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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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