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Journal readingIMPLANON USE LOWERS PLASMA CONCENTRATIONS OFHIGH-MOLECULAR-WEIGHT ADIPONECTINAisya SelviaNurmuthmainnahAngga FachrezaNur Egis VajwinCendra Viola ListiSuci Martha DaniElvicha Dwi NoverthaVitya R. MardiahHenny SavitriPembimbing:dr. Imelda E.B Hutagaol, Sp.OG-KFERKEPANITERAAN KLINIK SENIORBAGIAN OBSTETRI DAN GINEKOLOGIFAKULTAS KEDOKTERAN UNIVERSITAS RIAURSUD ARIFIN ACHMAD PROVINSI RIAUPEKANBARU2014ABSTRACTInvestigate the effect of the low-dosed etonogestrel-releasing contraceptive implant Implanon on new cardiovascular risk markers.

OBJECTIVEDesign Longitudinal study.In this journal studied the effect of this implant on adiponectin and its metabolicallyimportant isomer high-molecular-weight adiponectin (HMW). Low-dosed progestagen-only contraception ispreferentially prescribed to females with increased cardiovascular risks.2Setting 40 healthy nonsmoking women regular cyclesFamily-planning center of a university hospital.

Patient(s)Patients : (n 20 controls without hormonal contraception; n 20 cases wishing the insertion of Implanon).

Inter vention : Blood samples for the measurements of adiponectin, HMW, C-reactive protein (CRP), sex hormone binding globulin, sexual hormones, and plasma lipids were taken in the early follicular phase of the cycle in both groups. A second sample was taken 12 weeks after Implanon insertion or in the controls during the early follicular phase of cycle four.

Main Outcome MeasureAt baseline there was a significant correlation between adiponectin and the parametershsCRP and high-density lipoprotein. Implanon treatment caused a significant decrease in HMW and the HMW/adiponectin ratio.3INTERVENTION Blood samples measurements of adiponectin, HMW, C-reactive protein (CRP), sex hormone binding globulin, sexual hormones, and plasma lipids

A first sampel in the early follicular phase of the cycle in both groups.

A second sample 12 weeks after Implanon insertion or in the controls during the early follicular phase of cycle four.

ConclusionThe implant provides contraceptive protection for 3 years, and has been used in Switzerland for >10 years. Although etonogestrel plasma concentrations are low, the implant inhibits ovulation and provides very high contraceptive efficacy

the effect on novel risk factors have been less frequently investigated. In combined contraceptive pill (COC) users changes in plasma lipids and an elevation in plasma levels of C -reactive protein (CRP) and total adiponectin have been reported

Implanon does not exert a negativen effect on nitric oxide, endothelin-1, transforming growth factor-b, CRP, the cholesterol/high-density lipoprotein (HDL) ratio, and triglycerides7Implanon Insertion

Has been linked to Low levels of adiponectin have been found in patients with ischemic heart disease, hypertension, diabetes mellitus type II, and dyslipidemia. (1114). Sex hormones, in particular testosterone, and plasma lipids seem to be involved in the regulation (1517). Because Implanon causes a decrease in circulating testosterone, HDL and low-density lipoprotein (LDL), we hypothesized that the use of this implant might induce changes in adiponectin plasma levels

High-molecular-weight adiponectin is the active form in plasma, and is found at higher levels in females than in males. Recent studies suggest that HMW and the HMW/totaladiponectin ratio (HA-ratio) rather than total adiponectin are associated with insulin sensitivity, metabolic syndrome, and the predictionof cardiovascular events9Adiponectin10MATERIAL AND METHODShad cycles of 26 to 32 days during the 3 months preceding the start of the study, and did not want to become pregnant during the following 6 months Measurement of blood pressure had to be within the normal range.

Exclusion criteria were chronic illness necessitating the regular use of medicinal therapy, smoking, body mass index >30 kg/m2, and contraindications for the use of POP. Informed consent was obtained from all participants, and the study was approved by the institutional review board of the University Hospital of Zurich.11BLOOD SAMPLEenzyme-linked immunosorbent assay (ELISA)Sensitivity of the assayis 0.08 ng/mLCoefficients of intraassay variationsVenous blood samples were taken between 8 and 10 a.m. after overnight fasting and a regulated diet of 24 hours.

Baseline samples in the case group were taken before the insertion of the implant.

The second blood sample was drawn after 3 months of Implanon use or in the control group at days 1 to 4 of cycle 4. Plasma was separated within 30 minutes and stored at 70C until assayed.

Serum levels of both HMWand total adiponectin were determined by enzyme-linked immunosorbent assay (ELISA) detection (Multimeric Adiponectin ELISA Kit; Buhlmann Laboratories AG, Schonenbuch, Switzerland).

In addition to total adiponectin, HMW adiponectin serum levels can be determined by this ELISA after protease treatment to digest LWM and MMW adiponectin.

Coefficients of intraassay variations were 5.3% to 5.4% for total adiponectin and 3.3% to 5.0% for HMWadiponectin, interassay coefficient of variation (CV) were 5.0% and 5.7% for total adiponectin and for HMWadiponectin, respectively. The results are expressed as mg/mL. Serum controls for both total andHMWadiponectin were measured with each assay. The HMW/adiponectin ratio (HA-ratio) was calculated as another potential parameter for individual cardiovascular risk.

13Statistical AnalysisThe unpaired t test and MannWhitney U-testsPaired T tests or Wilcoxon signed rank testStatistical analyses were performed using SPSS 17.0 software

Data are presented as means (SD) or if not normally distributed as median (min;max). Skewed distributed parameters were logarithmically transformed before analysis (Adiponectin, HMW, CRP).

The unpaired t test and MannWhitneyU-tests : were used for comparisons between groups

Paired t tests orWilcoxon signed rank test : Within-treatment effects were compared by paired t tests orWilcoxon signed rank test as appropriate

To investigate correlations of adiponectin, HMW, and HA-ratio with plasma lipids, inflammatory parameters and hormones, baseline data of all participants were included. Correlation between two variables was expressed as the Spearman rank correlation coefficient. Statistical significance was accepted at P.05.

14RESULTReasons for dropout were pregnancy, withdrawal of informed consent, desire to use contraceptive hormones, and loss to follow-up.15Levels of high-molecular-weight adiponectin, adiponectin, high-molecular weight/adiponectin ratio, high-sensitivity C-reactive protein, plasma lipids, and sex hormones in controls and before and 3 months after implantation of Implanon.kontrol (n=15)Terapi implan (n=17)Nilai PVariabelbaseline3 moBaseline3 mo a bAdiponektinHMW HA-rasiohsCRPHDLLDLKolesterolSHBGEstradioltestosteron7,1 (3,4;11,4)5,0 (1,5;7,8)0,68(0,03)1,86 (2,70)1,57 (0,33)3,10 (1,02)5,08 (0,93)65,6 (35,9)116 (49)1,28 (0,47)6,9 (3,4;9,9)4,9 (1,4;8,0)0,68 (0,03)1,97 (2,55)1,57 (0,29)2,96 (1,08)4,92 (1,02)57,8 (13,5)112 (60)1,25 (0,41)6,05 (3,3;8,7)4,18 (1,4;6,2)0,68 (0,03)2,02 (1,59)1,34 (0,26)3,25 (1,12)4,92 (1,18)52,4 (32,6)184 (181)1,48 (0,45)5,77 (3,0;7,7)3,60 (1,2;5,8)0,60 (0,03)1,31 (1,07)1,24 (0,25)2,08 (0,99)4,41 (0,99)38,3 (14,7)262 (287)1,28 (0,42)86 0603 0305 1206 16 01 01 01 6401 1601 0159 0604 81Table 1Treatment group NControl NRESULTcharacteristics of age, body mass index, and blood pressure (37.2 vs. 33.1 years; 20.5 vs. 20.7 kg/m2 ; 120/79 vs. 115/7 6 mmHg).The two groups did not differ significantly in the baseline characteristics of age, body mass index, and blood pressure (37.2 vs. 33.1 years; 20.5 vs. 20.7 kg/m2 ; 120/79 vs. 115/7 6 mmHg). Baseline data and changes of the investigated parameters across treatment (control group change after threecycles) for both groups

Baseline levels of the investigated parameters were identical for both groups except for HMW and HDL. High-molecular-weight plasma levels were higher and HDL plasma levels were lower in the control group compared with the treatment group.17After three cycles all parameters in the control group were unchangedimplanon treatment did not cause any significant changes in adiponectin, CRP, or estradiol.HMW and the HA-ratio decreased significantly 3 months after insertion of the implant.Furthermore, there weresignificant decreases in SHBG, testosterone, and the plasma lipids cholesterol, HDL, and LDL. At baseline CRP and HDL were significantly correlated with adiponectin (Table 2). Testosterone was negatively correlated with the HA-ratio. No correlations were found between HMWand CRP, sex hormones, or plasma lipids.18DISCUSSIONThis study investigate the effect of a progestagen-only contraceptive preparation on plasma concentrations of the cardiovascular risk marker total adiponectin and its HMW isomer. The main finding of this prospective nonrandomized controlled study is a significant decrease of HMW in Implanon users 3 months after insertion.Because total adiponectin plasma concentrations remained unchanged we assume that Implanon causes a shift in the relation between the adiponectin isomers toward a lower production of HMW

This assumption is reflected in the decrease of the HMW/total adiponectin ratio. Low HMW plasma levels are considered to be unfavorable with regard to cardiovascular risk and only the HMW isoform suppresses endothelial cell apoptosis

Gender affects both total adiponectin and HMW, with women showing a higher content of theHMWisoforms19CRP and HDL are associated with adiponectin levelsBased on the finding that baseline testosteroneAlthough CRP and HDL are associated with adiponectin levels and despite the fact that Implanon causes a decrease in CRP and HDL, we did not observe a change of total adiponectin in Implanon users

Based on the finding that baseline testosterone was associated with the HA-ratio and because the HA-ratio and HMW decreased significantly during use of the implant, we hypothesize that a hormone-dependent mechanism like a decrease in testosterone might be causally related to the observed lowering of HMW. Regarding sex hormones, most investigators did not find a direct association between adiponectin and testosterone serum levels20Reduction of HMW adiponectin is associated with the risk of insulin resistance and type 2 diabetes mellitusthe area under the curve increases for both parameters, which indicates the induction of aninsulin resistance. Although these changes are small, they may contribute to the reduction in HMW observed in our study.In healthy subjects changes in insulin levels after glucose loading correlate negatively withHMW. During 12 months after insertion insulinand glucose levels before and after glucose load are within the normal range in Implanon users21The more important clinical question is to understand the consequence of the change in HMW together with the variations in other risk markers with respect to the potential cardiovascular risk of the individual Implanon user.The concentrations of two favorable cardiovascular risk markers HDL and HMW-adiponectin concentrations decrease.In coc user In parameters increase. The clinical relevance of these metabolic findings is difficult to interprete because of the combination of favorable (CRP; LDL) and unfavorable findings (HMW; HDLBecause the cholesterol/HDL ratio remains stable, the decrease in HDL has not been considered as relevant for cardiovascular risk

The reduction in the risk marker CRP and in the protective marker HMW was unexpected. Interestingly, the phenomenon that levels of adiponectin and CRP change in the same direction was also found in COC users

Low levels of adiponectin have been shown to be predictive for hypertension in normotensive females, and can be used to identify insulin resistancebefore the development of diabetes22High-molecular-weight adiponectin is a predictor of progression to metabolic syndromeThe difference in HMW levels between cases and controls in studies investigating HMW in relation to other cardiovascular risks is 15% to 25%Implanon is not only used in healthy females,Nonetheless, it remains unclear if HMW levels that are artificially suppressed by contraceptive hormones may be considered a harmless pharmacologic effect without clinical impact, or if they will have the same relevance for the prediction of metabolic syndrome and cardiovascular disease, as in untreated females.

Implanon is not only used in healthy females, but also in women with obesity, metabolic syndrome, and diabetes mellitus, all conditions associated with low HMW. A further decrease of HMW in these females might be more harmful 23A major strength of the present study is the prospective controlled designIn conclusion, short-term Implanon use in healthy premenopausal women was associated with a decrease in WadiponectinRandomization was not performed because it was considered unethical to perform randomized placebo-controlled clinical trials in women requiring contraception

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