Berger, GMB

Maritz, JS

Sapire, KE

English

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376SAMJ VOL 79 6 APR 1991·The clinical and biochemical effects of twocombination oral contraceptive agentsK. E. SAPIRE G BERGER, .M.B. , J. S. MARITZSummary: compa~is.on of the effects of two low-dose oral contracep-ves on h~ld met~bolism was undertaken in an open-group·comparative deSign stUdy at the Family Planning Clinic,;roote Schuur Hospital, Cape Town. Sixty healthy womeng~ 18 - 35 years requesting oral contraception were allo-~a e . ~Iternately to use a monophasic oral contraceptive~ntalnlng 30 J.Lg ethinyloestradiol and 150 ",g desogestrelfn a!:oelon, group .A), or a triphasic oral contraceptive contain-Tg. - ~O J.Lg ethlny1oestradiol and 50 - 125 ",g levonorgestrel( .."phaSIl, group B). The changes in the lipoprotein profile: IClt~ by the two preparations differed significantly. Group4 su Jeets had a mUch greater triglyceridaemic responsef 2,~%) than.gr~up B (14,6%) and had a significant increasen hl~h-denslty hpoprotein cholesterol (HDL-C) and apolipo-protein A-l (Apo·~l). In rou B, HDL-C decreased andApo-Al showed hUle cha~g/Non-HDL-C (NHDL-C) andA~-B leVels hardly Changed in either group. The atherogenicratios, NHDL-C/HDL.C and Apo-B/Apo-Al were higher ingroup B.This study confi",:,ed a significant difference in the responsef-f plasma hp~prote,"s to the two oral contraceptive prepara-Ions. The eVidence Suggests that the desogestrel-containing:al contraceptive eliCit, a less atherogenic lipoprotein profilean does the levonorgeatrel_containing preparation. Although~n,upported by direct Clinical evidence that changes in thehpoprotein p~ttern indUCed by oral contraceptives causeathero~C:lerosls, these effects should be considered whenrr~cnblng oral contraceptives for women who have riskac ora for cardiovascUlar disease.S Atr Med J 1991; 79: 376-379.The adverse cardiovascular effects of oral contraceptives havebeen well.documented. I•2 These are probably mediated throughchanges. In 6 the plasma lipoprotein profrle/-s in the bloodcoagulatlon and fibrinolytic systems,7 and through effects onblood pressures and Carbohydrate metabolism.9 The risk of~oronary artery disease is exacerbated by smoking, especiallym women over the age of 35 IDS 'd . years.term ~Induced changes in plasma lipoprotein transporthave rec~Ived considerable attention due to the establishedrole of lipoprote~s in atherogenesis and as a risk factor forc~r~nary artery dIsease. II Oral contraceptive preparations con-tammg. 50 J.Lg ethinyloestradiol are associated with a signifi-c~t1y Increased risk of thrombo-embolic events, hypertension,weIght gain and with hyperinsulinism and impaired glucosetolerance. 12 Oestrogens also enhance plasma triglyceride andgepartment of Obstetrics and Gynaecology, University ofK apeE Town and Groote Schuur Hospital, Cape Town. . SAPlRE, M.B. CH.B~epart.ment.of Che~ical Pathology, Red Cross WarG emonal Children's lIospital Cape Town. M. B. BERGER M.B CH l:stitute for Bio~tatiSti~~':~Dilie South Mrican Medicalesearch Council, Parowvallei CPl S. MARITZ, D. se. '-------------------Accep,ed 24 July 1990.high-density lipoprotein cholesterol (HDL-C) levels, morespecifically the HDL2 subfraction; the latter effect is seen asbeneficial. Low-dose preparations containing 30 - 35 p.g ethinyl-oestradiol are associated with a significant reduction in theadverse oestrogenic effects 13,14 and may even be beneficial incertain categories of women as far as coronary artery disease isconcerned. ISIt has become apparent that the progestogen in oral contra-ceptives potentiates some of the adverse actions of oestrogensand may counteract the beneficial effects. 16 Progestogens haveandrogenic as well as progestational properties and, in addition,may possess anti-androgenic and anti-oestrogenic actions. Theeffects of any combined oral contraceptive preparation willtherefore depend on the nature and relative biological activity·of the oestrogen and progestogen used, as well as the absolutedose, and the characteristics of the recipient. 17 In this connec-tion, the increased risk of coronary artery disease associatedwith oral contraceptive use is mainly, although not entirely,confined to women over the age of 35 years, and especiallycurrent smokers. ID In developing new oral contraceptivesattention has been directed towards minimising risks by dosereduction, ancj. by modification of the progestogen component,while maintaining contraceptive efficacy. .In this study a monophasic oral contraceptive preparation(A) (Marvelon; Donmed) containing 30 J.Lg ethinyloestradioland 150 J.Lg desogestrel was compared with a triphasic prepara-tion (B) (Triphasil; Akromed) containing ethinyloestradiol30 - 40 J.Lg and levonorgestrel 50 - 125 J.Lg in two groups ofwomen. Both preparations contain low-dose ethinyloestradioland differ primarily in the amount and nature of the pro-gestogen.Subjects and methodsThis was an open group-comparative study involving 62 healthywomen who requested oral contraceptives, and gave informedconsent for this clinical study. They were alternately allocatedto group A (the monophasic preparation) or group B. (thetriphasic preparation), except that current cigarette smokers (5in each group) were allocated to each group alternately inequal numbers. ODly the research sister knew which oralcontraceptive constituted group A or B until the data werecomputerised. .The study period lasted 4 months and included 2 visits inthe pre-treatment month and 3 follow-up visits between day18 and day 21 of the treatment cycles 1, 2 and 3. At each visit,blood was collected after a l2-hour fast. Tablets were checkedat each visit to ensure compliance, and subjects were remindedto continue on·their normal diet and other lifestyles.All women selected were between 18 years and 35 years ofage, were normolipidaemic, and were healthy on routine ques-tioning and clinical examination. None took any hormonalpreparation or other medication in the 2 months before inclu-sion in the study or during the trial itself, except for the'prescribed oral contraceptive. Standard contraindications tooral contraceptives were applied. In addition, women with anintake of more than 2 glasses of alcohol per day and also thoseweighing over 80 kg or following a diet, and those who ·wereless than 3 months postpartum or post-abortion, were excluded.SAMJ VOL 79 6 APR 1991 377TABLE I. PRETREATMENT CLINICAL AND BIOCHEMICAL FEATURES OF GROUPS A AND B (MEAN±SD)Group (N) Age (yrs) BMI CHOL HDL-C" NHDL-C Triglycerides Apo-A1 Apo-BA (30) 22,6 ± 3,10 23,2 ± 3,2 4,43 ± 0,64 1,59 ± 0,28 2,84 ± 0,65 0,64 ± 0,23 149 ± 22,0 80,2 ± 18,0B (30) 22,0 ± 4,40 22,0 ± 2,9 4,30 ± 0,70 1,46 ± 0,24 2,84 ± 0,70 0,69 ± 0,18 141 ± 22,8 78,2 ± 22,6Upid and apolipoprotein values represent the mean of the first 2 visits.Fig. 1. Changes in plasma lipid and apolipoprotein levels inresponse to oral contraceptives A and B.TABLE 11. CHANGES IN LIPOPROTEIN COMPOSITION ANDLIPOPROTEIN RATIOS IN RESPONSE TO ORAL CONTRACEP-TIVES A AND BAPO BApo-AHDL-C5,1*8,7**Apo-BNHDL-C4,110,9*TRIO(')Apo-BApo-A1-10,4+5,9NHOl-CHOL-C(I)NHDL-C*'-HDL-C-8,7+3,5CHQl(')ABGroup-10 --P< 0,05."P<O,OO1.•• - Significant difference between groups (P < 0,05).50 -_Group A40 - ~Group Bw 30 -ClZ<J: 20 -Q...ZwQ lO-a::wl1.06,9% fall in HDL-C without significantly affecting Apo-Allevels. The responses of the two groups were significantlydifferent from one another at P = 0,001 and P = 0,003 forHDL-C and Apo-Al, respectively. Both preparations A and Belicited an increase in plasma triglyceride levels. Group Asubjects showed a 42,4% rise whereas triglyceride levels roseby 14,6% in group B subjects. The triglyceridaemic responsesof the two groups differed significantly (P = 0,0003) from oneanother.In contrast to the striking changes in HDL and triglycerideconcentrations, total plasma cholesterol and NHDL-C levelsaltered relatively little. Both groups showed a small, non-significant fall in NHDL-C concentration whereas group Ashowed a slight rise (2,1%) and group B a slight fall (-3,8%) intotal plasma cholesterol, presumably reflecting changes in theHDL-C values. Apo-B rose by 3,7% and 8,1% in groups A andB, respectively, but these changes also did not achieve statistical. significance, and the two groups did not differ significantlyfrom one another.The ratio of NHDL-C/HDL-C and Apo-B/Apo-Al maybe taken as a reflection of atherogenic potential. These ratioswere reduced by 8,7% (P = 0,04) and 10,4% (non-significant)Laboratory investigationsBlood was taken without venesta~is, placed in tubes contain-ing ethylenediarninetetra-acetic acid and centrifuged within 1hour at 4° to separate cells from plasma. Lipid assay wasperformed immediately or within 4 days. Apolipoprotein assaywas batched and carried out on samples stored at -70°C forless than 3 months.Total plasma cholesterol was estimated enzymatically usinga commercial kit (Boehringer-Mannheim CHOD-PAP HighPerformance kit) and triglyceride was similarly determined(Clinical Colorimetric Enzymatic Method, Carlo Erba, Milan).HDL-C was measured after precipitation of the low-densitylipoprotein (LDL), and very low-density lipoprotein (VLDL)by means of heparin-manganese according to the LipidResearch Clinics protocol. I8 VLDL-C plus LDL-C levelswere estimated by subtracting HDL-C from total plasmacholesterol. This product, termed non-HDL-cholesterol(NHDL-C), represents the cholesterol associated with the twoatherogenic apo B-containing fractions. Apolipoprotein A-I(Apo-Al) was determined by rate nephelometry on a BeckmanICS system according to the method of Weinstock er al. 19 andApo-B by an immuno-electrophoretic (rocket) procedure.20ResultsThe two groups were similar in age, body mass index, as wellas in dietary, smoking and alcohol consumption habits. Thebasal lipid and apolipoprotein values of the two groups werecomparable (Table I).Statistical analysisWithin-group comparisons of basal values with levelsachieved in the course of oral contraceptive therapy were madeby a procedure that is essentially a paired test, with allowancebeing made for the co-variates age and smoking. Between-group comparisons were made by two sample tests, that isANOVA, again with allowance for co-variates. The statisticalmethods were implemented by means of the general linearmodel procedure of Statistical Analysis System.21 All ANOVAand regression procedures were performed on actual observedchanges. In some summaries percentage change values areshown so as to facilitate interpretation. One patient from eachof the two groups dropped out of the trial after the 4th visitfor personal reasons. They were omitted from the statisticalanalysis, which was thus performed on 30 individuals in eachgroup.The percentage change· in plasma lipid and apolipoproteinlevels in the two groups is illustrated in Fig. 1. The effects ofthe two oral contraceptives differed strikingly in the directionof the HDL fraction change as well as in the extent of thehypertriglyceridaemic response.Preparation A elicited a significant increase in both HDL-C(7,9%) and Apo-Al (13%) whereas preparation B caused a

The clinical and biochemical effects of two combination oral contraceptive agents

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The clinical and biochemical effects of two combination oral contraceptive agents

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