Implanon use lowers plasma concentrations of

high-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, Zurich, Switzerland;
and b Institute of Clinical Chemistry, University Hospital, Zurich, 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 20 controls without hormonal contraception; n 20 cases wishing the insertion of Implanon).
Intervention(s): 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 Measure(s): At baseline there was a significant correlation between adiponectin and the parameters
hsCRP 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;95:237. 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 progestagen 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

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., Clinic for Reproductive
Endocrinology, Department of Gynecology and Obstetrics, University
Hospital, Frauenklinikstrasse 10, CH-8091 Zurich, Switzerland (FAX:
0114112554376; E-mail: gabriele.merki@usz.ch).

0015-0282/$36.00
doi:10.1016/j.fertnstert.2010.05.018

been found for progestagen-only preparations (POP) in epidemiologic 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 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 (4, 8).
Three isoforms of adiponectin circulate in plasma: highmolecular-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/totaladiponectin ratio (HA-ratio) rather than total adiponectin are associated with insulin sensitivity, metabolic syndrome, and the prediction
of cardiovascular events (1922). With the present prospective study

Fertility and Sterility Vol. 95, No. 1, January 2011

Copyright 2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

23

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)
Variable
Adiponectin (mg/mL)
HMW adiponectin (mg/mL)
HMW/total-adiponectin ratio
hsCRP (mg/L)
High-density lipoprotein (mmol/L)
Low-density lipoprotein (mmol/L)
Cholesterol (mmol/L)
SHBG (nmol/L)
Estradiol (pmol/L)
Testosterone (nmol/L)

Implanon treatment (n [ 17)

P value

Baseline

3 mo

Baseline

3 mo

7.1 (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)
2.80 (0.99)
4.41 (0.99)
38.3 (14.7)
262 (287)
1.28 (0.42)

.86
.03
.05
.06
.01
.01
.01
.01
.59
.04

.06
.03
.12
.16
.01
.64
.16
.01
.06
.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 high-molecular weight; SHBG sex hormone binding globulin.
a
P 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.

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

adiponectin and the metabolically more important HMW isomer.

MATERIALS AND METHODS

This 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 Zurich. Women
could be included if they were aged between 18 and 40 years, had 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.
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
70 C until assayed. For each patient, samples from all visits were thawed
and assayed in the same batch. Serum levels of both HMW and total adiponectin were determined by enzyme-linked immunosorbent assay (ELISA)
detection (Multimeric Adiponectin ELISA Kit; Buhlmann 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 coefficient 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 for both total and HMW adiponectin 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

24

Merki-Feld et al.

Low HMW levels in Implanon users

Ltd, Basel, Switzerland) (intraassay CV 2.3%, interassay CV <4.6%, detection 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 Corporation, Los Angeles, CA, USA) (intraassay CV 4.5% interassay 5.1% sensitivity 0.1 nmol/L; CIS diagnostic GmbH, Dreieich, Germany) (intraassay CV
2.8% interassay 7.9% sensitivity 0.04 nmol/L; Diagnostic Products Corporation). 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 Analysis
Statistical 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 MannWhitney U-tests were used for comparisons 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 P.05.

RESULTS
Of the 40 women recruited, 32 subjects completed the study (treatment group n 17; control n 15). Reasons for dropout were pregnancy, withdrawal of informed consent, desire to use contraceptive
hormones, and loss to follow-up. 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 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
Vol. 95, No. 1, January 2011

Fertility and Sterility

1.0
0.17 (0.50)

1.0

BMI

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

1.0
0.89 (0.01)
0.16 (0.38)
0.08 (0.75)
1.0
0.36 (0.04)
0.7 (0.69)
0.62 (0.01)
0.19 (0.46)
1.0
0.31 (0.08)
0.29 (0.10)
0.27 (0.13)
0.19 (0.92)
0.04 (0.81)
1.0
0.13 (0.48)
0.13 (0.46)
0.20 (0.26)
0.14 (0.43)
0.08 (0.65)
0.07 (0.91)
1.0
0.44 (0.01)
0.06 (0.73)
0.05 (0.79)
0.28 (0.11)
0.23 (0.19)
0.01 (0.98)
0.20 (0.42)
1.0
0.28 (0.12)
0.42 (0.02)
0.14 (0.42)
0.09(0.59)
0.19 (0.29)
0.16 (0.36)
0.18 (0.30)
0.008 (0.94)

1.0
0.34 (0.05)
0.15 (0.40)
0.06 (0.72)
0.45 (0.01)
0.37(0.04)
0.31 (0.08)
0.24 (0.19)
0.22 (0.22)
0.17 (0.35)
1.0
0.88 (0.001)
0.68 (0.001)
0.29 (0.10)
0.24 (0.18)
0.26 (0.51)
0.29 (0.10)
0.33 (0.06)
0.26 (0.15)
0.16 (0.38)
0.16 (0.36)
HMW
Total adiponectin
HMW/total adiponectin
Estradiol
Testosterone
hsCRP
HDL
LDL
Cholesterol
SHBG
BMI

Note: HMW high-molecular-weight; BMI body mass index; SHBG sex hormone binding globulin; HDL high-density lipiprotein; LDL low-density lipoprotein.

1.0
0.15 (0.56)
0.07 (0.77)

SHBG
Cholesterol
LDL
HDL
hsCRP
Testosterone
Estradiol
HMW/total
adiponectin
Total
adiponectin
HMW
Marker

levels (P values).

To our knowledge, this is the first study to 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
(21, 2426). 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 constellation 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 (2830). 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,
3134). 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 reactiveoxygen 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 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 levels (16, 3639). 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 speculates that the three oligomeric complexes of adiponectin might be
released from adipocytes via distinct secretory pathways, which renders it possible for testosterone 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

TABLE 2

DISCUSSION

Spearman correlations between high-molecular-weight adiponectin, total adiponectin, high-molecular weight/total adiponectin, hsCRP, plasma lipids, and female hormone

compared with the treatment group. After three cycles all parameters 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 significantly 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.

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 cardioprotective HMW plasma concentrations in Implanon users. Another 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 insulin 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 normal 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 contribute to the reduction in HMW observed in our study.
The 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. Because the cholesterol/HDL ratio remains stable, the
decrease in HDL has not been considered as relevant for cardiovascular risk (8). The reduction in the risk 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 findings 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-weight
adiponectin 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
will have the same relevance 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 etonogestrel 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. Nevertheless, 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 HMW are small, it
has to be considered that 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. 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 considered 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 cardiovascular 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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