two
thereafter
mean
mean
levels next
the
value
the
five in
LDL-choletserol
preinsertion in
of
decrease
progressive
stable
end
remained
The
a
the
in
preinsertion of
its
at
significant
still
years. its
remained
mean
two the
in below
the its
II).
1992 VOL. 45 NO. 2
CONTRACEPTION
II:
TABLE
BIOCHEMICAL CWNGES IN SILIPID HETABOLISM
AFTBR6 PARANBTBRS STUDIRD PREINSERTIONNURTRSOF USE
mm YRAR OP
1 USE
NoRPLAHT@ACCEPTORS:
AFTBR2 TBARSOF USB
AFTBR3 YRARS OF USE
AFTER4
AFTBR5 USE
YRARS OF USE YBARS OP
TRIGLPCBRIDES n “can f SD (eeolll) P value X difference preinsertion
97 1.21 t 0.74
97 0.86 ?. 0.46 < 0.001
96 0.89 f 0.45 ( 0.001
76 0.90 t 0.52 < 0.001
65 0.m 0.39 < 0.001
63 1.01 f 0.56 < 0.001
59 1.11 k 0.45 c 0.001
100
71
74
76
76
a4
90
97 5.05 f 1.02
97 4.66 ?. 0.81 < 0.001
96
4.64 ? 0.81 ( 0.001
76 4.73 f o.BJ < 0.001
65 4.73 f 1.00 < 0.001
63 4.89 f 0.85 < O.M)l
59 4.92 f 0.97 < 0.05
100
92
92
94
96
97
98
97 1.08 f 0.34
97 1.16 f 0.25 < 0.001
1.13 f 0.24 < 0.091
76 1.08 f 0.23 NS
63 0.96 f 0.20 < 0.01
59 1.08 f 0.06 NS
100
107
105
98
87
98
97 3.38 + 0.99
97 3.10 + 0.73 c 0,001
3.10 f 0.72 ( 0.001
92
92
from mean _
CBOLBSTBROL n mean f SD (mmolll) P value X difference from preinsertion mean EL-CBOLESTEROL n .ean f SD h~Ol/l) P value X difference from preinsertion mean
96
65
f 0.22 < 0.01
1.00
a6
LDL-CROLESTEROL n wan f SD hmolll) P value X difference from preinsertion mean
100
96
76 3.25 f 0.73 *< 0.05 95
64 3.36 + 0.87 NS
63 3.47 f 0.77 NS
IOU
101
59
* 0.87
3.33
NS 99
BDL-CBOLESTBBOL/TGTT CEOLBSTBROL BDLCBOLESTBROL ME
97
97
96.
0.308 t 0.164
0.331 f 0.121 < 0.001
0.342 + 0.111 c 0.001
76 0.311 f 0:098 NS
100
101
111
101
97 3.56 f 1.73
97 2.67 f 0.93 ( 0.001
96 2.85 f 0.90 ( O.Oul
100
75
81
”
mean * SD P value X difference from preinsertion mean
64 63 59 0.285 + 0.090 0.255 t 0.078 0.301 f 0.112 ( 0.05 < 0.05 < 0.05 83
85
98
76 3.17 f 1.13 ( 0.05
64 3.48 f I.12 ( 0.05
63 3.76 f 1.11 < 0.05
59 3.23 t 1.00 G 0.05
91
113
106
93
LDL-CBOLBSTBROLIBDL CEOLESTBROL RATIO n mean f SD P value I difference from preinsertion mean
FEBRUARY 1992 VOL. 45 NO. 2
147
CONTRACEPTION _Carboh&ate -___~ Metabolism
Oral
glucose
tolerance
insertion
before clinically
and
use
using
changes
50-gram
loads
annually
subsequently
significant
Norplant@
tests
were
observed
[15J
showed
were
after
performed NO
insertion.
during
the
five
years
of
III).
(Table
DISCDSSI~
Shaaban
et
bilirubin
in
Similarly the
of
for
our
of
population
The
highly and
the
of
study
other
below fourth
at
end
of
the
study.
in
Total
to
strongly
148
that
a
mean
remained
six
liver
level
1eve.I
within
increase
by
in
raised the
small
normal
change
significantly
function
decrease
its
that
in
seen
in
months.
function of
of
the
in
the
fifth
A rafsed
against a high
this
at
bilirubin.
bilirubln
and
clinical
range
Total
triglycerides, study
The
first
preinsertion and
total
[16-191. in
triglycerides,
be protective believed
to
significant
note
significantly to
reverted
investigators
the
said
to
only
studied.
in
a fall
the
liver
increasing the
only
LDL-cholesterol
increased
significantly
this
significant
cholesterol results
was
important
parameters the
and the
years
is
Egypt
study study,
five
it
However,
from
his
in
end
other
al,
to
reach
It
the
cardiovascular
next
its
HDL-cholesterol cholesterol
comparable
HDL-cholesterol
year.
mean in year
is
total
and disease
HDL-cholesterol/Total
FEBRUARY
in
then
this
decreased
2 years,
before
preinsertion
level
with
value
associated
with
LDL-cholesterol risk.
cholesterol
Thus,
is it
is
- HDL
1992 VOL. 45 NO.
2
CONTRACEPTION III:
TABLE
ORAL GLUOSE
TCXERRNCE
CHANGES IN SINGAPOREAN NORPLANTs
TEST
ACCEPTORS MG/DL
--
1-HOUR
FASTING
--
-----_
Z-HOUR
n = 97 Glucose
0 year(preinsertion) n = 97 1 year P value
Glucose
after
use
89.9
+ 9.9
91.5
89.1
131.3
*
32.1
112.7
f 9.8 NS
144.0 + 34.0 < 0.001
110.4
f 10.4 NS
143.8 f 35.5 < 0.001
112.1 zk29.8
139.7 f 43.0
108.1 + 32.7
NS
NS
135.7 + 38.3 NS
109.9 + 29.9 NS
132.7
108.2
__n = 76 Glucose 2 years P value
after
use
f
27.6
f 28.2 NS ---
NS
n = 65
Glucose 3 years after use
90.7 * 15.9
P value
Glucose
Glucose
n = 63 4 years P value
after
n = 59 5 years P value
after
cholesterol
at
risk
all of
low
In
reaching times
above
complications
the
first
almost
its
0.200
* 38.5 NS
LDL-cholesterol/HDL-cholesterol
cholesterol in
developing
disease
are
a
cardiovascular
increase
before
11.0
* 14.1 NS
88.0
HDL-cholesterol/Total
years
+
84.7
use
and
against
significant
was
use
NS
ratio
protective the
NS
-
coronary
-
year.
It
a value
heart
value
below
diseases
In this study,
HDL,-c:holesterol
preinsertion
which or
showed
in of
are
ratio
[:20,21].
decreased
f 33.6 NS
the
next
0.301.
there
is
progression
The
a.
three ratio
an
increased
of
existing
[ZZ]_
this
minimal
FEBRUARY
study, and
1992
the
are
effects
unlikely
VOL.
45
of
to
NO.
be
2
Norplant@ of
any
on
clinical
carbohydrate
metabolism
significance.
149
CONTRACEPTION _gj.nKLusIoN
It
would
bilirubin, of
appear
there
is
Norplant@
no
at
all, We
treat.ed
effects
could
have
of its
potential
evidence
of
may
be
not
ready
liver of
to
be
however,
to
observed
reversible
and
long-term
to
increasingly
used
in
use
lipid
the
and
absence
of
environmenta
changes.
Thus
contraceptive, the
the
cardiovascular,
extraneous
in
serum
cardiovascular
against
study,
the
he
on to
that
in
with
Norplant@
factor
the
increase
dysfunction
conclude
in
an
contributory
a protective
attributed a
besides
effects
controls
as
appear
that
The
must,
non-steroidal
study
appear
it
complications.
of
other
metabolism
If
implants
this
implants.
carbohydrate risk.
from
by
1
virtue
Norplant@
future
as
a method
contraception.
ACKNMLEDGEMMTS
We are Control The
study
are
also
grateful
Clinic,
to
the
National
was
supported
indebted
to
Medical
University by
Miss
Nursing
Hospital,
a grant Prema
and
from
for
her
staff
for
Family
of
.their
Health
secretarial
the
Fertility
invaluable
help.
International_
We
assistance.
REFWEWCES
1.
Bradley,
(I.D.,
Ramcharan, Women Using Med,
150
299,
Wingred,
S.
(1978).
Oral
J., Serum
Contraceptives,
Petitti, High
D.H., Density Estrogens
Krauss,
R.M.
Lipoprotein and
and Cholesterol
Progestins.
N Engl
in J
17-20.
FEBRUARY
1992 VOL. 45 NO. 2
CONTRACEPTION
2.
Brlggs,
M.
and
Effects
of
Four
Knopp,
R-H.,
Effect
of
4.
Oral
Oral
23,
V.
142,
and
Reference
Wahl,
to
and
Results
after
and
J.J.
Hoover,
Lipoprotein,
Estrogen
R.
6
(1982).
Triglycerides
Progestin
Density
The
(1982).
Contraceptives
High
Metabolic
and
Therapy.
Am J
725.
Oral
to
P.W.
on
Niththyananthan,
Combined
I.
of
463.
C-E.,
Relationship
Study
Contraceptives:
Contraceptives
Gynecol,
Wynn, in
Low-Estrogen
Walden,
Cholesterol: Obstet
(1981). A Randomised
M.
Contraception,
Cycles.
3.
Briggs,
Serum
on
Lipoproteins.
Effects
of
Lipids
wit.h
Am J
Obstet
Progestins Special
Gynecol,
142,
766.
5.
Cramp,
D.G.
Glucose
6.
7.
J Clin
Oxidase.
Weichselbaum,
T.E.
Determination
of
Plasma.
Am J Clin
Spencer,
K.
Reaction
Conditions
Bromocresol
New Automated
(1967).
and
Pathol,
Proteins
in
Pathol,
Price,
16,
C.P. on
Green-Dye
20,
An
(1946).
Method
Small
and
Rapid
Amounts
Glucose
by
Method
of
Blood
for
the
Serum
and
40-49.
Influence
Determination
B-inding
Measuring
910-912.
Accurate
(1977).
the
for
of of
Method.
Ann
Reagent
Serum Clin
Quality
Albumin
by
Biochenm,
and The 14,
105-115.
8.
Jendrassik, for
the
L.
and
Grof,
Determination
P. of
(1938). the
Blood
Simplified
Photometric
Bilirubin.
Biochem
Methods Z.,
297,
81-89.
FEBRUARY
1992
VOL.
45
NO.
2
151
CONTRACEPTION 9.
Bessey, Rapid
Lowry,
F.K.,
Determination
Millimetres
10.
the
with
11.
12.
of
Burstein, for
Isolation
Glucose
Oxidase
Biochem,
6,
Stahler,
F.,
with
Five
the
Cubic
R.
for
(1970).
Human
Rapid
Serum
by
Method
Precipitation
583-595.
of
Glucose
Alternative
in
Oxygen
Blood
Using C lin
Ann
Acceptor.
24-27.
Gruber,
Wahfield,
A.W.
W.
and
(1974).
H.U.
and
Stinohoff,
K.
(1977).
Eine
Cholesterin-Bestimrmng.
of
Cholesterol
Med
Lab
(Stuttg),
the
M.M.,
(1984).
Effect
Elwan,
on Liver
Function.
of
Analysis.
Weinheim
R.I.
and
Fredrickson,
Concentration
Clin
Shaaban,
Chemiw
Plasma,
Ultracentrifuge.
Enzymatic
and
In:
Academic
Press,
New
1831.
Levy,
in
of
Verlag
pp
W-I.,
Friedewald,
Methods
(ed).
London,
Estimation
152
with
for
321-329.
Morfin,
11,
A Method
29-37.
York
15.
and
Res,
an
(1946).
164,
Lipoproteins
Enzymatic
Bergmeyer,
14.
Chem,
Determination
(1969).
M.J.
Phosphatase
H.R.
J Lipid
P.
Brock,
J Biol
of
Polyanions.
and
Alkaline
Scholnik,
M.,
Praxisgerechte
13.
of
Serum.
Trinder,
30,
0-H.
18,
Contraception,
(1982).
Density
Lipoprotein
the
Preparative
of
499-502.
El-Sharkawy,
Levonorgestrel
Low Use
Without
Chem,
S-I.,
of
D.S.
M.M.
and
Contraceptive 30,
Farghaly,
Implants
A.S. (Norplant),
407-412.
FEBRUARY
1992
VOL.
45
NO.
2
CONTRACEPTION 16.
Croxatto,
H-D.,
Clinical
17.
Diaz,
Chemistry
(Norplant)
or
Robertson,
D.N.
Clinical
Effects,
Abdalla,
M.M.,
Effects
of
Norplant,
on Serum
P.
Castelli,
W.P.,
22.
T.,
Dawber,
T.R.
against
Coronary
Hjerman, of
diet
disease.
FEBRUARY
Kagan,
Darwish,
Use
Steroid
H.A.
(1984).
Hames,
in
Subdermal
(Z),
Zukel
Implants,
and of
32
T.,
and
413-419.
Cholesterol
and
Lipids
Other
,
Implants
163-171.
C.G.,
Hjortland,
W. J.
(1977).
Coronary
Heart
HDLDisease.
767-772.
Castell,
W-P.,
(1977).
High
Heart
I.,
Velve
and
smoking
Lancet,
A.
Fertility
127-147.
30,
Contraception,
S.B.,
Human
Rates.
Long-acting
and
During
Gordon,
Release
Contraceptive
(1985).
Human
J.T.,
55,
Gordon,
in
Doyle,
and
S.A.
Rods:
Vivo
pp
Contraception,
D.N.
in
2: USA,
Implants
281-288.
in
Levonorgestrel
Values
Hulley,
Anch,
Lipids.
Levonorgestrel.
Circulation,
S.I.,
Robertson,
Cholesterol
21.
Advances
(1983).
Levonorgestrel
and
New York,
M.
Silastic
Vol
Press,
Releasing
M.C.,
(ed).
Subdermal
and
Pavez,
27,
Effects
Endocrinology,
Shaaban,
with
Contraception,
Jr
Raven
and
Norgestrel-Releasing
D.R.
HDL-Cholesterol
20.
D.N.
Treated
Biochemical
Contraception,
19. Holma,
Women
(X983).
Reproductive
18.
in
Robertson,
TCu-ZOO-IUD.
Mischell,
In:
S.,
Byre,
2,
Hjortland,
M.C.,
Density
Disease.
K.,
intervention
Kannel,
W-B.
as
a Protective
Lipoprotein Am J Med,
Holme. on
I. the
and
62,
and Factor
707-714.
Leren.
incidence
P.
(1981).
of
coronary
Effect heart
1303-1310.
1992 VOL. 45 NO. 2
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