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The effect of an oral contraceptive on serum lipoproteins and skinfold thickness in young women
CONTRACEPTION
THE
AN
ORAL
SKINFOLD
EFFECT
THICKNESS
IN
H.
der Steeg,
J.
OF
vm
Department The J.
C.
of
o,d
ON
SERUM
LIPOPROTEINS
AND
WOMEN*
Gynaecolog/,
(Head Prof.
Pronk,
institute The
YOUNG
M.D.
of Obstetrics
Netherlands
CONTRACEPTIVE
Dr.
A.
A.
Univzrsity
Hospital,
Utrecht,
Haspels)
M.Sc. Human
Netherlands
Biology,
State
(Hea,d Prof.
Dr.
University J.
Utrecht,
Utrecht,
Huizingo)
ABSTRACT The and 250 studied
effect
of CI six-month
rncg d-norgestrel in 26
2.
The
following
STgnificant No
significant
+ 6.8
4.
No
&cmges
5.
A shift
*.--
Thus study Hague,
of tota!
changes
in
lipids
and B-lipoproteins
in n-lipoproteins
bodyweight
the total mass from
!las been made possible Dr.
taken
was
hormonal
(H .D.L.)
(L.D.L.) and
(V.L.D.L.)
for publication
to Prof.
and skinfolds
previously
from
63.2
kg (mean + s.d.)
of fat
50 mcg ethinyloestradiol
lipoproteins
who had never
of the total
61.5
Accepted
The
lncreaje
containing
lipids,
revere noted:
increase
pre-B-lipoproteins 3.
serum
young nulligravidae,
contraceptives. I.
use of a pill
on total
J.
JULY 1977 VOL. 16 NO. 1
body fat
6.5
to
percentage
the extremities
April
t -
to the trunk.
4, 1977
by CI grant
from
the Praeventie
Fonds,
Huizinga.
29
CONTRACEPTION
INTRODUCTION It has long been recognized partially
that serum lipid
due to the increase
the introduction
effects
on lipid
metabolism.
summarized
extensively
metabolism
are supposed to be related
epidemiologic
studies
increase
receiving
by Alfin-Slater Vessey
on the effects
triglyceride
and Aftergocd (3,4)
containing
levels
Wynn
(11) found no relation
levels
and the nature
between
diseases
(6-16).
the magnitude
and secondly
Disturbances
diseases.
of lipid
In (5) found a
among women
agents on lipoproteins,
of the estrogen-progestagen
studied
has
has been
and lnman and Vessey
are conflicting
main reasons for this lack of correlation the preparations
(2).
is
Since
50 mcg or more estrogen.
of contraceptive
and cholesterol
This
(1).
much attention
The literature
to trombo-embolic
and Doll
pregnancy.
and progesterone
in death rate from thrombo-embolic
oral contraceptives
The reports
rise during
estrogen
of these compounds in oral contraceptives,
been drawn to their
significant
levels
of circulating
serum
Although
combinations,
are firstly
Door and
of change of serum triglyceride we feel
the different
that the
composition
the fact that the groups of patients
of
cannot
be compared. The precise
mechanism
behind
They seem to be related mestranol lipid
or ethinyloestradiol.
metabolism
Certain
steroid
(17,18,19),
partly
we studied
various
approximately body
half
chose this pill
fat,
skinfold
or antagonistic
to predict
rather
the effect
of any
of the lipoprotein
containing
status
50 mcg
on the serum concentration in use throughout
an indication
thicknesses
either
upon
of the
because at the time of the study
the oral contraceptives
(21). To obtain
effect
metabolism,
of an oral contraceptive
and 250 mcg d-norgestrel
lipoproteins.We
d-norgestrel
it is difficult lipid
unclear.
agent,
the changes due to the estrogens.
of fats in serum is a reflection
the effects
ehtinyloestradiol
on
remains
have an opposite
correcting
Therefore
combination
Because the concentration
metabolism
of the contraceptive
appear to act in a synergistic
manner (20).
estrogen-progestagen
content
The progestagens
combinations
than an additive
(16),
the changes in lipid
to the estrogen
of the possible
the world
effect
contained
on the amount of
were measured and correlations
with
weight
changes
were mode. MATERIAL The group consisted had never previously had normal
regular
known to affect All
aged 16-30
menses and for the length
I ipid metabolism.
the subjects
After
cycle(22).
measurement
in diet or activity. of the blood
kg (mean 60.2
in the fasting
kg).
Blood was
state before
starting
a half year use of the contraceptive
agent,
blood
We did not take into account the day
The blood was clotted
at 4’C
a few drops of merthiolate minutes at 3,000 r.p.m., which was stored at 4OC until analysis.
30
who
of the study took no other drugs
including
was drawn again under the same conditions. of the menstrual
years (mean 21 years),
They were al I in good health,
were no restrictions
ranged from 47.8-73.2
with
contraception.
There
examination
The body weight
taken by venipuncture hormonal
METHODS
taken an oral contraceptive.
women had a medical
pressure.
AND
of 26 nulligravidae,
and centrifuged
for 10
were added to the serum,
JULY 1977 VOL. 16 NO. I
CONTRACEPTION
Total
serum lipids
described
and lipoproteins
by Van Gent
(23).
fractions
had to be within
Skinfold
thickness
95-105%
at five
sites
supra-iliacal
Harpenden
Skinfold
and pora-umbilical The skinfolds
value.
a half
to Muller’s
method,
the sum of the lipoprotein
lipid
and after
according
Caliper.
by the ultracentrifugal
control
of the total
was measured before
in 22 individuals subscapular,
were estimated
As an internal
year hormonal
contraception
study (24) (bicipital,
skinfold)
with
tricipital,
the aid of the
of the left side of the body were
measured five
times in the some sequence by one investigator. Mean results and The amount of body fat expressed as percentage of deviations ore given.
standard
the body weight Womersley Each subject values.
was calculated
from four skinfolds,
as described
by Durnin
and
(25). in the pretreatment
Statistical
of the hormonal
state served as her own control
comparisons contraceptive
between
the results
were made with
before
for posttreatment
and after six month use
the Student’s
t-test
for paired
observations. As indicated performed analysis
by Durnin
and Rohaman (42) a logarithmic
on fat percentage
and para-umbilical
transformation
skinfold,
was
before statistical
was done. RESULTS
Table
I
shows the results
increased women.
during
The slight
increase
mg/lOO ml,
and lipoproteins
low density
which
lipoproteins
for the chylomicrons
(V. L. D. L.)
of the low density
was significant lipoproteins
Total
lipids
agent in all but six
(p C O,OOl),
Th e meon increase
change in the high density
analysis.
of the contraceptive
was significant
of the very
significant.
The low values
lipid
the administration
The meon increase
statistically was 53.1
of total
at the 0.1%
(H.D.L.)(a)
level.
d uring
were in agreement
(pre-B)
lipoproteins
There was no
the contraceptive
with
was not (L. D. L.)(B) therapy.
the fasting
state of
The bicipital
skinfold
the subjects. Table
II shows the mean values
decreased 2 mm which significant
change in the tricipital,
para-umbilical significant
of the skinfold
was statistically
skinfold
at the 0.1%
The mean percentage
however
thicknesses,
significant subscapular
increased
3.9
at the 1% level. and suprailiacal
mm which
There was no
skinfold.
The
was statistically
level. of body fat,
calculated
did not change significantly
(29.1
The m+ean total
increase
body weight
? 3.4%
from four skinfolds
to 29.1
was statistically
as stated earlier,
2 3.9). significant
(~(0.01)
from
60.2_6.5kg(meanfs.d.)to61.5?6.8kg.
JULY 1977 VOL. 16 NO. 1
31
CONTRACEPTION
Table
I. Total
lipids
and lipoproteins
month use of an oral contraceptive
in 26 nulligravidae containing
before and after
50 mcg ethinyloestradiol
six-
and
250 mcg d-norgestrel I N
Total
lipids
26
before
after $ year
Student’s
mean +_ s.d.
mean + s.d.
t-test
486.0
545.0
P< 0.001
+ 04.6
+ 64.5
mg/lOO ml chylomicrons
26
6.9+
8.02
3.9
4.4
n.s.
+ 24.4
n.s.
mg/lOO ml very low density lipoproteins
26
(pre-B)
54.7
62.0
+ 22.7
mg/lOO ml low density
(6)
26
(a)
26
lipoproteins
264.1
‘r55.0
317.2258.1
P
mg/lOO ml high density I ipoproteins
156.9;
27.0
155.8
-f 18.6
n.5.
mg/lOO ml Table
II.
Skinfold
contraceptive
Skinfold
thicknesses*
containing
thickness
N
in mm
I
bicipitalis
I
tricipitolis
32
use of an oral
and 250 mcg d-norgestrel
before
after 4 year
Student’s
mean 2 s.d
mean 2 s.d.
t-test
22
9.8f4.0
22
14.2T4.2
22
16.92
22
21.0f7.5
22
* These 22 individuals
before and after six-month
50 mcg ethinyloestradiol
1 19.827.4
7.8
+ 2.5
P
14.023.6
17.5
7.5
I
n.s.
+4.8
22.9z8.1
1 23.7z8.5
I
n.s.
1 P
were measured by one investigator.
JULY 1977 VOL. 16 NO. 1
CONTRACEPTION
DISCUSSION Although
most previous
investigators
studies
reported
elevated
levels
found no change in serum triglycerides
(7,9,12,14,22,29),
(15,26,27,28)
a few
during
hormonal
contraception. Although
the most constant
lipoproteins very
(16),
low density
significant
has been raised
in the low density
high cholesterol
content.
lipoproteins
These results
confirm
activity.
As early
triglycerides
as 1958 Furman
and phospholipids,
cholesterol with
more than triglyceride
levels,
although
the observations
counteracted An interesting during
finding
hormonal
Although
effect
i.e.
hormonal
et al. (21).
are protein-rich
(32,34,35)
estrogen
constancy
the small
(7,32,33). levels
by estrogen
in this study might be the androgenic
Despite
therapy,
by Durnin
of 1.3
kg is in agreement
study in 1971 (37) however because it also occurred
no indication
whether
the individual
weight
(25).
This
points
the report
of
suggested
in the
gain is the result
that the weight
in women receiving
gain was not
a placebo.
the body fat or the lean body mass mainly
There was
contributed
to
gain.
It seems unlikely
that such a weight
pharmacological mass.
action
in our study
of the agent,
gain,
which
is not caused by a
is the result
is the significant
increase
site and the decrease of the bicipital
does not contribute
to the predicted
at four sites are more representative important
with
there was no change in the percentage
and Womersley
Goldzieher’s
activity
studied.
this observation
pill-related,
it remains
lipoproteins
lipoprotein
may increase
of LeCocq et al. (36) that the weight -in lean body mass.
of an increase
skinfolds
could be
important
of the finding
Remarkable
also agree
and lipid-poor,
that high density
compound in the pill
of body fat as predicted
para-umbilical
upon the serum results
who showed that the
they carry may be clinically
The change in the mean body weight
skinfold
Our
of the high density
in women than in men,
for their
of the progestational
direction
(12),
decreased serum
contraception.
An explanation
Wynn
increased.
increase
androgenic
effect
dose of a synthetic
lipoproteins
which
higher
will
s
in the literature
are already
derivatives
because of their
of this study is the stability
the high density
It is suggested
of Osman
doses of norethisteronacetate.
contraception
amount of cholesterol which
and Wynn
of a single
by increasing
mostly
but a
have a
the findings
there was a varying
made by Stokes
hypertriglyceridemic
which
(32) showed that androgenics
these levels
in the
(30) and Beck (31) who stated,
levels,
while
low density
increase
triglycerides,
(L. D. L.)
Wynn -et al.(22), Bierman and Hazzard that oral contraceptives containing nortestosterone levels
of very
containing
et al.(13),
cholesterol
levels
not significant
(V. L. D. L. ), mainly
lipoproteins
increase
relatively
observation
in our study there was a slight,
to look at individual
JULY 1977 VOL. 16 NO. 1
total
of an increase
of the skinfold skinfold.
at the The pora-umbilical
body fat percentage.
of the percentage
skinfolds
in lean body
to recognize
Although
of body fat (25,38), a possible
shift.
33
CONTRACEPTION
In our study of
the fat
Finally, taken
we found
mass from
no increase
we can conclude, hormonal
density
This
hyperlipidemia
frequency
of
that
contraceptives
lipoproteins.
between
of
the percentage
the extremities
to the trunk
the main
before,
agrees
with
infarction
body
change
in
young
is the significant the continuing
and thrombo-embolic
myocordial
of
(as seen in
but an exchange
women who had never
increase reports
diseases,
in young
fat
pregnancy).
of
especially
women using
the
about
low
the relation
the higher
hormonal
contraceptives
(39,40,41). Therefore, effects lower
oral
contraceptives
of
are to be preferred. doses of estrogens
moment
the combined
Further
combined
we are carrying
out
studies
with
type with
should
nortestosterone
such a study
in our
minimal
hyperlipidemic
be made into
the effects
derivatives.
At
of
the
clinic.
ACKNOWLEDGEMENTS The
authors
wish
assistance, blood
Dr.
samples,
Gaubius
to thank
Mrs.
Dr.
Institute
stimulating
E.
Mrs.
Leny
Dufay
Brost-Eilers
C .M.
van
Mieke
and Mr.
H .A.
Gent
for Atherosclerosis
and Mrs.
and Miss at
Leiden
llja
Pronk
Moes
van
for
for
der Voort
are thanked
their
technical
collection
for
of
from
their
the
the
help
and
discussions. REFERENCES
1.
de Alvarez,
I .:
R.R.
Jahed
influence
The
Am.J.Obstet.Gynecol. 2.
Alfin-Slater, 705,
Spitalny,
contraceptive ll6:727,
R.B
K.J
,
steroids
Elkin,
H.
on serum
and
taunakais,
lipids.
1973.
and Aftergood,
L.:
Lipids
and the pill.
Lipids
6:693-
1972.
Vessey,
3.
F.M.,
of oral
and Doll,
M.P.
contraceptives
R.:
Investigation
diseases.
and thromboembolic
of relation Brit.
between
Med.
use of oral
11: 199-205,
J.
1968. Vessey,
4.
M. P.
and
contraceptives J. 5.
11~651,
age. Pincus,
6.
New
34
G
York
investigation
and Vessey,
and cerebral
Brit.
R.:
of
diseases.
relation
between
A further
use of oral
report.
Brit.
Med.
1969.
W.H.W.
Inman, coronary
Doll,
and thromboembolic
Med. (editor): and
M. P.:
thrombosis 11: 193-199,
J.
In The
London,
Investigation
and embolism
Control
of deaths
from
in women of child
pulmonary, bearing
1968. of
Fertility,
p.
277,
Academic
Press,
1965.
JULY
1977
VOL.
16 NO. I
CONTRACEPTION
7. Aurell,
M.,
longterm
Cramer,
The Lancet 8.
Brody,
I, 291,
S.,
and Rybo,
183:
l-7,
Hulse,
H., with
L.
on the different
Stand.
Gershberg, treatment
Nilsson,
J.,
inhibitors
Acta Med.
Serum
G.:
lipids
and lipoproteins
during
of an oral contraceptive.
1966.
Kerstell,
ovulation
9.
K.
administration
lipid
A.:
The effects
of some
fractions.
1968.
M.
estrogen
and Svanborg, plasma
and Javier,
2.:
Hyperglyceridemia
and oral contraceptives.
during
An alteration
of hepatic
function? Obstet.
and Gynec.
10. Wynn,
‘J.,
ceptives
Doar,
Doar,
II,
720,
J.W.H.
J.Clin.Path. Stokes,
Th.
13.
Osman,
14.
V.:
suppl.3,
and Wynn,
55-61,
V.:
Contraception
5: 105-l
Donde,
and Virkar,
Tankeyoon,
M.,
lipids
H.K.,
carbohydrate
Effect
K.:
U.:
Glueck,
C.J.,
18.
Larsson-Cohn, dose gestagen phospholipids.
JULY 1977
S.,
on serum lipids.
and Larsson-Cohn, and lipids
of oral contraceptives
Suppl.
Berlin,
116:
Buxton,
P.,
on lipids
U.:
in women using oral contraceptive.
on vitamins
and
on plasma 63,
1976. S.
and Fallat,
R.:
Effects
of a
and lipases.
689-693,
Endocrionologica:
16 NO. 1
54: 5-13,
R. and Vikrot,
oral contraceptives
VOL.
V.
and a combination-type
Steiner,
Gynecol.
Acta
steroids
1975.
metabolism. Stand.
U.,
F.K.:
1976.
oral contraceptive
Amer. J . Obstet.
and Guergis,
of contraceptive
serum transaminase
Some effects
Ford,
progestational
M.H.
Poshyachinda,
N.,
14: 199-215,
and lipid
in women on oral contraceptives.
Ghanem,
123: 736-742,
tolerance,
Acta Obstet.Gynec. 17.
oral contraceptive
on serum lipids.
depot-medroxyprogesterone-acetate
Larsson-Cohn,
during
1972.
Dusitsin,
A study of glucose
16.
levels
1969.
Serum
18,
Gynec.
Contraception
of oral contra-
1971.
Toppozado,
U. M.
Some effects
levels.
Serum lipid
of an oral contraceptive
Amer. J . Obstet. 15.
G.L.:
1966.
I, 677-681,
M. M.,
The effect
and Mills,
administration.
23,
The Lancet
1968.
and lipoprotein
and Wynn,
and glucocorticoid
12.
186-189,
J.W.H.
on serum lipid
The Lancet 11.
31:
1973. 0.:
Effects
of combined and low-
lipids;
including
717-735,
1970.
individual
35
CONTRACEPTION
19.
Beck, J.
20.
P.:
Alterations
of Ster.
Biochem.
Hood,
B. and Cramer,
in combination
21.
Acta Med.
Stand.
Wynn,
Adams,
V.,
Second Wynn,
V.,
therapy.
Muller,
25.
II,
Lipid
Durnin,
Uitg.
J .V. G.A.
density
cholesterol
of estrogen
and methyltestosterone.
M.:
Metabolic
plus 15Oug
G.L.
756-760,
47-54,
1974.
and Stokes, levels
investigations
d-norgestrel.
during
Th.:
Fasting
serum
oral contraceptive
1969.
composition fluids.
of lipoprotein
Ed.
by H.
fractions
Peeters,
in:
Pergamon
Press,
Oxford
1972.
Een orienterend
Leiden,
and Seed,
and lipoprotein
75-79,
H. K.:
Thesis
testosterone
Symposium,
Mills,
J.W.H.,
steroids.
1959. N.
Norgestrel
G.M.:
on serum lipoprotein
Oakley,
of the biological
and New York,
Effects
ethinyloestradiol
cholesterol
van Gent,
by contraceptive
1975.
459-466,
P.,
30wg
The Loncet
Protides
24.
165:
Doar,
metabolism
-4 androstendione,
International
triglyceride,
23.
K.:
withA
in women taking
22.
of lipid
6: 957-9.59,
Kok,
somatometrisch
Kampen,
onderzoek.
J .: Body fat assessed from total
and Womersley,
and its estimation
en densitometrisch
1972.
from skinfold
thickness:
measurements
body
on 481 men
and women aged from 16 to 72 years. Brit. 26.
Journal
Brody,
S.,
Hagdahl,
The effect
Lehnert,
Stand.
Klin. 28.
H.,
Schneider,
Kaffarnik,
Klin. 29.
oraler
H., R.
:
Svanborg,
on the lipid
A.
and Vikrot,
0.:
metabolism.
1966. Gassel,
W.D.,
and Kaffarnik,
49: 280-282,
Lehnert,
H.
Ztrfel,
:
P.,
Karsznio,
R.,
Plasmal ipide nach 12-24
1971.
H.,
Meyer-Bertenrath, der Plasmalipide
J.G.,
Zafel,
P. and
vor und nach 6-monatiger
mit Ovulationshemmern.
W. R.,
48: 439-441,
Spiger,
on the mechanism
36
L.,
Untersuchungen
Behandlung
contraceptives.
Nilsson,
Gabe von Ovulationshemmern.
Wochenschrift
Hazzard,
1974.
inhibitors
J.,
J. G.
Wochenschrift,
Karsznia, oraler
A.M., 179: 501,
Meyer-Bertenrath, monatiger
32: 77,
of some ovulation
Acta Med. 27.
of Nutrition
M. J.,
of increased
New.
Engl.J.of
1970. Bagdade,
J .D.
plasma triglyceride Med.
and Bierman, levels
280: 471-474,
E. L.:
Studies
induced by oral
1969.
JULY 1977 VOL. 16 NO. 1
CONTRACEPTION
30.
Bierman,
E. L. and Hazzard,
hormones
on lipid
34, 31.
suppl.
Beck.
141,
P.:
32.
69-72,
Furman,
steroids:
:
Metabolism
R.M.,
influence
Influence
of aging and gonadal steroid
The Scand.J.of
in man.
Clin.
and Lab.
invest.
1974.
Contraceptive
metabolism.
W.R.:
transport
Howard,
22,
modifications
841-855,
R.P.,
Norcia,
of androgens,
estrogens
of Med.:
80-97,
of carbohydrate
and lipid
1973. L. N.
and related
and Keaty, steroids
E.C.:
The
on serum lipids
and
lipoproteins.
33.
34.
Amer.
J.
Kuku,
S.B.
and Akinyanja,
lipoprotein
distribution
J.
Gynaec.
Obstet.
Rifkind,
B.M.:
Clinics 35.
Gustafson,
A.
J.
37.
Clin.
Br.
Amer.
J.
Goldzieher,
Fert. 38.
J.J.L., J.F.:
40.
T.V.
Mann,
Gonadal
steroid
effects
on plasma
1972.
and Goldzieher,
and chlormadinone 99: 374-381,
L. E.,
J .W.:
Metabolic
balance
acetate. 1974.
Averkin,
E.,
crossover
investigation
double blind
Post,
G.B.,
De betekenis
Scheel,
C.
and Taber,
B.Z.:
of the side effects
i onge
van Oosten-v.d.
120,
Vessey,
M.P.,
1363-1368,
practice.
Brit.
J.
J. I. and Inman,
myocardial
infarction.
G.J.C.
and
voor de schatting
van het
1976.
Thorogood,
in young women with Med.
Goes,
vrouwen.
Geneesk.
J. I.,
1971.
van lichaamsmaten
infarction
Mann,
1973.
35: 203-207,
22: 609-624,
vetpercen tage van
39.
in Nigerians.
1973.
to oral contraceptives.
de Wijn, Ned.
A.:
E. M.
Moses,
and Sterility
Pieters,
73: 750-754,
2: 3,
and Gynec.
J.W.,
and serum
therapy
phospholipids.
norethynodrel
A placebo-controlled
serum lipids
and hyperlipcproteinaemia.
and Metab.
Obstet.
attributed
Commonw.
and Svanborg,
Bradley,
F.R., with
Fasting
oral contraceptive
and Metab.
Endocr.
Lecocq,
P.A.:
and individual
studies
1958.
during
Lipoproteins
in Endocr.
lipoproteins
36.
24,
special
II: 241-245, W.H.W.:
Brit,
JULY 1977 VOL. 16 NO. I
Med.
and Doll,
R.:
Myocardial
to oral contraceptive
1975.
Oral J.
M.
reference
contraceptives
II: 245-248,
and death from
1975.
37
CONTRACEPTION
41.
Mann,
J. I.,
Inman,
W.H.W.
older women and fatal Brit. 42.
Med.
Durnin,
J.
II: 445447,
J .V.G.A.
and Thorogood,
myocardial
38
J.
of Nutrition
and Rahaman, 7: 21,
Oral
contraceptive
use in
1976. M.M.:
fat in the human body from measurements Brit.
M.:
infarction.
681,
The assessment of the amount of of skinfold
thickness.
1967.
JULY 1977 VOL. 16 NO. 1
THE
AN
ORAL
SKINFOLD
EFFECT
THICKNESS
IN
H.
der Steeg,
J.
OF
vm
Department The J.
C.
of
o,d
ON
SERUM
LIPOPROTEINS
AND
WOMEN*
Gynaecolog/,
(Head Prof.
Pronk,
institute The
YOUNG
M.D.
of Obstetrics
Netherlands
CONTRACEPTIVE
Dr.
A.
A.
Univzrsity
Hospital,
Utrecht,
Haspels)
M.Sc. Human
Netherlands
Biology,
State
(Hea,d Prof.
Dr.
University J.
Utrecht,
Utrecht,
Huizingo)
ABSTRACT The and 250 studied
effect
of CI six-month
rncg d-norgestrel in 26
2.
The
following
STgnificant No
significant
+ 6.8
4.
No
&cmges
5.
A shift
*.--
Thus study Hague,
of tota!
changes
in
lipids
and B-lipoproteins
in n-lipoproteins
bodyweight
the total mass from
!las been made possible Dr.
taken
was
hormonal
(H .D.L.)
(L.D.L.) and
(V.L.D.L.)
for publication
to Prof.
and skinfolds
previously
from
63.2
kg (mean + s.d.)
of fat
50 mcg ethinyloestradiol
lipoproteins
who had never
of the total
61.5
Accepted
The
lncreaje
containing
lipids,
revere noted:
increase
pre-B-lipoproteins 3.
serum
young nulligravidae,
contraceptives. I.
use of a pill
on total
J.
JULY 1977 VOL. 16 NO. 1
body fat
6.5
to
percentage
the extremities
April
t -
to the trunk.
4, 1977
by CI grant
from
the Praeventie
Fonds,
Huizinga.
29
CONTRACEPTION
INTRODUCTION It has long been recognized partially
that serum lipid
due to the increase
the introduction
effects
on lipid
metabolism.
summarized
extensively
metabolism
are supposed to be related
epidemiologic
studies
increase
receiving
by Alfin-Slater Vessey
on the effects
triglyceride
and Aftergocd (3,4)
containing
levels
Wynn
(11) found no relation
levels
and the nature
between
diseases
(6-16).
the magnitude
and secondly
Disturbances
diseases.
of lipid
In (5) found a
among women
agents on lipoproteins,
of the estrogen-progestagen
studied
has
has been
and lnman and Vessey
are conflicting
main reasons for this lack of correlation the preparations
(2).
is
Since
50 mcg or more estrogen.
of contraceptive
and cholesterol
This
(1).
much attention
The literature
to trombo-embolic
and Doll
pregnancy.
and progesterone
in death rate from thrombo-embolic
oral contraceptives
The reports
rise during
estrogen
of these compounds in oral contraceptives,
been drawn to their
significant
levels
of circulating
serum
Although
combinations,
are firstly
Door and
of change of serum triglyceride we feel
the different
that the
composition
the fact that the groups of patients
of
cannot
be compared. The precise
mechanism
behind
They seem to be related mestranol lipid
or ethinyloestradiol.
metabolism
Certain
steroid
(17,18,19),
partly
we studied
various
approximately body
half
chose this pill
fat,
skinfold
or antagonistic
to predict
rather
the effect
of any
of the lipoprotein
containing
status
50 mcg
on the serum concentration in use throughout
an indication
thicknesses
either
upon
of the
because at the time of the study
the oral contraceptives
(21). To obtain
effect
metabolism,
of an oral contraceptive
and 250 mcg d-norgestrel
lipoproteins.We
d-norgestrel
it is difficult lipid
unclear.
agent,
the changes due to the estrogens.
of fats in serum is a reflection
the effects
ehtinyloestradiol
on
remains
have an opposite
correcting
Therefore
combination
Because the concentration
metabolism
of the contraceptive
appear to act in a synergistic
manner (20).
estrogen-progestagen
content
The progestagens
combinations
than an additive
(16),
the changes in lipid
to the estrogen
of the possible
the world
effect
contained
on the amount of
were measured and correlations
with
weight
changes
were mode. MATERIAL The group consisted had never previously had normal
regular
known to affect All
aged 16-30
menses and for the length
I ipid metabolism.
the subjects
After
cycle(22).
measurement
in diet or activity. of the blood
kg (mean 60.2
in the fasting
kg).
Blood was
state before
starting
a half year use of the contraceptive
agent,
blood
We did not take into account the day
The blood was clotted
at 4’C
a few drops of merthiolate minutes at 3,000 r.p.m., which was stored at 4OC until analysis.
30
who
of the study took no other drugs
including
was drawn again under the same conditions. of the menstrual
years (mean 21 years),
They were al I in good health,
were no restrictions
ranged from 47.8-73.2
with
contraception.
There
examination
The body weight
taken by venipuncture hormonal
METHODS
taken an oral contraceptive.
women had a medical
pressure.
AND
of 26 nulligravidae,
and centrifuged
for 10
were added to the serum,
JULY 1977 VOL. 16 NO. I
CONTRACEPTION
Total
serum lipids
described
and lipoproteins
by Van Gent
(23).
fractions
had to be within
Skinfold
thickness
95-105%
at five
sites
supra-iliacal
Harpenden
Skinfold
and pora-umbilical The skinfolds
value.
a half
to Muller’s
method,
the sum of the lipoprotein
lipid
and after
according
Caliper.
by the ultracentrifugal
control
of the total
was measured before
in 22 individuals subscapular,
were estimated
As an internal
year hormonal
contraception
study (24) (bicipital,
skinfold)
with
tricipital,
the aid of the
of the left side of the body were
measured five
times in the some sequence by one investigator. Mean results and The amount of body fat expressed as percentage of deviations ore given.
standard
the body weight Womersley Each subject values.
was calculated
from four skinfolds,
as described
by Durnin
and
(25). in the pretreatment
Statistical
of the hormonal
state served as her own control
comparisons contraceptive
between
the results
were made with
before
for posttreatment
and after six month use
the Student’s
t-test
for paired
observations. As indicated performed analysis
by Durnin
and Rohaman (42) a logarithmic
on fat percentage
and para-umbilical
transformation
skinfold,
was
before statistical
was done. RESULTS
Table
I
shows the results
increased women.
during
The slight
increase
mg/lOO ml,
and lipoproteins
low density
which
lipoproteins
for the chylomicrons
(V. L. D. L.)
of the low density
was significant lipoproteins
Total
lipids
agent in all but six
(p C O,OOl),
Th e meon increase
change in the high density
analysis.
of the contraceptive
was significant
of the very
significant.
The low values
lipid
the administration
The meon increase
statistically was 53.1
of total
at the 0.1%
(H.D.L.)(a)
level.
d uring
were in agreement
(pre-B)
lipoproteins
There was no
the contraceptive
with
was not (L. D. L.)(B) therapy.
the fasting
state of
The bicipital
skinfold
the subjects. Table
II shows the mean values
decreased 2 mm which significant
change in the tricipital,
para-umbilical significant
of the skinfold
was statistically
skinfold
at the 0.1%
The mean percentage
however
thicknesses,
significant subscapular
increased
3.9
at the 1% level. and suprailiacal
mm which
There was no
skinfold.
The
was statistically
level. of body fat,
calculated
did not change significantly
(29.1
The m+ean total
increase
body weight
? 3.4%
from four skinfolds
to 29.1
was statistically
as stated earlier,
2 3.9). significant
(~(0.01)
from
60.2_6.5kg(meanfs.d.)to61.5?6.8kg.
JULY 1977 VOL. 16 NO. 1
31
CONTRACEPTION
Table
I. Total
lipids
and lipoproteins
month use of an oral contraceptive
in 26 nulligravidae containing
before and after
50 mcg ethinyloestradiol
six-
and
250 mcg d-norgestrel I N
Total
lipids
26
before
after $ year
Student’s
mean +_ s.d.
mean + s.d.
t-test
486.0
545.0
P< 0.001
+ 04.6
+ 64.5
mg/lOO ml chylomicrons
26
6.9+
8.02
3.9
4.4
n.s.
+ 24.4
n.s.
mg/lOO ml very low density lipoproteins
26
(pre-B)
54.7
62.0
+ 22.7
mg/lOO ml low density
(6)
26
(a)
26
lipoproteins
264.1
‘r55.0
317.2258.1
P
mg/lOO ml high density I ipoproteins
156.9;
27.0
155.8
-f 18.6
n.5.
mg/lOO ml Table
II.
Skinfold
contraceptive
Skinfold
thicknesses*
containing
thickness
N
in mm
I
bicipitalis
I
tricipitolis
32
use of an oral
and 250 mcg d-norgestrel
before
after 4 year
Student’s
mean 2 s.d
mean 2 s.d.
t-test
22
9.8f4.0
22
14.2T4.2
22
16.92
22
21.0f7.5
22
* These 22 individuals
before and after six-month
50 mcg ethinyloestradiol
1 19.827.4
7.8
+ 2.5
P
14.023.6
17.5
7.5
I
n.s.
+4.8
22.9z8.1
1 23.7z8.5
I
n.s.
1 P
were measured by one investigator.
JULY 1977 VOL. 16 NO. 1
CONTRACEPTION
DISCUSSION Although
most previous
investigators
studies
reported
elevated
levels
found no change in serum triglycerides
(7,9,12,14,22,29),
(15,26,27,28)
a few
during
hormonal
contraception. Although
the most constant
lipoproteins very
(16),
low density
significant
has been raised
in the low density
high cholesterol
content.
lipoproteins
These results
confirm
activity.
As early
triglycerides
as 1958 Furman
and phospholipids,
cholesterol with
more than triglyceride
levels,
although
the observations
counteracted An interesting during
finding
hormonal
Although
effect
i.e.
hormonal
et al. (21).
are protein-rich
(32,34,35)
estrogen
constancy
the small
(7,32,33). levels
by estrogen
in this study might be the androgenic
Despite
therapy,
by Durnin
of 1.3
kg is in agreement
study in 1971 (37) however because it also occurred
no indication
whether
the individual
weight
(25).
This
points
the report
of
suggested
in the
gain is the result
that the weight
in women receiving
gain was not
a placebo.
the body fat or the lean body mass mainly
There was
contributed
to
gain.
It seems unlikely
that such a weight
pharmacological mass.
action
in our study
of the agent,
gain,
which
is not caused by a
is the result
is the significant
increase
site and the decrease of the bicipital
does not contribute
to the predicted
at four sites are more representative important
with
there was no change in the percentage
and Womersley
Goldzieher’s
activity
studied.
this observation
pill-related,
it remains
lipoproteins
lipoprotein
may increase
of LeCocq et al. (36) that the weight -in lean body mass.
of an increase
skinfolds
could be
important
of the finding
Remarkable
also agree
and lipid-poor,
that high density
compound in the pill
of body fat as predicted
para-umbilical
upon the serum results
who showed that the
they carry may be clinically
The change in the mean body weight
skinfold
Our
of the high density
in women than in men,
for their
of the progestational
direction
(12),
decreased serum
contraception.
An explanation
Wynn
increased.
increase
androgenic
effect
dose of a synthetic
lipoproteins
which
higher
will
s
in the literature
are already
derivatives
because of their
of this study is the stability
the high density
It is suggested
of Osman
doses of norethisteronacetate.
contraception
amount of cholesterol which
and Wynn
of a single
by increasing
mostly
but a
have a
the findings
there was a varying
made by Stokes
hypertriglyceridemic
which
(32) showed that androgenics
these levels
in the
(30) and Beck (31) who stated,
levels,
while
low density
increase
triglycerides,
(L. D. L.)
Wynn -et al.(22), Bierman and Hazzard that oral contraceptives containing nortestosterone levels
of very
containing
et al.(13),
cholesterol
levels
not significant
(V. L. D. L. ), mainly
lipoproteins
increase
relatively
observation
in our study there was a slight,
to look at individual
JULY 1977 VOL. 16 NO. 1
total
of an increase
of the skinfold skinfold.
at the The pora-umbilical
body fat percentage.
of the percentage
skinfolds
in lean body
to recognize
Although
of body fat (25,38), a possible
shift.
33
CONTRACEPTION
In our study of
the fat
Finally, taken
we found
mass from
no increase
we can conclude, hormonal
density
This
hyperlipidemia
frequency
of
that
contraceptives
lipoproteins.
between
of
the percentage
the extremities
to the trunk
the main
before,
agrees
with
infarction
body
change
in
young
is the significant the continuing
and thrombo-embolic
myocordial
of
(as seen in
but an exchange
women who had never
increase reports
diseases,
in young
fat
pregnancy).
of
especially
women using
the
about
low
the relation
the higher
hormonal
contraceptives
(39,40,41). Therefore, effects lower
oral
contraceptives
of
are to be preferred. doses of estrogens
moment
the combined
Further
combined
we are carrying
out
studies
with
type with
should
nortestosterone
such a study
in our
minimal
hyperlipidemic
be made into
the effects
derivatives.
At
of
the
clinic.
ACKNOWLEDGEMENTS The
authors
wish
assistance, blood
Dr.
samples,
Gaubius
to thank
Mrs.
Dr.
Institute
stimulating
E.
Mrs.
Leny
Dufay
Brost-Eilers
C .M.
van
Mieke
and Mr.
H .A.
Gent
for Atherosclerosis
and Mrs.
and Miss at
Leiden
llja
Pronk
Moes
van
for
for
der Voort
are thanked
their
technical
collection
for
of
from
their
the
the
help
and
discussions. REFERENCES
1.
de Alvarez,
I .:
R.R.
Jahed
influence
The
Am.J.Obstet.Gynecol. 2.
Alfin-Slater, 705,
Spitalny,
contraceptive ll6:727,
R.B
K.J
,
steroids
Elkin,
H.
on serum
and
taunakais,
lipids.
1973.
and Aftergood,
L.:
Lipids
and the pill.
Lipids
6:693-
1972.
Vessey,
3.
F.M.,
of oral
and Doll,
M.P.
contraceptives
R.:
Investigation
diseases.
and thromboembolic
of relation Brit.
between
Med.
use of oral
11: 199-205,
J.
1968. Vessey,
4.
M. P.
and
contraceptives J. 5.
11~651,
age. Pincus,
6.
New
34
G
York
investigation
and Vessey,
and cerebral
Brit.
R.:
of
diseases.
relation
between
A further
use of oral
report.
Brit.
Med.
1969.
W.H.W.
Inman, coronary
Doll,
and thromboembolic
Med. (editor): and
M. P.:
thrombosis 11: 193-199,
J.
In The
London,
Investigation
and embolism
Control
of deaths
from
in women of child
pulmonary, bearing
1968. of
Fertility,
p.
277,
Academic
Press,
1965.
JULY
1977
VOL.
16 NO. I
CONTRACEPTION
7. Aurell,
M.,
longterm
Cramer,
The Lancet 8.
Brody,
I, 291,
S.,
and Rybo,
183:
l-7,
Hulse,
H., with
L.
on the different
Stand.
Gershberg, treatment
Nilsson,
J.,
inhibitors
Acta Med.
Serum
G.:
lipids
and lipoproteins
during
of an oral contraceptive.
1966.
Kerstell,
ovulation
9.
K.
administration
lipid
A.:
The effects
of some
fractions.
1968.
M.
estrogen
and Svanborg, plasma
and Javier,
2.:
Hyperglyceridemia
and oral contraceptives.
during
An alteration
of hepatic
function? Obstet.
and Gynec.
10. Wynn,
‘J.,
ceptives
Doar,
Doar,
II,
720,
J.W.H.
J.Clin.Path. Stokes,
Th.
13.
Osman,
14.
V.:
suppl.3,
and Wynn,
55-61,
V.:
Contraception
5: 105-l
Donde,
and Virkar,
Tankeyoon,
M.,
lipids
H.K.,
carbohydrate
Effect
K.:
U.:
Glueck,
C.J.,
18.
Larsson-Cohn, dose gestagen phospholipids.
JULY 1977
S.,
on serum lipids.
and Larsson-Cohn, and lipids
of oral contraceptives
Suppl.
Berlin,
116:
Buxton,
P.,
on lipids
U.:
in women using oral contraceptive.
on vitamins
and
on plasma 63,
1976. S.
and Fallat,
R.:
Effects
of a
and lipases.
689-693,
Endocrionologica:
16 NO. 1
54: 5-13,
R. and Vikrot,
oral contraceptives
VOL.
V.
and a combination-type
Steiner,
Gynecol.
Acta
steroids
1975.
metabolism. Stand.
U.,
F.K.:
1976.
oral contraceptive
Amer. J . Obstet.
and Guergis,
of contraceptive
serum transaminase
Some effects
Ford,
progestational
M.H.
Poshyachinda,
N.,
14: 199-215,
and lipid
in women on oral contraceptives.
Ghanem,
123: 736-742,
tolerance,
Acta Obstet.Gynec. 17.
oral contraceptive
on serum lipids.
depot-medroxyprogesterone-acetate
Larsson-Cohn,
during
1972.
Dusitsin,
A study of glucose
16.
levels
1969.
Serum
18,
Gynec.
Contraception
of oral contra-
1971.
Toppozado,
U. M.
Some effects
levels.
Serum lipid
of an oral contraceptive
Amer. J . Obstet. 15.
G.L.:
1966.
I, 677-681,
M. M.,
The effect
and Mills,
administration.
23,
The Lancet
1968.
and lipoprotein
and Wynn,
and glucocorticoid
12.
186-189,
J.W.H.
on serum lipid
The Lancet 11.
31:
1973. 0.:
Effects
of combined and low-
lipids;
including
717-735,
1970.
individual
35
CONTRACEPTION
19.
Beck, J.
20.
P.:
Alterations
of Ster.
Biochem.
Hood,
B. and Cramer,
in combination
21.
Acta Med.
Stand.
Wynn,
Adams,
V.,
Second Wynn,
V.,
therapy.
Muller,
25.
II,
Lipid
Durnin,
Uitg.
J .V. G.A.
density
cholesterol
of estrogen
and methyltestosterone.
M.:
Metabolic
plus 15Oug
G.L.
756-760,
47-54,
1974.
and Stokes, levels
investigations
d-norgestrel.
during
Th.:
Fasting
serum
oral contraceptive
1969.
composition fluids.
of lipoprotein
Ed.
by H.
fractions
Peeters,
in:
Pergamon
Press,
Oxford
1972.
Een orienterend
Leiden,
and Seed,
and lipoprotein
75-79,
H. K.:
Thesis
testosterone
Symposium,
Mills,
J.W.H.,
steroids.
1959. N.
Norgestrel
G.M.:
on serum lipoprotein
Oakley,
of the biological
and New York,
Effects
ethinyloestradiol
cholesterol
van Gent,
by contraceptive
1975.
459-466,
P.,
30wg
The Loncet
Protides
24.
165:
Doar,
metabolism
-4 androstendione,
International
triglyceride,
23.
K.:
withA
in women taking
22.
of lipid
6: 957-9.59,
Kok,
somatometrisch
Kampen,
onderzoek.
J .: Body fat assessed from total
and Womersley,
and its estimation
en densitometrisch
1972.
from skinfold
thickness:
measurements
body
on 481 men
and women aged from 16 to 72 years. Brit. 26.
Journal
Brody,
S.,
Hagdahl,
The effect
Lehnert,
Stand.
Klin. 28.
H.,
Schneider,
Kaffarnik,
Klin. 29.
oraler
H., R.
:
Svanborg,
on the lipid
A.
and Vikrot,
0.:
metabolism.
1966. Gassel,
W.D.,
and Kaffarnik,
49: 280-282,
Lehnert,
H.
Ztrfel,
:
P.,
Karsznio,
R.,
Plasmal ipide nach 12-24
1971.
H.,
Meyer-Bertenrath, der Plasmalipide
J.G.,
Zafel,
P. and
vor und nach 6-monatiger
mit Ovulationshemmern.
W. R.,
48: 439-441,
Spiger,
on the mechanism
36
L.,
Untersuchungen
Behandlung
contraceptives.
Nilsson,
Gabe von Ovulationshemmern.
Wochenschrift
Hazzard,
1974.
inhibitors
J.,
J. G.
Wochenschrift,
Karsznia, oraler
A.M., 179: 501,
Meyer-Bertenrath, monatiger
32: 77,
of some ovulation
Acta Med. 27.
of Nutrition
M. J.,
of increased
New.
Engl.J.of
1970. Bagdade,
J .D.
plasma triglyceride Med.
and Bierman, levels
280: 471-474,
E. L.:
Studies
induced by oral
1969.
JULY 1977 VOL. 16 NO. 1
CONTRACEPTION
30.
Bierman,
E. L. and Hazzard,
hormones
on lipid
34, 31.
suppl.
Beck.
141,
P.:
32.
69-72,
Furman,
steroids:
:
Metabolism
R.M.,
influence
Influence
of aging and gonadal steroid
The Scand.J.of
in man.
Clin.
and Lab.
invest.
1974.
Contraceptive
metabolism.
W.R.:
transport
Howard,
22,
modifications
841-855,
R.P.,
Norcia,
of androgens,
estrogens
of Med.:
80-97,
of carbohydrate
and lipid
1973. L. N.
and related
and Keaty, steroids
E.C.:
The
on serum lipids
and
lipoproteins.
33.
34.
Amer.
J.
Kuku,
S.B.
and Akinyanja,
lipoprotein
distribution
J.
Gynaec.
Obstet.
Rifkind,
B.M.:
Clinics 35.
Gustafson,
A.
J.
37.
Clin.
Br.
Amer.
J.
Goldzieher,
Fert. 38.
J.J.L., J.F.:
40.
T.V.
Mann,
Gonadal
steroid
effects
on plasma
1972.
and Goldzieher,
and chlormadinone 99: 374-381,
L. E.,
J .W.:
Metabolic
balance
acetate. 1974.
Averkin,
E.,
crossover
investigation
double blind
Post,
G.B.,
De betekenis
Scheel,
C.
and Taber,
B.Z.:
of the side effects
i onge
van Oosten-v.d.
120,
Vessey,
M.P.,
1363-1368,
practice.
Brit.
J.
J. I. and Inman,
myocardial
infarction.
G.J.C.
and
voor de schatting
van het
1976.
Thorogood,
in young women with Med.
Goes,
vrouwen.
Geneesk.
J. I.,
1971.
van lichaamsmaten
infarction
Mann,
1973.
35: 203-207,
22: 609-624,
vetpercen tage van
39.
in Nigerians.
1973.
to oral contraceptives.
de Wijn, Ned.
A.:
E. M.
Moses,
and Sterility
Pieters,
73: 750-754,
2: 3,
and Gynec.
J.W.,
and serum
therapy
phospholipids.
norethynodrel
A placebo-controlled
serum lipids
and hyperlipcproteinaemia.
and Metab.
Obstet.
attributed
Commonw.
and Svanborg,
Bradley,
F.R., with
Fasting
oral contraceptive
and Metab.
Endocr.
Lecocq,
P.A.:
and individual
studies
1958.
during
Lipoproteins
in Endocr.
lipoproteins
36.
24,
special
II: 241-245, W.H.W.:
Brit,
JULY 1977 VOL. 16 NO. I
Med.
and Doll,
R.:
Myocardial
to oral contraceptive
1975.
Oral J.
M.
reference
contraceptives
II: 245-248,
and death from
1975.
37
CONTRACEPTION
41.
Mann,
J. I.,
Inman,
W.H.W.
older women and fatal Brit. 42.
Med.
Durnin,
J.
II: 445447,
J .V.G.A.
and Thorogood,
myocardial
38
J.
of Nutrition
and Rahaman, 7: 21,
Oral
contraceptive
use in
1976. M.M.:
fat in the human body from measurements Brit.
M.:
infarction.
681,
The assessment of the amount of of skinfold
thickness.
1967.
JULY 1977 VOL. 16 NO. 1