Klin Wochenschr(1982) 60:153 157
Wochen-
The Influence of Oral Contraceptives on the Composition of Bile*
P. Brockerhoff 1, M. H6ckel, K.H. Holtermfiller, M. K6hl, H.J. Weis2~ and G.H. Rathgen
1 Frauenklinik undi. Medizinische Klinik und Poliklinik der Johannes Gutenberg-Universit/it, Mainz
z II. Medizinische Klinik des Allg. Stadtkrankenhauses, Bamberg
Summary. The increased risk of cholelithiasis during
intake of oral contraceptives may be due to estrogen-
induced saturation of the bile with cholesterol. In
a randomized, prospective, crossed-over double-blind
study 20 healthy women after roentgenological exclu-
sion of gall-stones received either 1.0 mg of norethin-
drone acetate and 50 lag ethinyl estradiol daily - as
usual in oral contraception - for 21 days with 7 days
of placebo treatment in each cycle or one fifth of
this hormone dose in form of a continuous daily medi-
cation. After a 4 month's treatment the medication
form was crossed-over. At the beginning of the study,
before the cross-over and after the study bile was
collected by duodenal intubation after a 12-h fast
and the lithogenic index as a measure for cholesterol
saturation of the bile was determined. N o correlation
between the dose and the lithogenic index was demon-
strated, neither in 15 women, who had used oral con-
traceptives before the study nor in five women with-
out any previous hormonal contraception.
Key words: Oral contraception - Cholelithiasis -
Lithogenic index Bile composition
Der Einflu6 oraler Kontrazeptiva auf die Zusammen-
setzung der Gallenfliissigkeit
Zusammenfassung. Das erh6hte Risiko hinsichtlich
der Gallensteinbildung bei der Einnahme oraler Kon-
trazeptiva beruht m6glicherweise auf einer 6strogen-
bedingten Zunahme der Cholesterinsfittigung der Gal-
lenflfissigkeit. In einer prospektiven, gekreuzten Dop-
pelblindstudie erhielten 20 gesunde Frauen nach r6nt-
genologischem Ausschlul3 yon Gallensteinen random-
isiert entweder wie bei der routinemfil3igen oralen
Kontrazeption tiblich zyklisch fiber 21 Tage 1,0 mg
* This work was in part supported by grants of the Deutsche
Forschungsgemeinschaft
** Dedicated to Prof. Dr. V. Friedberg, Mainz, on the occasion
of his 60th birthday
Offprint requests to: Dr. P. Brockerhoff(address see page I57)
Klinische
schrift
(~') Springer-Verlag 1982
**
Norethindronazetat und 50 lag )kthinyl6stradiol trig-
lich mit anschliel3ender 7tfigiger Placebogabe oder
aber ein Ffinftel dieser Hormondosis als tfigliche kon-
tinuierliche Medikation. Nach jeweils 4monatiger
Behandlungsdauer erfolgte der {)bergang auf die an-
dere Medikationsform. Zu Beginn der Studie sowie
vor dem {Jbergang auf die andere Medikationsform
und nach AbschluB der Studie wurde nach 12sttin-
diger Nahrungskarenz mittels einer Duodenalsonde
Gallenfltissigkeit gewonnen und der lithogene Index
als Mal3 fiir die CholesterinsS.ttigung der Gallenfliis-
sigkeit bestimmt. Eine AbhS.ngigkeit des lithogenen
Index v o n d e r Dosis der applizierten H o r m o n e liel3
sich weder bei 15 Frauen, die bereits vor der Studie
orale Kontrazeptiva eingenommen batten, noch bei
ffinf Frauen ohne vorherige hormonale Kontrazep-
tion nachweisen.
Schliisselw6rter: Orale Kontrazeption - Cholelithiasis
Lithogener Index Zusammensetzung der Gallen-
flfissigkeit
Introduction
The incidence of cholelithiasis in the Western indus-
trialized countries has been reported to be between
10 and 20% so that cholecystectomy has become the
most frequent operation. The risk of suffering from
cholelithiasis is about twice as high in women as in
men. Particularly in those countries in which the
number of gall-bladder operations has increased with
increasing affluence, oral contraceptives are also used
on a wide scale. Direct or indirect relations between
steroid hormones and changes of the composition
of bile have been discussed in various publications
(Nilson 1966; Lynn etal. 1973; Javitt etal. 1975;
Davies and Kern 1976; Schwarz et al. 1977).
In 1973 the Boston Surveillance Group reported
for the first time that women taking hormonal contra-
ceptives suffer from gallstones twice as frequently as
154 P. Brockerhoff et al. : Oral Contraceptives and Bile Composition

u n t r e a t e d w o m e n . T h e o b s e r v a t i o n o f B e n n i o n et al. Table 1. Clinical observations in 153 medication cycles on compar-

(19761) w h o f o u n d a n i n c r e a s e in c h o l e s t e r o l s a t u r a t i o n ision of two differently dosaged oral contraceptives. Before the
start of the study the systolic blood pressure was 125 + 2.1 mm Hg,
o f bile in w o m e n t a k i n g o r a l c o n t r a c e p t i v e s p r o v i d e d
the diastolic blood pressure was 82 + 1.4 mm Hg and the body
t h e e x p e r i m e n t a l e x p l a n a t i o n f o r t h e clinical f i n d i n g . weight was 61.4_+ 1.8 kg (x_+sx)
H y p e r s a t u r a t i o n o f bile c a u s e s a n i n c r e a s e d r i s k f o r
the f o r m a t i o n of cholesterol gall-stones. 1 mg NA 0.2mgNA
+ +
A c c o r d i n g to K e r n (1978) t h e f o l l o w i n g m e c h a -
50 btg EE 10 lag EE
n i s m s c a n l e a d t o p r o d u c t i o n o f b i l e w h i c h is h y p e r s a -
turated with cholesterol: Observed cycles 76 77
1. I n c r e a s e d c h o l e s t e r o l s e c r e t i o n
Cycles with weight gain 3.0-1.5 kg 3 4
2. R e d u c e d bile a c i d s y n t h e s i s a n d s e c r e t i o n 1.4-0.5 kg 7 4
3. R e d u c e d l e c i t h i n s e c r e t i o n Cycles with weight loss 0.5 1.4 kg 2 3
4. S e l e c t i v e a b s o r p t i o n o f bile a c i d s a n d / o r l e c i t h i n 1.5-3.0 kg 9 3
Cycles without weight 17 17
in t h e g a l l - b l a d d e r
change
5. D i s t u r b e d e v a c u a t i o n o f g a l l - b l a d d e r Body weight in kg (2+sx) 61.2-- 1.7 60.7+1.7
The p u r p o s e o f the p r e s e n t s t u d y was to e x a m i n e
Blood pressure in mm Hg (R-+sx)
the hypothesis that low dose hormonal contraceptives systolic 124_+2.2 121 +2.0
r e d u c e t h e r i s k o f c h o l e s t e r o l h y p e r s a t u r a t i o n o f bile. diastolic 80 + 1.4 79 _+1.1
A d e c r e a s e in c h o l e s t e r o l s a t u r a t i o n w o u l d d i m i n i s h Average duration of menstruation in
t h e p o t e n t i a l risk o f c h o l e l i t h i a s i s in w o m e n t a k i n g days per cycle 5.8 6.1
oral contraceptives.
The differences are not statistically significant (p > 0.05)
(NA = norethindrone acetate ; EE - ethinyl estradiol
M a t e r i a l and M e t h o d s
Twenty healthy women, aged 24.4_+3.3 years, of normal body
Table 2. Incidence of subjective symptoms (%) in 19 test subjects
weight and with regular menstrual periods agreed to participate
in the double-blind study on 16 weeks intake of two differently
in a prospective double blind study. The patients were allocated
dosaged oral contraceptives
in two groups each consisting of ten women in randomized se-
quence. One group received a daily oral dose of 0.2 mg of norethin-
1 mgNA+ 0.2mgNA+
drone acetate and 10 lag of ethinyl estradiol continuously. The
50 lag EE 10 I-tg EE
other received 1 mg of norethindrone acetate and 50 lag of ethinyl
estradiol over 21 days with subsequent administration of a placebo
over 7 days 1. After 16 weeks the medication was crossed over increase in vaginal discharge 4.0 2.6
from the lower dosage to the higher dosage or vice versa. Headache 1.3 6.5
Cholelithiasis was excluded before the start of the study in Increase in libido 1.3 0
all patients by an oral cholecystogram. The test subjects underwent Mastodynia 2.6 0
medical examination including a gynaecological status before the Nausea 1.3 0
start of the study and after medication over 16 and 32 weeks. Vomiting 1.3 1.3
Fasting bile was obtained before the start of the study and Hyopogastric pain 0 3.9
again after each cycle of four treatments. For this purpose a radio- Backache 0 1.3
opaque duodenal tube was introduced in each patient after anaes-
thesia of the pharynx. The position of the orifice of the tube NA-norethindrone acetate; EE--ethinyl estradiol
in the descending portion of the duodenum was checked fluoro-
scopically. After intravenous administration of cholecystokinin (75
units). (Karolinska institute, Stockholm) a gall-bladder contraction
Lipoprotein electrophoresis was performed and haematologi-
in all women resulted. The first 5 10 ml of secretion were dis-
cal parameters were determined (leucocyte count, eryhtrocyte
carded: the next 20 ml of clear, dark bile were drained into a
closable container. Cholesterol was determined by the method of count, haemoglobin concentration, haematocrit, MCHC, MCV).
All methods of determination were checked continuously by exter-
Sperry and Webb (1950) using 3H-cholesterol as an internal stan-
nal and internal quality controls. The statistical analysis was carried
dard. Bile acids and phospholipids were determined by the methods
out using the t-test and the analysis of variance including Scheff~'s
of Talalay (1960) and Zilversmit and Davies (19501) respectively.
test by the formation of orthogonal contrasts. With the exception
The lithogenic index of the bile was derived from the ratio
of cholesterol to bile acids and lecithin as a measure for the ten- of Table 4 the reported results summarize the cycles with lower
dency of bile to lithiasis in accordance with Carey and Small (1968). and higher dosage.
Venous blood was obtained before the intravenous administra-
tion of cholecystokinin. The concentration of total lipids, triglycer-
Results
ides, cholesterol and glucose and the activities of GOT, GPT and
gamma-GT were determined in the serum by enzymatic or colori- N i n e t e e n o f t h e 20 t e s t s u b j e c t s w e r e o b s e r v e d o v e r
metric tests 2.
t h e t o t a l s t u d y p e r i o d o f 32 w e e k s . O n e w o m a n
1 Supplied by Parke, Davis and Comp., Munich d r o p p e d o u t a l r e a d y in t h e 2 n d w e e k o w i n g t o p e r s o n -
2 Test sets: Boehringer Comp., Mannheim al r e a s o n s . N o p r e g n a n c i e s o c c u r e d t h e p e r i o d o f t h e
P. Brockerhoff et al. : Oral Contraceptives and Bile Composition 155

Table 3. Enzyme activities, lipid levels and haematological parame- Table 5. Lithogenic index in the bile in five women without any
ters in 19 test subjects in the double-blind study before and during previous intake of oral contraceptives before and during intake
intake of two differently dosaged oral contraceptives of two different dosaged contraceptives. In 14 women, who had
used oral contraceptives before, the prestudy lithogenic index was
Before start l mg N A + 0.2mgNA+ 1, 11 +0.36 (X±Sx)
of the study 50 g g E E 101.tgEE
mean standard
SGPT (mU/ml) 6.6 _+0.5 7.1 _+0.4 6.8 _+0.6 value (x) deviation (sx)
SGOT (mU/ml) 7.7 _+0.5 7.8 _+0.4 7.1 _+0.4
g a m m a - G T (mU/ml) 6.7 +_0.7 7.7 _+0.5 7.8 ---0.7 Before the start of the study 1.30 0.25
Cholesterol 4.04_+ 1.62 4.89_+0.91 4.81 +0.65 0.2 mg N A + 1 0 ~tg EE 1.19 0.18
(mmol/1) 1.0 mg N A + 5 0 gg EE 1.32 0.37
Triglycerides 1.02+0.56 1.09+0.39 1.07_+0.34
(retool/l) t-Test and the analysis of variance with Scheffa's test did not
Phospholipids 3.04_+0.40 3.29+0.43 3.53+0.87 reveal any statisticals significant difference (p>0.05). Abbrevia-
(retool/l) tions see Table 4
Total lipids (g/l) 6.42_+1.13 6.93_+0.98 6.96_+1.18
Haemaglobin(g%) 13.2 _+0.3 12.4 _+0.4 13.1 _+1.4
Haematocrit (%1) 39.5 _+ 1.1 40.0 _+ 1.4 41.4 ± 1.1
Leucocytes 6,093 +411 6,513 _+506 6,006 +459 The changes of the lithogenic index are given in
Table 4. The lithogenic index in the premedication
The differences between the mean values are not statistically signifi-
cant (p >0.05) phase and at the end of all treatment was greater
(NA = n o r e t h i n d r o n e acetate; EE =ethinyl estradiol (2 + sO than 1 independent of the dosage and of the se-
quence and thereby being in the pathological range.
However, the measured differences were not statisti-
cally significant neither by the t-test nor by the analy-
study. Considerable errors of intake could not be sis of variance and the test according to Scheff6 (1953,
registrated. The subjective symptoms in the test sub- 1959, 1969).
jects did not differ for the two forms of medication The hormon-free interval before the study was
(Table 2). Although weight gains or losses were found different in the test subjects. In two subjects it was
in some test subjects during the course of the study more, in 13 it was less than 4 weeks, as most of
in various menstrual cycles, the mean body weight the volunteers did not want to loose contraceptive
during the higher dosage period did not differ signifi- protection even shortly. Five test subjects had never
cantly from that during the lower dosage period. No taken any hormonal therapy before. The data of these
significant dose related changes of the systolic or dia- patients were analysed separetely in addition
stolic blood pressure were found. A comparison of (Table 5).
the clinical observations during intake of the two dos- There were no statistically significant differences
age forms is given in Table 1. in the lithogenic index of these patients compared
The results of laboratory studies of chemical pa- with those women who had taken various oral contra-
rameters are presented in Table 3, namely serum lipid ceptives before. During the study no significant
concentrations, serum activities of various enzymes changes of the lithogenic index were observed in the
and haematological findings before the start of the patients without previous hormonal treatment under
study and during intake of the two medications. both medication forms, too.

Table 4. Lithogenic index in the bile, calculated from the concentrations of cholesterol, phospholipids and
bile acids in 19 w o m e n before and during intake of two differently dosaged contraceptives

Before start After 16 weeks After 32 weeks

of the study
1 mg N A + 0.2 mg N A + 1 mg NA+ 0.2 mg N A +
50 gg EE 10 gg EE 50 gg EE 10 gg EE

mean value (2) 1.26 1.26 1.22 1.10 1.36

standard deviation (sx) 0.47 0.31 0.59 0.17 0.29
median (x) 1.15 1.12 1.12 1.23 1.35

t-Test and the analysis of variance with Scheff6"s test did not reveal any statistically significant difference
(p > 0.05)
( N A = n o r e t h i n d r o n e acetate; E E = e t h i n y l estradiol in a cross-over, double-blind study
 156
Discussion
The present study was carried out in 20 healthy volun-
teers of normal weight with regular menstrual cycle.
For optimal standardization and to exclude subjective
influence the form of a prospective, cross-over, dou-
ble-blind study was chosen. The women received a
hormone dose over 4 months which corresponds to
a commercial preparation (Orlest) and only one fifth
of this dose over a further 4 months. The incidence
rate of subjective symptoms was low in both forms
of medication, and no significant alterations of the
mean blood pressure values and body weight were
observed. Although the average duration of menstru-
ation per medication cycle did not differ significantly,
intermediate bleeding or amenorrhoea occurred more
frequently at the lower dosage.
The investigated laboratory parameters did not
reveal any statistically significant differences which
were related to the medication (Table 3). Hence con-
stancy of these laboratory parameters was guaranteed
during the entire study period. No significant changes
of the lipid parameters occured in this prospective
study (Brockerhoff et al. 1979).
Under the prevailing conditions intake of oral
c o n t r a c e p t i v e s could not be used as a criterion for
exclusion or selection of the test subjects. Only five
women took oral contraceptives for the first time
during the study period. In the other subjects, most
of whom did not wish to loose contraceptive protec-
tion even transiently, the hormone-free interval in
the prestudy phase covered 1-4 weeks.
These groups did not differ significantly on com-
parison of all determined parameters. As one cannot
definitely exclude any connection between previous
intake of oral contraceptives and the lithogenic index
which was greater than 1 in 75% of the test subjects,
the data of patients without any previous intake of
oral contraceptives were analysed separetely. Also in
this group no influences of the two medication forms
could be observed.
There were no clinical or roentgenological signs
of pre-existing or newly formed gall-stones before or
after the study. An elevated lithogenic index greater
than 1 is also found in persons without choMithiasis
so that a lithogenic index greater than 1 is not synony-
mous with cholelithiasis (Vlahcevic et al. 1971 ; Holz-
bach et al. 19731). In this study an elevated lithogenic
index was found in most of the test subjects after
4 and 8 months both on the higher and the lower
dosage. This seems to confirm the observations of
Bennion et al. (1976) who found a lithogenic index
greater than 1 on intake of oral contraceptives in
a dosage which was comparable to that in the com-
mercial preparation used in this study. Even on intake
P. Brockerhoff et al. : Oral Contraceptives and Bile Composition
of the contraceptive containing one fifth of this dose
we found an elevated lithogenic index. Bennion's re-
sults, however, are hardly comparable with those of
the present study as his patient population consists
of women taking oral contraceptives routinely with-
out standardization of medication forms and of the
time schedule for obtaining the bile in relation to
the hormone intake.
Consequently under the present experimental con-
ditions no dose-related increase in the lithogenic index
was demonstrable after the intake of oral contracep-
tives.
It is reported in various publications that the risk
of cholelithiasis increases up to twofold in women
who take oral contraceptives (Boston Collaborative
Drug Surveillance P r o g r a m m e 1973, Coronary Drug
Research G r o u p 1977). The m a x i m u m of incidence
is reached already after 6-12 months intake of these
drugs (Braendli and Filippini 1979).
Possibly the increase in the lithogenic index in
the human is not the only pathophysiological alter-
ation which leads to the formation of gall-concre-
ments. Other factors such as disturbed evacuation
of the gall-bladder which promote aggregation of cho-
lesterol crystals to form stones may also be involved.
According to Braverman (1979) evacuation of the en-
larged gall-bladder in pregnancy during the 2nd and
3rd trimester is less complete than in healthy nonpreg-
nant women. (Erfling (1978) reported that particularly
estrogens play a decisive role in the aetiology of cho-
lestasis. Whether pure gestagen preparations have a
different influence on the lithogenic index than combi-
nations of estrogens and gestagens is still unclear.
A lithogenic index which is elevated owing to es-
trogen containing contraceptives can be significantly
reduced by cicloxilic acid (Zuin et al. 1979) but this
observation remains to be investigated in a larger
group of subjects.
Acknowledgements. We are indebted to Dr. K.H. Schicketanz (Inst.
f. Med. Documentation and Statistics, University of Mainz) for
his help in performing the statistical evaluation of the results.
We thank all our test subjects, who could be motivated to complete
the study in spite of the intensive diagnostic technique.
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Received September 25, 1980
Accepted Mai 14, 1981
Dr. P. Brockerhoff
UniversitS.ts-Frauenklinik
Postfach 3960
D-6500 Mainz
Federal Republic of Germany