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Klin Wochenschr(1982) 60:153 157 Klinische

Wochen-
schrift
(~') Springer-Verlag 1982

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 Norethindronazetat und 50 lag )kthinyl6stradiol trig-
intake of oral contraceptives may be due to estrogen- lich mit anschliel3ender 7tfigiger Placebogabe oder
induced saturation of the bile with cholesterol. In aber ein Ffinftel dieser Hormondosis als tfigliche kon-
a randomized, prospective, crossed-over double-blind tinuierliche Medikation. Nach jeweils 4monatiger
study 20 healthy women after roentgenological exclu- Behandlungsdauer erfolgte der {)bergang auf die an-
sion of gall-stones received either 1.0 mg of norethin- dere Medikationsform. Zu Beginn der Studie sowie
drone acetate and 50 lag ethinyl estradiol daily - as vor dem {Jbergang auf die andere Medikationsform
usual in oral contraception - for 21 days with 7 days und nach AbschluB der Studie wurde nach 12sttin-
of placebo treatment in each cycle or one fifth of diger Nahrungskarenz mittels einer Duodenalsonde
this hormone dose in form of a continuous daily medi- Gallenfltissigkeit gewonnen und der lithogene Index
cation. After a 4 month's treatment the medication als Mal3 fiir die CholesterinsS.ttigung der Gallenfliis-
form was crossed-over. At the beginning of the study, sigkeit bestimmt. Eine AbhS.ngigkeit des lithogenen
before the cross-over and after the study bile was Index v o n d e r Dosis der applizierten H o r m o n e liel3
collected by duodenal intubation after a 12-h fast sich weder bei 15 Frauen, die bereits vor der Studie
and the lithogenic index as a measure for cholesterol orale Kontrazeptiva eingenommen batten, noch bei
saturation of the bile was determined. N o correlation ffinf Frauen ohne vorherige hormonale Kontrazep-
between the dose and the lithogenic index was demon- tion nachweisen.
strated, neither in 15 women, who had used oral con-
Schliisselw6rter: Orale Kontrazeption - Cholelithiasis
traceptives before the study nor in five women with-
Lithogener Index Zusammensetzung der Gallen-
out any previous hormonal contraception.
flfissigkeit
Key words: Oral contraception - Cholelithiasis -
Lithogenic index Bile composition

Introduction
Der Einflu6 oraler Kontrazeptiva auf die Zusammen-
setzung der Gallenfliissigkeit The incidence of cholelithiasis in the Western indus-
trialized countries has been reported to be between
Zusammenfassung. Das erh6hte Risiko hinsichtlich 10 and 20% so that cholecystectomy has become the
der Gallensteinbildung bei der Einnahme oraler Kon- most frequent operation. The risk of suffering from
trazeptiva beruht m6glicherweise auf einer 6strogen- cholelithiasis is about twice as high in women as in
bedingten Zunahme der Cholesterinsfittigung der Gal- men. Particularly in those countries in which the
lenflfissigkeit. In einer prospektiven, gekreuzten Dop- number of gall-bladder operations has increased with
pelblindstudie erhielten 20 gesunde Frauen nach r6nt- increasing affluence, oral contraceptives are also used
genologischem Ausschlul3 yon Gallensteinen random- on a wide scale. Direct or indirect relations between
isiert entweder wie bei der routinemfil3igen oralen steroid hormones and changes of the composition
Kontrazeption tiblich zyklisch fiber 21 Tage 1,0 mg of bile have been discussed in various publications
(Nilson 1966; Lynn etal. 1973; Javitt etal. 1975;
* This work was in part supported by grants of the Deutsche
Forschungsgemeinschaft Davies and Kern 1976; Schwarz et al. 1977).
** Dedicated to Prof. Dr. V. Friedberg, Mainz, on the occasion In 1973 the Boston Surveillance Group reported
of his 60th birthday for the first time that women taking hormonal contra-
Offprint requests to: Dr. P. Brockerhoff(address see page I57) 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 P. Brockerhoff et al. : Oral Contraceptives and Bile Composition

Discussion of the contraceptive containing one fifth of this dose


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

after the study. An elevated lithogenic index greater


than 1 is also found in persons without choMithiasis References
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