Implanon Use Lowers Plasma Concentration of High-molecular-weight Adiponectin

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Implanon use lowers plasma concentrations ofhigh-molecular-weight adiponectin

Gabriele S. Merki-Feld, P.D., Dr.,a Bruno Imthurn, Prof.,a Marinella Rosselli, P.D., Dr.,a

and Katharina Spanaus, Dr.b

a Clinic for Reproductive Endocrinology, Department of Gynecology and Obstetrics, University Hospital, Z€urich, Switzerland;

and b Institute of Clinical Chemistry, University Hospital, Z€urich, Switzerland

Objective: To investigate the effect of the low-dosed etonogestrel-releasing contraceptive implant Implanon on

new cardiovascular risk markers, we studied the effect of this implant on adiponectin and its metabolically

important isomer high-molecular-weight adiponectin (HMW). Low-dosed progestagen-only contraception is

preferentially prescribed to females with increased cardiovascular risks.

Design: Longitudinal study.

Setting: Family-planning center of a university hospital.

Patient(s): Forty healthy nonsmoking women with regular cycles (n ¼ 20 controls without hormonal contracep-

tion; n ¼ 20 cases wishing the insertion of Implanon).

Intervention(s): Blood samples for the measurements of adiponectin, HMW, C-reactive protein (CRP), sex hor-

mone 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 Measure(s): At 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. Additionally plasma lipids (cholesterol, high-density lipoprotein, low-density lipoprotein), sex

hormone binding globulin, and testosterone levels decreased significantly. Adiponectin plasma concentrations

were not affected.

Conclusion(s): Short-term Implanon use in healthy premenopausal women was associated with a decrease in the

cardioprotective adiponectin isomer HMW. It remains to be investigated if this decrease persists after longer use of

the implant. (Fertil Steril 2011;95:23–7. 2011 by American Society for Reproductive Medicine.)

Key Words: Progestagen-only contraception, Implanon, cardiovascular risk, high-molecular-weight adiponectin,

contraceptive pill

Implanon is a single-rod contraceptive implant that releases the pro-

gestagen etonogestrel, which is the active metbolite of desogestrel.

The 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 (1). Plasma concentrations

are highest during the initial 6 months of use (2). Previous studies

demonstrated the modest effects of the implant on plasma lipids

and hemostasis (3, 4). However, 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 (5). These data partially explain the increased

cardiovascular risk associated with the use of these preparations.No evidence for an increased risk of cardiovascular disease has

been found for progestagen-only preparations (POP) in epidemio-

logic studies (6, 7). However, the number of investigations

concerning this issue is small. Implanon does not exert a negative

effect on nitric oxide, endothelin-1, transforming growth factor-b,

CRP, the cholesterol/high-density lipoprotein (HDL) ratio, and

triglycerides (4, 8, 9). The effect of this implant on adiponectin

has not yet been investigated.

Adiponectin is a novel collagen-like protein synthesized by white

adipose tissue. It circulates in high serum concentrations and has

been linked to cardiovascular disease (10). Low levels of adiponec-

tin have been found in patients with ischemic heart disease, hyper-

tension, diabetes mellitus type II, and dyslipidemia. (11–14). Sex

hormones, in particular testosterone, and plasma lipids seem to be

involved in the regulation (15–17). Because Implanon causesa decrease in circulating testosterone, HDL and low-density lipopro-

tein (LDL), we hypothesized that the use of this implant might

induce changes in adiponectin plasma levels (4, 8).

Three isoforms of adiponectin circulate in plasma: high-

molecular-weight adiponectin (HMW), low-molecular-weight

adiponectin (LMW), and medium-molecular-weight (MMW)

adiponectin (18). 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/total-

adiponectin ratio (HA-ratio) rather than total adiponectin are associ-

ated with insulin sensitivity, metabolic syndrome, and the prediction

of cardiovascular events (19–22). With the present prospective study

Received February 9, 2010; revised April 29, 2010; accepted May 11,

2010; published online June 23, 2010.

G.S.M-F. has nothing to disclose. B.I. has nothing to disclose. M.R. has

nothing to disclose. K.S. has nothing to disclose.

The study has been approved by the local ethical committee. Participants

gave their consent before inclusion.

Reprint requests: Gabriele S. Merki-Feld, P.D., Dr.,Clinicfor Reproductive

Endocrinology, Department of Gynecology and Obstetrics, University

Hospital, Frauenklinikstrasse 10, CH-8091 Zurich, Switzerland (FAX:

0114112554376; E-mail: [email protected] ).

0015-0282/$36.00 Fertility and Sterility Vol. 95, No. 1, January 2011 23doi:10.1016/j.fertnstert.2010.05.018 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

mailto:[email protected]

mailto:[email protected]



we aimed to investigate the effect of Implanon on plasma levels of

adiponectin and the metabolically more important HMW isomer.

MATERIALS AND METHODSThis study derives from a more extensive prospective clinical trial addressing

the effects of progestagen contraception on cardiovascular risk parameters.

Some data have been previously reported (8). Forty volunteers were recruited

from the Family Planning Center of the University Hospital Z€urich. Women

could beincluded iftheywere agedbetween 18and 40 years,had cycles of26

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. In-

formed consent was obtained from all participants, and the study was ap-

proved by the institutional review board of the University Hospital of Z€urich.

Venous blood samples were taken between 8 and 10 a.m. after overnight

fasting and a regulated diet of 24 hours. Although several investigators

have not observed fluctuations of adiponectin during the cycle, we collected

baseline samples during cycle days 1 to 4 (cycle 1), because we thought that

plasma levels of the HMW isoform might vary (23). 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. For each patient, samples from all visits were thawed

and assayed in the same batch. Serum levels of both HMW and total adipo-

nectin were determined by enzyme-linked immunosorbent assay (ELISA)

detection (Multimeric Adiponectin ELISA Kit; B€uhlmann Laboratories

AG, Sch€onenbuch, 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. Sensitivity of the assay

is 0.08 ng/mL. Coefficients of intraassay variations were 5.3% to 5.4% for

total adiponectin and 3.3% to 5.0% for HMW adiponectin, interassay coeffi-

cient of variation (CV) were 5.0% and 5.7% for total adiponectin and for

HMW adiponectin, respectively. The results are expressed as mg/mL. Serum

controls forboth total and HMWadiponectin were measured with each assay.

The HMW/adiponectin ratio (HA-ratio) was calculated as another potential

parameter for individual cardiovascular risk.

C-reactive protein concentrations were determined as high sensitive CRP

using a latex-enhanced immunoturbidimetric (Wako Chemicals GmbH,

Neuss, Germany) on a Cobas Fara centrifugal analyzer (Roche Diagnosics

Ltd, Basel, Switzerland) (intraassay CV 2.3%, interassay CV <4.6%, detec-

tion limit 0.425 mg/L). Estradiol, progesterone, testosterone, and sex

hormone binding globulin (SHBG) were analyzed by commercially available

radioimmunoassays (intraassay CV 4.2%, interassay 4.9%, sensitivity18

pmol/L; Sorin Biomedica Diagnostics, Saluggia, Italy) (intraassay CV

3.6%, interassay 3.9%, sensitivity 0.06 nmol/L; Diagnostic Products Corpo-

ration, Los Angeles, CA, USA) (intraassay CV 4.5% interassay 5.1% sensi-

tivity 0.1 nmol/L; CIS diagnostic GmbH,Dreieich, Germany) (intraassayCV

2.8% interassay 7.9% sensitivity 0.04 nmol/L; Diagnostic Products Corpora-

tion). Cholesterol, HDL, and LDL were measured automatically (Hitachi

747; Roche Diagnostics). The free androgen index (FAI) was calculated as

100 testosterone (nmol/L)/SHBG (nmol/L).

Statistical AnalysisStatistical analyses were performed using SPSS 17.0 software (SPSS Inc.,

Chicago, IL, USA). 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).

Antilogarithms of transformed variables were used to obtain geometric

means.The unpaired t test and Mann–Whitney U -tests were used forcompar-

isons between groups. Within-treatment effects were compared by paired

t tests or Wilcoxon 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 P¼.05.

RESULTSOf the 40 women recruited, 32 subjects completed the study (treat-

ment group n¼ 17; control n¼ 15). Reasons for dropout were preg-

nancy, withdrawal of informed consent, desire to use contraceptive

hormones, and loss to follow-up. The two groups did not differ sig-

nificantly 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 three

cycles) for both groups are presented in Table 1. 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

TABLE 1

Levels 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.

Control (n[ 15) Implanon treatment (n[ 17) P value

Variable Baseline 3 mo Baseline 3 mo a b

Adiponectin ( mg/mL) 7.1 (3.4;11.4) 6.9 (3.4;9.9) 6.05 (3.3;8.7) 5.77 (3.0;7.7) .86 .06

HMW adiponectin ( mg/mL) 5.0 (1.5;7.8) 4.9 (1.4;8.0) 4.18 (1.4;6.2) 3.60 (1.2;5.8) .03 .03

HMW/total-adiponectin ratio 0.68 (0.03) 0.68 (0.03) 0.68 (0.03) 0.60 (0.03) .05 .12hsCRP (mg/L) 1.86 (2.70) 1.97 (2.55) 2.02 (1.59) 1.31 (1.07) .06 .16

High-density lipoprotein (mmol/L) 1.57 (0.33) 1.57 (0.29) 1.34 (0.26) 1.24 (0.25) .01 .01

Low-density lipoprotein (mmol/L) 3.10 (1.02) 2.96 (1.08) 3.25 (1.12) 2.80 (0.99) .01 .64

Cholesterol (mmol/L) 5.08 (0.93) 4.92 (1.02) 4.92 (1.18) 4.41 (0.99) .01 .16

SHBG (nmol/L) 65.6 (35.9) 57.8 (13.5) 52.4 (32.6) 38.3 (14.7) .01 .01

Estradiol (pmol/L) 116 (49) 112 (60) 184 (181) 262 (287) .59 .06

Testosterone (nmol/L) 1.28 (0.47) 1.25 (0.41) 1.48 (0.45) 1.28 (0.42) .04 .81

Note: Data are presented as mean (SD) or as median (min;max) if distribution is skewed. No significant changes were observed in the control group.

HMW ¼ high-molecular weight; SHBG ¼ sex hormone binding globulin.aP value of changes during treatment ( t test).

b Difference between groups after 3 months (unpaired t test).

Merki-Feld. Low HMW levels in Implanon users. Fertil Steril 2011.

24 Merki-Feld et al. Low HMW levels in Implanon users Vol. 95, No. 1, January 2011



compared with the treatment group. After three cycles all parame-

ters in the control group were unchanged. Implanon treatment did

not cause any significant changes in adiponectin, CRP, or estradiol.

High-molecular-weight and the HA-ratio decreased significantly 3

months after insertion of the implant. Furthermore, there were

significant decreases in SHBG, testosterone, and the plasma lipids

cholesterol, HDL, and LDL. At baseline CRP and HDL were signif-

icantly correlated with adiponectin (Table 2). Testosterone was

negatively correlated with the HA-ratio. No correlations were found

between HMW and CRP, sex hormones, or plasma lipids.

DISCUSSIONTo our knowledge, this is the first study to investigate the effect of

a progestagen-only contraceptive preparation on plasma concentra-

tions 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 HMWin Implanon users

3 months after insertion. Because total adiponectin plasma concen-

trations 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

(21, 24–26). Gender affects both total adiponectin and HMW, with

women showing a higher content of the HMW isoforms (27). Today,

it is not known if this contributes to the in comparison with men

lower cardiovascular risk in premenopausal women. The in the

present study observed shift in adiponectin isoforms with a decrease

in HMW during Implanon use alters the for women favorable con-

stellation of adiponectin isoforms.

Plasma levels of adiponectin and HMW adiponectin in our study

are in the range of those reported by other investigators for healthy

females (28–30). In accordance with previous studies we observed

a positive association between adiponectin and the

cardioprotective lipid HDL and a negative association between the

inflammatory cytokine CRP and adiponectin at baseline (5, 22,

31–34). The physiologic mechanisms underlying these

associations and the molecular mechanisms involved in

adiponectin secretion and multimerisation have not been

elucidated. However, it is known that in addition to reactive-

oxygen species, inflammatory cytokines inhibit adiponectin gene

expression in vitro (35).

Although 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 hor-mone-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 be-

tween adiponectin and testosterone serum levels (16, 36–39). Xu

(40), however, demonstrated in rodents and hypogonadal men that

testosterone selectively reduces circulating concentrations of

HMW, but not LMW and MMW adiponectin. Xu (40) further spec-

ulates that the three oligomeric complexes of adiponectin might be

released from adipocytes via distinct secretory pathways, which ren-

ders it possible fortestosterone to selectively impede the secretion of

HMW from adipocytes. However, this thesis is not in accordance

with our data showing falling plasma levels of both HMW and T A B L E

2

S p e a r m a n c o r r e l a t i o n s b e t w e e n h

i g h - m o l e c u l a r - w e i g h t a d i p o n e c t i n , t o t a l a d i p o n e c t i n , h i g h - m o l e c u l a r w e i g h t / t o t a l a d i p o n e c t i n , h s C R P , p l a s m a l i p i d s , a n d f e m a l e h o r m o n e

l e v e l s ( P

v a l u e s ) .

M a r k e r

H M W

T o t a l

a d i p o n e c t i n

H M W / t o t a l

a d i p o n e c t i n

E s t r a d i o l

T e s t o -

s t e r o n e

h s C R P

H D L

L D L

C h o l e s -

t e r

o l

S H B G

B M I

H M W

1 . 0

—

—

T o t a l a d i p o n e c t i n

0 . 8 8 ( 0 . 0 0 1 )

1 . 0

H M W / t o t a l a d i p o n e c t i n

0 . 6 8 ( 0 . 0 0 1 )

0 . 3 4 ( 0 . 0 5 )

1 . 0

E s t r a d i o l

0 . 2 9 ( 0 . 1 0 )

0 . 1 5 ( 0 . 4 0 )

0 . 2 8 ( 0 . 1 2 )

1 . 0

T e s t o s t e r o n e

0 . 2 4 ( 0 . 1 8 )

0 . 0 6 ( 0 . 7 2 )

0 . 4 2 ( 0 . 0 2 )

0 . 4 4 ( 0 . 0 1 )

1 . 0

h s C R P

0 . 2 6 ( 0 . 5 1 )

0 . 4 5 ( 0 . 0 1 )

0 . 1 4 ( 0 . 4 2 )

0 . 0 6 ( 0 . 7 3 )

0 . 1 3 ( 0 . 4 8 )

1 . 0

H D L

0 . 2 9 ( 0 . 1 0 )

0 . 3 7 ( 0 . 0 4 )

0 . 0 9 ( 0 . 5 9 )

0 . 0 5 ( 0 . 7 9 )

0 . 1 3 ( 0 . 4 6 )

0 . 3 1 ( 0 . 0

8 )

1 . 0

L D L

0 . 3 3 ( 0 . 0 6 )

0 . 3 1 ( 0 . 0 8 )

0 . 1 9 ( 0 . 2 9 )

0 . 2 8 ( 0 . 1 1 )

0 . 2 0 ( 0 . 2 6 )

0 . 2 9 ( 0 . 1

0 )

0 . 3 6 ( 0 . 0 4 )

1 . 0

C h o l e s t e r o l

0 . 2 6 ( 0 . 1 5 )

0 . 2 4 ( 0 . 1 9 )

0 . 1 6 ( 0 . 3 6 )

0 . 2 3 ( 0 . 1 9 )

0 . 1 4 ( 0 . 4 3 )

0 . 2 7 ( 0 . 1

3 )

0 . 7 ( 0 . 6 9 )

0 . 8 9 ( 0 . 0 1 )

1 .

0

S H B G

0 . 1 6 ( 0 . 3 8 )

0 . 2 2 ( 0 . 2 2 )

0 . 1 8 ( 0 . 3 0 )

0 . 0 1 ( 0 . 9 8 )

0 . 0 8 ( 0 . 6 5 )

0 . 1 9 ( 0 . 9

2 )

0 . 6 2 ( 0 . 0 1 )

0 . 1 6 ( 0 . 3 8 )

0 . 1 5 ( 0 . 5 6 )

1 . 0

B M I

0 . 1 6 ( 0 . 3 6 )

0 . 1 7 ( 0 . 3 5 )

0 . 0 0 8 ( 0 . 9 4 )

0 . 2 0 ( 0 . 4 2 )

0 . 0 7 ( 0 . 9 1 )

0 . 0 4 ( 0 . 8

1 )

0 . 1 9 ( 0 . 4 6 )

0 . 0 8 ( 0 . 7 5 )

0 . 0 7 ( 0 . 7 7 )

0 . 1 7 ( 0 . 5 0 )

1 . 0

N o t e : H M W

¼

h i g h - m o l e c u l a r - w e i g h t ; B M

I ¼

b o d y m a s s i n d e x ; S H B G ¼

s e x h o r m o n e

b i n d i n g g l o b u l i n ; H D L ¼

h i g h - d e n s i t y l i p i p r o t e i n ; L D L ¼

l o w - d e n s i t y l i p o p r o t e i n .

M e r k i - F e l d .

L o w H M W l e v e l s i n I m p l a n o n u s e r s . F e r t i l S t e r i l 2 0 1 1 .

Fertility and Sterility 25



testosterone. To test if perhaps not total testosterone but circulating

levels of free testosterone are associated with HMW or the HA-ratio

we also calculated the FAI. The FAI was positively associated with

the HA-ratio at baseline (P<.004) and increased during Implanon

use (P<.02). Our data therefore suggest that changing levels of

free androgens could be causally involved in the decrease of cardi-

oprotective HMW plasma concentrations in Implanon users. An-

other explanation for falling HMW after Implanon insertion could

be a direct inhibitory effect of the progestagen etonogestrel on the

release of HMW. However, the overall underlying mechanisms are

complex, and our study was not designed to clarify mechanisms.

Reduction of HMW adiponectin is associated with the risk of in-

sulin resistance and type 2 diabetes mellitus (19, 28). In healthy

subjects changes in insulin levels after glucose loading correlate

negatively with HMW (41). During 12 months after insertion insulin

and glucose levels before and after glucose load are within the nor-

mal range in Implanon users (42). However, the area under the curve

increases for both parameters, which indicates the induction of an

insulin resistance. Although these changes are small, they may con-

tribute to the reduction in HMW observed in our study.

The more important clinical question is to understand the conse-

quence 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 cardio-

vascular risk markers HDL and HMW-adiponectin concentrations

decrease. Because the cholesterol/HDL ratio remains stable, the

decrease in HDL has not been considered as relevant for cardiovascu-

lar risk (8). The reduction in therisk marker CRP and in the protective

marker HMW in our study was unexpected. Interestingly, the

phenomenon that levels of adiponectin and CRP change in the same

direction was also found in COC users (5). In users of COC both

parameters increase. The clinical relevance of these metabolic find-

ings is difficult to interprete because of the combination of favorable

(CRP; LDL) and unfavorable findings (HMW; HDL). Low levels of

adiponectin have been shown to be predictive for hypertension in

normotensive females, and can be used to identify insulin resistance

before the development of diabetes (43, 44). High-molecular-weightadiponectin is a predictor of progression to metabolic syndrome

(28). Nonetheless, it remains unclear if HMW levels that are artifi-

cially suppressed by contraceptive hormones may be considered

a harmless pharmacologic effect without clinical impact, or if they

willhave the samerelevance for the prediction of metabolic syndrome

and cardiovascular disease, as in untreated females. The difference in

HMW levels between cases and controls in studies investigating

HMW in relation to other cardiovascular risks is 15% to 25% (21,

28, 34). The decrease in HMW levels predictive for metabolic

syndrome is even above 30% (34). Therefore, and because etonoges-

trel levels fall during longer use of the implant, we propose that the

much smaller changes in HMW (13%) during short-term use may

not markedly effect individual long-term cardiovascular risk. Never-

theless, future investigations should study if HMW levels return to

baseline in long-term users of Implanon.

Even if the observed changes of the implant on HMWare small, it

has to be considered that Implanon is not only used in healthy fe-

males, but also in women with obesity, metabolic syndrome, and di-

abetes mellitus, all conditions associated with low HMW. A further

decrease of HMW in these females might be more harmful. To get

a more entire imagine of the effect of hormonal preparations on

HMW, further studies are needed to obtain more information about

the effect of not only low-dosed progestagen preparations but also

combined preparations on this important cytokine in women with

preexisting risk factors. At the moment we propose that the lower

the hormone dosage, the smaller the effect on the adipocytokines.

A major strength of the present study is the prospective controlled

design. Randomization was not performed because it was consid-

ered unethical to perform randomized placebo-controlled clinical

trials in women requiring contraception. The investigation of both

adiponectin and the HMW isoform that is important for cardiovas-

cular risk provides new insights into the metabolic effects of POP.

The study included healthy women of normal weight to avoid

confounders like obesity or hypertension. Limitations of the study

are the observation period of 3 months and the sample size. Because

etonogestrel levels are highest after insertion, it is possible, that

HMW levels would return to normal with longer use of the implant.

The number of participants was not very high, but sufficient to detect

clinically relevant changes.In conclusion, short-term Implanon use in healthy premenopausal

women was associated with a decrease in HMW adiponectin.

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Fertility and Sterility 27

Implanon Use Lowers Plasma Concentration of High-molecular-weight Adiponectin

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