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Contraceptives on Bile Lipid Composition

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Gut: first published as 10.1136/gut.24.3.253 on 1 March 1983. Downloaded from Guit, 1983, 24, 253-259 Effect of synthetic oestrogens and progestagens in oral contraceptives on bile lipid composition R H L DOWN, M J WHITING, J McK WATTS, AND W JONES From the Departments ofSurgery and Obstetrics and Gynaecology, Flinders Medical Centre, and Flinders University ofSouith Australia, NSW, Australia SUMMARY The prevalence of cholesterol gall stones in young women has increased since the introduction of oral contraceptives. The synthetic female sex hormones used in these preparations, increase the degree of cholesterol saturation in bile. To determine whether oestrogens, progestagens, or both, are responsible for the change in biliary cholesterol saturation index, a prospective randomised, controlled study was performed. A significant increase in the cholesterol saturation index of bile was observed when either 30 ug ethinyloestradiol plus 150 ,g norgestrel (p=001) or 50 ,ug ethinyloestradiol plus 250 gg norgestrel (p<0.01) were ingested daily for two months. No change in the cholesterol saturation index was observed when 30 ,g ethinyloestradiol alone, or 30 ,ug ethinyloestradiol plus 2.5 mg norethisterone were used. The mechanism for the increase in cholesterol saturation index did not appear to involve bile acid metabolism. These results indicate that the progestagen, norgestrel, and not as previously thought the oestrogen, ethinyloestradiol, is responsible for the increase in cholesterol saturation of bile which accompanies the use of oral contraceptives. http://gut.bmj.com/ Epidemiological studies'-"' have suggested that relative time periods of cholesterol unsaturation to there must be a causal relationship between female supersaturation during the day in favour of sex hormones and gall-stone disease. Gall stones are cholesterol supersaturation within the gall bladder twice as common in females once puberty4 has been and lead to cholesterol crystal formation and gall- reached. After the menopause2-3 this sex difference stone growth.'6 gradually diminishes. Similarly, pregnancy3 and the Studies'7-25 have been performed in reproductive on September 24, 2021 by guest. Protected copyright. use of synthetic female sex hormones for contra- women to investigate the effect of female sex ception>-9 or the prevention of postmenopausal hormones on the cholesterol saturation index of symptoms"' have been shown to increase the bile. Physiological changes in natural sex hormones incidence of gall-stone disease. during a normal menstrual cycle have been shown to Approximately 85% of gall stones are composed have no effect in four separate studies,'7-20' and a predominantly of cholesterol. It is now recognised small effect in a study by Low-Beer et al.2' The that cholesterol gall stones will form only when bile withdrawal of natural female sex hormones by is supersaturated with cholesterol." Conversely, oophorectomy in one woman reduced the dissolution of cholesterol gall stones may occur cholesterol saturation index of bile.22 The ingestion when bile becomes unsaturated with chol- of synthetic female sex hormones in oral contra- esterol. 12-14 In 1973 Thomas and Hofmann'5 intro- ceptive doses has been shown to increase both the duced the cholesterol saturation index (CSI) to cholesterol saturation index of bile and the propor- quantify the degree of cholesterol saturation in bile. tion of women with supersaturated (CSI >1.0) Any substance or factor that increases the bile.2>25 It has been claimed that oestrogen is cholesterol saturation index of bile may alter the responsible for these changes.2$28 The evidence, however, is circumstantial. Studies in rats,29 Address for correspondence: Discipline of Surgical Science. Facultv of monkeys, 30 and baboons3' which used oestrogen Medicine. The Universitv of Newcastle. David Maddison Clinical Sciences unit than Building. The Royal Newcastle Hospital. Newcastle. New South Wales. doses up to 1000 times per weight greater Australia 2300. that used in oral contraceptives have shown that Received for publication 1 June 1982 oestrogens can alter the lipid composition and the '53 Gut: first published as 10.1136/gut.24.3.253 on 1 March 1983. Downloaded from 254 Down, Whiting, Watts, and Jones bile acid kinetics of bile, but not always in favour of biliary cholesterol saturation index, the bile acid cholesterol supersaturation. Clearly, species differ- profile, the total bile acid pool size, and the level of ences exist. We therefore decided to investigate in circulating serum progesterone. humans, firstly, whether contraceptive doses of synthetic oestrogens or progestagens were BIL1E SAMPLING responsible for the reported rise in the biliary Duodenal collections of gall-bladder bile were made cholesterol saturation index and, secondly, whether exactly 12 hours after the ingestion of a standard this could be attributed to an effect on bile acid meal - two slices of bread and butter and a glass of metabolism. milk. The subjects swallowed an AN-20 weighted duodenal tube (Anderson Products Inc, Oyster Bay, Methods New York, USA). Gall-bladder bile samples were aspirated from the duodenum after a slow intra- The original objective was to evaluate the effect on venous injection of 1 U/kg Pancreozymin (Boots Co the biliary cholesterol saturation index of equivalent Ltd, Nottingham, England). A 2 ml sample of the pharmacological doses of the synthetic female sex most concentrated bile was immediately sent to the hormones commonly used in oral contraceptives: laboratory for lipid analysis. Excess bile was 30 jig ethinyloestradiol alone, 150 ,ug norgestrel returned to the duodenum to avoid depletion of the alone, 30 ,g ethinyloestradiol plus 150 ug bile acid pool. norgestrel, and 30 ,ug ethinyloestradiol plus 2.5 mg norethisterone. Fears were raised about possible BILE LIPID ANALYSIS side effects from the use of 150 ,ug norgestrel alone The biliary lipids (cholesterol, total bile acids, and because this dose was five times that currently used phospholipids) were assayed using fresh bile for in progestagen alone oral contraceptives. A brief solvent extraction as described by Whiting et al.'8 pilot trial showed that the use of this dose of Assays were performed in several batches as norgestrel alone for longer than one month caused samples became available during the study. The persistent nausea and breakthrough uterine cholesterol saturation index was calculated by the bleeding. Therefore, the part of the study dealing method of Thomas and Hofmann'5 using the with norgestrel alone had to be replaced. A 'high' cholesterol equilibrium saturation limit of Holzbach http://gut.bmj.com/ oestrogen dose oral contraceptive, 50 ,ug ethinyl- et al.32 oestradiol plus 250 ,ug norgestrel, was chosen Individual bile acids in the gall-bladder bile because most of the oral contraceptives used in the samples were deconjugated and quantified by gas original study of Bennion et a123 contained 50 ,ug liquid chromatography as described by Whiting and ethinyloestradiol. Watts.33 Individual bile acid profiles were deter- We undertook a prospective controlled trial in 10 mined by expressing the relative concentrations of healthy female volunteers, aged 19 to 35 years, the individual bile acids as moles per cent. on September 24, 2021 by guest. Protected copyright. known to have normal oral cholecystograms. Intra- uterine contraceptive devices were used as necessary BILE ACID POOL SIZE to prevent pregnancy. The study was approved by The total bile acid pool size was measured by the the Hospital's ethics committee. simplified isotope dilution technique of Duane et The design of the study was as follows: there were al.3 Two minor modifications were used. Firstly, five phases - a physiological control menstrual cycle the 10 ml intravenous injection of radioactive and four oestrogen/progestagen phases. The order cholate was always given half an hour before eating of participation in each phase was randomised. In the standard evening meal. Secondly, the addition each oestrogen/progestagen phase, the prescribed of non-radioactive sodium cholate to the vial of dose (see above) of the synthetic female sex radioactive cholic acid proved essential to prevent hormone(s) was ingested daily from the fifth to the major losses from the solution of radioactive cholate 26th day of the 28-day cycle for two cycles. When a by absorption to glass surfaces. 14C-carboxyl cholic control menstrual cycle followed an oestrogen/ acid (specific activity 50-60 mCi/mol; the Radio progestagen phase, two physiological menses were Chemical Centre, Amersham, England) and (2,4- allowed to elapse before bile sampling to ensure 3H) cholic acid (specific activity 14 Ci/mmol; New complete elimination of the synthetic hormones and England Nuclear, Boston, USA) were purchased as allow ovulation to start again. Gall-bladder bile and sterile solutions in ethanol. Each isotope was blood samples were taken on the 23rd and 26th day repackaged in a 100 ml sterile injection vial of 0.9% of the second month in each of the oestrogen/ sodium chloride with 175 meq/1 sodium bicarbonate, progestagen phases, and on the third, 13th, and 21st 0.2 mg/ml cold carrier sodium cholate and either 2.5 day of the control menstrual cycle to measure the ,Ci 'C cholate or 12.5 ,uCi 3H cholate per 10 ml. Gut: first published as 10.1136/gut.24.3.253 on 1 March 1983. Downloaded from Effect ofsynthetic oestrogens and progestagens in oral contraceptives otn bile lipid composition 255 SERUM PROGESTERONE Control 30 ,ug EE Control 30 yug EE Ten millilitres of blood were obtained by 2.5 mg Nor venepuncture with each bile sample. The serum was separated and snap frozen at -70(C for subsequent 1*0- I batch hormone analysis. The serum progesterone was determined by radioimmunoassay after hexane extraction. 08- STATISTICS x 06- A precise measure of the cholesterol saturation of -a W duodenal bile requires multiple samples. 18 35 There- .c c fore, the average of the two or three cholesterol 0 saturation index measurements in each phase of the study was used for statistical analysis.
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