Serum lipids in Norplant® implants users : A cross-sectional study

CONTRACEPTION

SERUM LIPIDS IN NCRPL&?I'=IMPLANTSUSERS : ACROSS-SECTIONALSTUDY

B. Affandi*, Suharti K. Suherman**, Djajalelanal: J. Prihartono$**, F. Lubis%t*, R.S. Samil* *Klinik Raden Saleh Department of Obstetrics and Gynaecology School of Medicine, University of Indonesia Dr. Cipto Mangunkusumo General Hospital Jakarta, Indonesia $tDepartment of Pharmacology School of Medicine, University of Indonesia Jakarta, Indonesia ***Department of Public Health and Preventive Medicine School of Medicine, University of Indonesia Jakarta, Indonesia

ABSTRACT

One of the methods to establish the safety and risk profile of hormonal contraceptives is employing a study on their metabolic effects. In order to evaluate the effect of Norplant@ implants on serum lipids, a cross-sectional study was undertaken at Klinik Raden Saleh, Jakarta. The subjects recruited were divided into 8 groups depending on the length of Norplanteuse, i.e. before insertion, 6 months, 12 months, 24 months, 36 months, 48 months, 60 months and one week after the removal of Norplant@. Blood samples were collected from the subjects after an overnight fast. The parameters studied were triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. There were no the between the groups regarding significant differences were There HDL-cholesterol (p>O.O5). triglycerides and significant differences_ between the groups regarding the total cholesterol and LDL-cholesterol fp
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INTlDDUCl'ION Two different methods are employed today when trying to establish the safety and risk profile of hormonal contraceptives. The first method is to employ an epidemiological study. Two kinds of epidemiological studies that are most often used are casecontrol study and cohort study. The other method is a laboratory study of possible metabolic changes caused by the contraceptive method (1). Several studies have shown that lipoprotein levels can be appreciably by administration of estrogen and influenced progestogens. In the past all the blame was placed on the estrogen component of pill contraceptives until it was recognized that the progestogen component plays an important role in lowering HDL-cholesterol and possibly predisposing the subject to cardiovascular disease (2). Several cross-sectional and longitudinal studies have been undertaken to determine the metabolic and biochemical effects of NORJ?LAN!r@at different intervals of up to 3 years. The results were reviewed during a WHO consultation meeting and sunmerized as follows : "Studies on lipid metabolism have given inconsistent results : triglycerides were reported to be significantly decreased as were cholesterol and LDL-cholesterol with up to 37 months of use. Widely discrepant changes in HDL-cholesterol have been reported, however, including: no changes; decreases; or no change initially but a significant increase at 12 months. Decrease in HDLcholesterol levels were reported from two laboratories where decreases in total cholesterol were also reported giving an unchanged cholesterol/HDL-cholesterol ratio. In the centre reporting increased HDL-cholesterol levels, the cholesterol/HDLcholesterol was reduced at 6 months and further at 12 months. A recent with rods releasing equivalent amounts of study levonorgestrel has shown alterations in some sub-fractions of lipoproteins. HDL-Za, HDL-2b and I-DL-3were reduced after l-2 months of use; these were less pronounced at 6 months and there was a subsequent return to normal levels after 12 months. Because of differences in methodology, quality control and population studied, further studies are needed to clarify the effects of levonorgestrel from released NORPLANT@ on lipids and lipoproteins" (3). The present study provides further information regarding effects of Norplant@ on lipid patterns.

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MATERIALSANDMEIHCDS

Two-hundred-and-forty Indonesian women who came to Klinik Haden Saleh, Department of Obstetrics and Gynaecology, School of Medicine, University of Indonesia/Dr. Cipto Mangunkusumo General Hospital, Jakarta, for Norplanteinsertion or follow-up visit volunteered for were this cross-sectional study. They multiparous, non-lactating, non-smoking and non-alcoholic with average calories intake approximating 2000 calories. The inclusion criteria for having Norplant@ inserted and the technique of insertion have been published elsewhere (4,5). The subjects recruited were divided into 8 groups, depending on the length of Norplant@ use : Group Group Group Group Group Group Group Group

: I II : III : IV : : V VI : VII : VIII:

before insertion 6 months after insertion 12 months after insertion 24 months after insertion 36 months after insertion 48 months after insertion 60 months after insertion one week after removal.

Each group consisted of 30 subjects. Peripheral blood samples (10 ml) were drawn from the antecubital vein contralateral to the Norplant@ site after an overnight fast and were sent to the Department of Pharmacology, University of Indonesia, for lipids analysis. The lipids that were measured in the serum were triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol. The methods and procedures for determination of the lipids were Lipoprotein according to 'Methods Manual for Lipid and Determinations", issued by W.H.O. Special Programme of Research, Development and Research Training in Human Reproduction (6). The ANOVA test was used for significant differences. In cases the data did not follow a normal distribution, anormal logarithmic transformation procedure was applied beforehsnd.

RESULTS

1. Characteristics of the subjects. including the Selected characteristics of the subjects, Quetelex index or body mass index (W/H2) are listed in Table I.

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Table I Selectedcharacteristicsof the subjects

Education Parity Quetelex Group/Charscteristics(y%k) index (years) X f SD X f SD X_+SD X _+SD _-___--__---__--_~~--_~~--~~--_~ .__-___-_-___ .-___---__-__-___--__27.aok4.05 8.77k2.73 2.73k1.34 18.77k2.70 Group I 27.47*3.63 9.33f3.24 2.63k1.16 21.45k3.02 Group II Group III 27.1oi3.98 9.10*2.55 2.aok1.37 21.76ka.38 28.07i3.62 a.aok2.48 3.23k1.10 20.69k3.43 Group IV Group V 28.073134.27 7.aof2.57 3.43i1.48 20.41&3.02 Group VI 26.60k3.43 9.50f3.32 2.87k1.28 21.03k3.26 Group VII 27.53f3.79 9.37k2.71 3.37k1.43 20.36k3.24 Group VIII 28.47k3.42 9.07*3.30 3.03*1.00 19.13*5.52

There was no significant difference between the groups regardingage, education,parity snd Quetelex index (p>O.O5).

2. Triglycerides. Table II shows the mean triglycerideslevel of each group.

Table II Triglycerideslevel by group _~---~---~---_~--_~~--_----~---~---_~--_~~--~~~-_~~--~~~--~~--~~~ Group Mesn Triglyceridesa SD _---__--__--__---_~--__---_~---~---_~---_--_~----_--_~~--_~~--~~~ I 69.27 f 27.56 II 66.07 t 23.57 III 61.90 f 30.22 IV 76.27 f 41.77 V 77.50 f 33.27 VI 80.63 ?:35.19 VII 71.57 f 28.00 VIII 78.60 +-65.38 _____________-___-__~~-~~~-~~~-~~~--~~--~~~--~~--~~--~~~~-~~~-~~~

There was no significant difference between the (p>O.O5).

groups

3. Tots1 cholesterol,HDL-cholesterolsnd LDL-cholesterol. Table III describesthe level of total cholesterol, HDLcholesterolsnd LDL-cholesterolby group.

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Table III Total cholesterol, HDL-cholesterol and LDL-cholesterol by group

~~~~~~~~~~~~--------------------~~~~~~~~~~~~~~~~~~~~~~~~~~~~~---Total cholesterol

HI&cholesterol

LDL-cholesterol

Group MeankSD I II III IV V VI VII VIII

Mean -+SD

120.77 f 33.61 141.30 f 23.97 138.23 + 30.36 131.80 f 27.00 141.67 + 20.71 151.30 f 29.46 141.77 f 30.76 145.60 f 33.78 ._---------------_

Mean+SD

37.40 -+ 10.99 97.80 f 153.27 40.43 !: 8.75 124.53 f 112.76 38.30 + 32.06 94.57 + 29.40 41.73 -+ 8.91 72.43 + 26.42 35.33 f 7.42 90.47 -+ 17.94 36.17 f 20.74 102.33 _+ 29.80 37.93 -+ 10.09 89.93 -+ 28.76 37.70 f 8.27 92.00 f 34.55 .____-_-------_-_-----------------

At various time intervals, from 6 months up to 5 years after Norplant@insertion (group II-VIII), the total cholesterol level was significantly higher than before Norplandinsertion (Group I; pO.O5). The LDL-cholesterol level at 6 months of Norplani!?use (Group II) WSS significantly higher than the LDL-cholesterol in the preAt one year up to 5 years after treatment group (p
DISCUSSION

The results of the present study show that there were no significant differences between the groups regarding the triglycerides and HDL-cholesterol. However, there were significant differences between the groups regarding the total variably. These cholesterol and I&L-cholesterol, which changed results are somewhat contradictory with the results of the decrease of total cholesterol, triglycerides and LDL-C in a longitudinal study reported by Shaaban et al. (2) and in a crosssectional study reported by Croxatto -et al. (7). They are also contradictory with the results of decrease of total cholesterol and H&-C reported by Holma and Robertson (8) and the results of significant decrease of total cholesterol reported by Lithe11 &. a. (9). The differences between these studies could be due to the quality control of the lipids differences in methodology, analyses and populations studied. Therefore,further multicentre with standardized methodology and quality control studies, with different populations, are reccnmnended.

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Sudjadi, BSc, from The authors wish to thank Mr. Department of Public Health, University of Indonesia, for statistical analyses.

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REFENKES

1. Hoppe,G. Methodology of evaluating the pill safety. Presented at the Tenth Asian and Oceanic Congress of Obstetrics snd Gynaecology, Colombo, Sri Lanka, 5-10 Sept 1985 2. Shaaban,M.M., Elwan,S.I., Abdalla,S.A., Darwish,H.A. Effect of sutdetmal levonorgestrel contraceptive implants, Norplane, on serum lipids. Contraception 30: 413-419 (1984) 3. World Facts about an implantable Health Organization. contraceptive. Bulletin of the W.H.O., 63: 485-494 (1985) Boomkasemsanti,W., 4. Affandi,B., Cekan,S.Z., Samil,R.S., Diczfalusy,E. The interaction between sex hormone binding globulin and levonorgestrel released from Norplant~ an implantable contraceptive. Contraception 35: 135-145 (1987) 5. Affandi,B., Ssntoso,S.S.I., Djajadilaga, Hsdisaputra,W., Moeloek,F.A., Sami1,R.S. Five-year experience with Norplan@6. Presented and at the XII, World Congress of Fertility Sterility, Singapore, 26-31 October 1986 6. World Health Organizationn Special Prograsmre of Research, DeveloInrent and Research Training in Human Reproduction. Method Manual for Lipid and Lipoprotein Determination, 2nd Edition, June 1986 7. Croxatto,H.B., Diaz,S., Robertson,D.N., Pavez,M. Clinical chemistry in women treated with levonorgestrel implants (Norplan@) or a 'Ku 200 IUD. Contraception 27: 281-288 (1983) 8. Holma,P., Robertson,D.N. Cholesterol and HDL-cholesterol values in women during use of subdermal implants releasing levonorgestrel. Contraception 32: 163-171 (1985) 9. Lithell,H., Weiner,E., Vessby,B., Johannsson,E.D.B. Effects of continuous levonorgestrel treatment (subcutaneous capsules) on the lipoprotein and carbohydratimetabolism in fertile women. Upsala J Med sci 88: 103-108 (1983)

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