The European Journal of Contraception and Reproductive Health Care June 2008;13(S1):13–28

The effects of Implanon1 on menstrual

bleeding patterns
Diana Mansour{, Tjeerd Korver{, Maya Marintcheva-Petrova{ and Ian S. Fraserx
{
Newcastle Contraception and Sexual Health Services, Graingerville Clinic, Newcastle General Hospital, Newcastle
upon Tyne, UK; {Organon, part of Schering-Plough, Global Clinical Development, Oss, The Netherlands; and
x
University of Sydney, Department of Obstetrics and Gynaecology, Sydney, Australia

...........................................................................................................................................................................................................

ABSTRACT Objectives To evaluate an integrated analysis of bleeding patterns associated with use of
the subdermal contraceptive implant Implanon1 (etonogestrel, Organon, part of Schering-
Plough) and to provide physician guidance to optimize patient counselling.
Methods Data from 11 clinical trials were reviewed (N ¼ 923). Assessments included
bleeding-spotting records, dysmenorrhoea, and patient-perceived reasons for discontinua-
tion. Bleeding patterns were analysed via reference period (RP) analyses.
Results Implanon1 use was associated with the following bleeding irregularities:
amenorrhoea (22.2%) and infrequent (33.6%), frequent (6.7%), and/or prolonged bleeding
(17.7%). In 75% of RPs, bleeding-spotting days were fewer than or comparable to those
observed during the natural cycle, but they occurred at unpredictable intervals. The bleeding
pattern experienced during the initial phase predicted future patterns for the majority of
women. The group of women with favourable bleeding patterns during the first three
months tended to continue with this pattern throughout the first two years of use, whereas
the group with unfavourable initial patterns had at least a 50% chance that the pattern would
improve. Only 11.3% of patients discontinued owing to bleeding irregularities, mainly
because of prolonged flow and frequent irregular bleeding. Most women (77%) who had
baseline dysmenorrhoea experienced complete resolution of symptoms.
Conclusion Implanon1 use is associated with an unpredictable bleeding pattern, which
includes amenorrhoea and infrequent, frequent, and/or prolonged bleeding. The bleeding
pattern experienced during the first three months is broadly predictive of future bleeding
patterns for many women. Effective preinsertion counselling on the possible changes in
bleeding patterns may improve continuation rates.

KEYWORDS Implanon1, Etonogestrel, Contraception, Irregular bleeding, Dysmenorrhoea,

Discontinuation
...........................................................................................................................................................................................................

INTRODUCTION

Changes to the menstrual bleeding pattern are the contraception and constitute the most important
most common adverse effect of progestogen-only reason that women discontinue these methods1,2.

Correspondence: Tjeerd Korver, PhD, Organon, part of Schering-Plough - Global Clinical Development, PO Box 20, 5340 BH Oss, The
Netherlands. Tel: þ31 412 661840. E-mail: tjeerd.korver@organon.com

ª 2008 European Society of Contraception

DOI: 10.1080/13625180801959931
Effects of Implanon1 on menstrual bleeding patterns
Bleeding patterns become unpredictable and irregular,
occasionally with bleeding occurring more frequently
and/or becoming prolonged or infrequent, with
episodes of amenorrhoea. The total measured volume
of endometrial blood loss in women using subdermal
progestogen implants is usually significantly smaller
than their natural menstrual loss3. Although these
changes have no serious effects on health, they can
interfere with daily activities and have an impact on
general well-being. Therefore, patient counselling is
an important tool for the clinician that may help put
bleeding changes in perspective and potentially
improve continuation rates.
The mechanisms behind the bleeding pattern
disturbance are still not completely understood but
appear to be the combined result of fluctuating ovarian
oestradiol secretion and continuous progestogenic
exposure of endometrial glands, stroma and vascula-
ture4,5. There is increasing evidence that this leads to
disturbed endometrial angiogenesis, with fragile, thin-
walled surface vessels, lack of pericytes, defective
basement membrane, altered migratory leukocytes,
and disturbed matrix metalloproteinase release4. Stra-
tegies to manage bleeding and improve awareness of
possible bleeding patterns should be developed and
implemented. Further research on the mechanisms
underlying unscheduled endometrial bleeding and on
potential methods to prevent endometrial breakdown
and promote repair should be actively encouraged.
Implanon1 (etonogestrel, Organon, part of Scher-
ing-Plough, Oss, The Netherlands) is a subdermal
contraceptive implant that is more than 99% effective,
with a duration of use of three years and a quick return
to fertility6. This review describes an analysis from 11
integrated clinical trials of bleeding patterns associated
with the use of Implanon1. Recommendations and
guidance to the prescribing physician are presented to
foster optimum patient education.
METHODS
Subjects
Subjects enrolled in the clinical trials were between 18
and 40 years of age, were sexually active, were of
childbearing potential, and had regular menstrual
cycles. They were in good physical and mental health
and had no contraindications to the use of contra-
ceptive steroids. In most trials subjects were not
14
Mansour et al.
allowed to have used oral contraceptives for at least
one month or implantable contraceptives for at least
two months before the start of study medication. The
use of injectable contraceptives within three months
before the start of study medication was prohibited in
all studies. In two studies subjects were allowed to
switch from oral and implantable contraceptives.
Except for switchers from hormonal methods,
Implanon1 was inserted between days 1 and 5 of
the menstrual cycle. All subjects gave written
informed consent.
Clinical trials
Table 1 provides an overview of the studies included
in the integrated analysis of menstrual bleeding
patterns. Data from 11 clinical trials conducted in
the United States, Thailand, Chile, Singapore, Austria,
Germany, Finland, Hungary, The Netherlands,
Russia, and Malaysia were included. The trials all
had an open-label design and were noncomparative or
comparative with either Norplant1 or a nonmedi-
cated intrauterine device. Most trials were at least two
years in duration, had contraceptive efficacy and
bleeding among their outcome measures, and had a
three-month visit schedule up to and including three
months after implant removal. The pooled set for the
integrated bleeding pattern analysis presented in this
paper excludes breast-feeding women, who were
allowed to participate in the studies conducted in
Russia (n ¼ 2) and Malaysia (n ¼ 14). Appropriate
institutional ethics committee approval was obtained
for all trials.
All subjects were given diary cards to record daily
occurrences of bleeding, spotting, or absence of
bleeding or spotting. Data were recorded in a suitable
format for reference period (RP) analysis in which
medically relevant bleeding variables were identified
and evaluated over consecutive 90-day RPs.
Discontinuation due to bleeding irregularities
Reasons for discontinuation were recorded using
predefined codes identifying the patient-perceived
reasons for discontinuations. Those related to bleeding
patterns were categorized under ‘menstrual problems’
as follows: frequent irregular bleeding, heavy men-
strual flow, prolonged menstrual flow, amenorrhoea,
spotting, or other bleeding problems. The term
The European Journal of Contraception and Reproductive Health Care
Effects of Implanon1 on menstrual bleeding patterns Mansour et al.

Table 1 Overview of studies included in the integrated analysis of bleeding patterns

Implanon1

Number of reference periods

Study Country/ Treatment
number region duration (years) N Up to 2 years Up to 3 years

069001* United States 2 327 1674 –

34502 Southeast Asia 5 15 120 165
34505 Southeast Asia 4 100 679 904
34507 Europe/Chile 3 267 1638 2152
34510 Southeast Asia 2 15 109 0
34511 Southeast Asia 2 40 304 0
34512 Europe 2 20 104 0
34515 Southeast Asia 2 10 74 0
34522 Europe 2 46 308 0
34525* Russia 1 28 101 0
E-1729* Southeast Asia 3 55 315 426
Total 923 5426 3647

*Breast-feeding women from studies 34525 (n ¼ 2) and E-1729 (n ¼ 14) and subjects without postbaseline
assessments (study 069001, n ¼ 3) were excluded from the analysis.

bleeding irregularities has been used to include all
disturbances of bleeding including amenorrhoea. It
should be noted that these reasons refer to the
perception of the patients; they are to be distinguished
from the objective definitions from the RP analysis as
described below.
The cumulative net probability of discontinuation
due to bleeding irregularities (as defined above) was
calculated by the Kaplan-Meier approach7.
Reference period analysis
The RP analysis divides a subject’s bleeding informa-
tion into 90-day segments8–10. Each segment repre-
sents one RP, starting with the day of implant
insertion as the first day of the first RP. The RP
analysis included all subjects who had at least one RP
that could be evaluated. An RP was considered invalid
and excluded from analysis if bleeding information was
missing for three or more consecutive days or if
nonpermitted concomitant medications were used. If
missing data were spread across two RPs, then both
RPs were excluded. If diary data were missing for 2
consecutive days, the missing values were converted
into the same bleeding-spotting (B-S) response
reported on the day immediately preceding the
missing values. If the data were missing on the first
one or two days of treatment, then the day
immediately following the missing data was used.
The following definitions were used to assess
bleeding patterns during the studies:
. Bleeding day: any day with vaginal discharge
containing blood that required more than one
sanitary towel or tampon per day.
. Spotting day: any day with vaginal discharge con-
taining blood that required at most one sanitary
towel or tampon per day.
. Bleeding-free day: a day during which neither
bleeding nor spotting was entered in the diary.
. B-S episode: one or more consecutive days during
which bleeding or spotting was entered in the
diary, bounded by bleeding-free days.
If a B-S episode started in an RP and continued into the
next one, it was counted in the RP in which it started.
The characterization of clinically important types of
bleeding patterns was based on the original World Health
Organization (WHO)-recommended definitions8–10:
. Amenorrhoea: no bleeding or spotting days
throughout the 90-day RP.
. Infrequent bleeding: less than three B-S episodes in a
90-day RP, excluding amenorrhoea.

The European Journal of Contraception and Reproductive Health Care 15

Effects of Implanon1 on menstrual bleeding patterns
. Normal frequency: three to five B-S episodes in a
90-day RP.
. Frequent bleeding: more than five B-S episodes in a
90-day RP.
. Prolonged bleeding: any B-S episode (uninterrupted)
lasting more than 14 days in a 90-day RP.
Because for most women implants were inserted
during day 1 through 5 of a menstrual period and
therefore might have disturbed the bleeding pattern
analysis, RP 1 was excluded from the analyses. When
applicable, a shifted first reference period, RP 1.1, was
defined (see below). Overall summary statistics per
RP were calculated for all patients from RP 2 through
RP 12. Although Implanon1 may be used for three
years, a minority of the studies covered a treatment
period of at least that duration, so that many analyses
focused on two-year data, for this purpose defined as
the first 720 days (the equivalent of eight RPs) after
insertion.
Bleeding patterns of continuers and discontinuers
were compared to explore the acceptability of various
bleeding pattern variables, as well as to address the
possible bias introduced by time resulting in the
exclusion of subjects with the least acceptable bleeding
pattern. This analysis was based on descriptions of
averages and incidences. The analysis was restricted to
RP 2 through RP 6 because only a few patients who
discontinued after 1.5 years contributed data beyond
RP 6. Possible determinants of bleeding patterns were
explored by an analysis of covariance on the mean
number of B-S days with body weight, body mass
index (BMI), and age as covariates and nulliparity and
geographic location as factors.
Bleeding pattern predictability was studied by the
progression of the bleeding characteristics over time in
categories of patients with a certain pattern as observed
during the initial phase of Implanon1 use. To
minimize the influence of the menstrual period at
the start of RP 1, RP 1.1 was defined as running from
day 29 (four weeks after implant insertion) through
day 118. There was an overlap (starting on day 91 and
continuing through day 118) between RP 1.1 and RP
2. Subject categories were defined according to the
number of B-S days in RP 1.1, and the B-S
experience in the various groups during later RPs
was subsequently explored. Four categories were
defined with respect to the number of B-S days in a
natural cycle: 0 to 14 B-S days per RP (fewer), 15 to
16 The European Journal of Contraception and Reproductive Health Care
Mansour et al.
28 B-S days (comparable), 29 to 49 B-S days
(elevated), and 50 B-S days (excessive).
Dysmenorrhoea
Dysmenorrhoea was investigated in 5 of the 11
studies. At baseline and at the end of treatment,
dysmenorrhoea intensity was recorded for all subjects
according to the following categories: none, mild,
severe, and very severe. Presence and severity of
dysmenorrhoea were compared between baseline and
end of treatment.
Haemoglobin
To assess whether blood loss associated with the use of
Implanon1 resulted in anaemia, haemoglobin blood
levels were measured at baseline and at the end of
treatment in five studies and in eight subjects from
another study.
RESULTS
Subject disposition and demographics
Out of a total of 923 non-breast-feeding subjects with
postbaseline efficacy data (all-subjects-treated popula-
tion), 889 had at least one RP that could be evaluated.
The mean age of the population was 27.7 years, and
the mean BMI was 23.0 kg/m2. Women in the
Europe/Chile and United States subgroups had a
comparable mean weight: 60.4 kg and 63.1 kg,
respectively. In contrast, women from the Southeast
Asia region weighed less (mean 54.0 kg). The most
common previous method of contraception in the
European/Chilean population was oral contraceptives.
Women in the United States most often used foam,
condoms, diaphragms, or spermicides, and 30% of
women in the Southeast Asia cohort indicated that
they did not use any form of contraception before
study entry. Parity varied greatly amongst the
geographic subgroups, with nulliparity being most
prevalent in the United States (59.0%), followed by
Europe/Chile (19.4%) and Southeast Asia (8.1%).
Discontinuation due to bleeding irregularities
Table 2 presents the discontinuations due to bleeding-
related reasons. It should be noted that the reasons
Effects of Implanon1 on menstrual bleeding patterns Mansour et al.

Table 2 Bleeding irregularities as primary reason for discontinuation*

Europe/Chile Southeast Asia United States All regions combined

n ¼ 361 n ¼ 235 n ¼ 327 n ¼ 923
Primary reason for discontinuation n (%) n (%) n (%) n (%)

Amenorrhoea 2 (0.6) 1 (0.6) 4 (1.2) 7 (0.8)

Frequent irregular bleeding 27 (7.5) 3 (7.5) 9 (2.8) 39 (4.2)
Heavy menstrual flow 1 (0.3) 1 (0.3) 6 (1.8) 8 (0.9)
Prolonged menstrual flow 10 (2.8) 4 (2.8) 17 (5.2) 31 (3.4)
Spotting 8 (2.2) 3 (2.2) 2 (0.6) 13 (1.4)
Other bleeding problems 1 (0.3) 0 (0.0) 5 (1.5) 6 (0.7)
Total 49 (13.6) 12 (5.1) 43 (13.1) 104 (11.3)

*Implanon-treated subjects, excluding breastfeeding subjects and subjects without postbaseline efficacy data.

given are based on the subjects’ perceptions of their
bleeding pattern and should be distinguished from the
definitions applied in the RP analysis. Overall, 32.9%
of the subjects discontinued the use of Implanon1
before completion of their respective trial; however,
only 11.3% of subjects discontinued Implanon1
because of bleeding irregularities. Among the bleed-
ing-related reasons for discontinuation, amenorrhoea
(0.8%) and heavy menstrual flow (0.9%) were
quantitatively unimportant, whereas prolonged flow
and frequent irregular bleeding caused 3.4% and 4.2%
of subjects to interrupt the treatment, respectively.
Bleeding-related discontinuation was much more
frequent in the United States (13.1%) and Europe/
Chile (13.6%) than in Southeast Asia (5.1%).
The probability of discontinuation by time is pre-
sented in Figure 1. During the first year of use, the
cumulative rate of discontinuation due to bleeding
irregularities increased to 7.6%, followed by a more
gradual increase to 12.2% by the end of the second year.
Note that absolute values deviate from the rates pre-
sented in Table 2. This is due to the correction for
discontinuing subjects (discontinuing because of reasons
other than bleeding irregularities) in the Kaplan-Meier
approach. A plateau is reached during the third year.
Bleeding pattern analysis
Overview
During three years of treatment (RPs 2 through 12),
the median number of B-S days per 90-day RP varied
between 13 and 16, without a particular trend over
time (Table 3). A relatively constant bleeding profile
distribution was observed over time, with a mean
number of B-S episodes of 2.4 per 90-day RP and
34% to 52% of subjects experiencing three to five B-S
episodes. Less favourably perceived bleeding patterns,
such as frequent and/or prolonged bleeding, occurred
in 18% to 27% of subjects.
Comparison of bleeding patterns between continuers and
discontinuers
The exploration of the bleeding pattern over time as
described above is affected by selection effects due to
subject discontinuations and differences in study
length. Therefore, a separate analysis was performed
on subjects who continued treatment beyond two
years and those who discontinued treatment for
bleeding irregularities other than amenorrhoea. In this
analysis, subjects who discontinued due to perceived
amenorrhoea were not included in the discontinuers
group because it was a minor reason for discontinua-
tion (Table 2). The analysis was restricted to RP 2
through RP 6 because few patients who discontinued
contributed data after RP 6 (Table 4).
The total group experienced a mean of 18 B-S days
per 90-day RP, of which fewer than half were
bleeding days. Those subjects who discontinued
because of perceived bleeding irregularities other than
amenorrhoea showed a far greater number of B-S days
(mean, 45.2 d) than those who continued treatment
with Implanon1 (mean, 16.5 d). Infrequent bleeding
was not largely different between continuers and
discontinuers. Amenorrhoea was almost absent among
discontinuers, whereas frequent and/or prolonged
bleeding was strongly elevated in this group.

The European Journal of Contraception and Reproductive Health Care 17

Effects of Implanon1 on menstrual bleeding patterns
Figure 1 Cumulative net probabilities of discontinuation due to bleeding irregularities: Kaplan-Meier approach (all-
treated group)
Determinants of bleeding pattern
The database was checked for a possible association
between geographic location of subjects and the
number of B-S days experienced (Figure 2). An
increased number of B-S days was observed among
women from the United States and Europe. Women
from Southeast Asia (Malaysia, Singapore, Thailand)
had the lowest number of B-S days per RP – about
five to seven fewer B-S days than women from the
United States and Europe, respectively.
The association was further explored by an analysis
of covariance with body weight (kg), BMI (kg/m2),
and age (y) as covariates, and nulliparity and geogra-
phic location as factors. The analysis showed no
significant correlation between mean number of B-S
days and age or nulliparity (p 4 0.05) and they were
excluded from the analysis model. A weak but
statistically significant positive correlation was found
between mean number of B-S days and body weight
(regression coefficient of 0.421, p ¼ 0.0003), but a
negative correlation was found for BMI (regression
18
Mansour et al.
coefficient of 71.772, p 5 0.0001). Geographic loca-
tion was also identified as a statistically significant
determinant of mean number of B-S days (p ¼ 0.025),
with the estimated mean number of B-S days about
four days lower in Southeast Asia than in the United
States and Europe/Chile.
Prognosis for bleeding pattern
To investigate whether the bleeding experience
during the initial phase of Implanon1 use would help
predict B-S patterns in the subsequent two years, all
patients were categorized based on the number of B-S
days they experienced during RP 1.1 (day 29–118;
Table 5). Subsequently, the discontinuation rates and
number of B-S days experienced during RP 2 through
RP 8 were determined.
Figure 3 presents the cumulative discontinuation
rate for bleeding irregularities or amenorrhoea per
category and RP. Based on these rates, experiencing
up to 49 B-S days in RP 1.1 does not appear to predict
an elevated discontinuation rate. Within the time
The European Journal of Contraception and Reproductive Health Care
 Table 3 Number of B-S days, B-S episodes and categories of bleeding pattern indices over time (RP analysis group)

B-S, d B-S Episodes Bleeding incidences (%)*

Infrequent Normal Frequent Prolonged Frequent

Amenorrhoea 53 B-S 3-5 B-S 45 B-S 414 B-S days and/or
RP n Med Mean SD Med Mean SD No B-S episodes episodes episodes uninterrupted prolonged{
Effects of Implanon1 on menstrual bleeding patterns

1.1 808 22.0 27.9 23.8 3.0 2.8 2.3 10 39 39 12 31 38

2 783 15.0 20.5 21.1 2.0 2.5 2.1 19 34 39 8 21 27
3 727 13.0 17.1 18.1 2.0 2.2 2.0 25 36 34 6 19 23
4 693 14.0 17.2 17.1 2.0 2.3 1.9 23 32 39 6 17 22
5 634 14.0 16.8 15.7 2.0 2.4 1.9 21 34 38 7 16 22

The European Journal of Contraception and Reproductive Health Care

6 618 15.0 17.3 15.7 2.0 2.4 1.9 21 33 41 6 15 20
7 584 14.0 16.7 15.4 2.0 2.4 1.9 21 32 42 5 14 19
8 547 16.0 17.4 13.8 3.0 2.5 1.6 17 33 47 4 15 18
9 240 15.0 17.1 14.7 2.0 2.4 1.8 18 36 41 5 17 21
10 227 15.0 16.9 13.9 2.0 2.4 1.8 17 35 44 4 17 20
11 226 15.0 17.9 14.5 2.0 2.4 1.5 15 39 43 3 18 20
12 202 16.0 18.1 14.1 3.0 2.6 1.5 12 34 52 2 17 19

B-S ¼ bleeding-spotting; RP ¼ reference period.

*Subjects with prolonged bleeding appear in more than one category.
{
Consists of the combinations prolonged þ infrequent; prolonged þ normal; prolonged þ frequent; frequent without prolonged.

19
Mansour et al.
Effects of Implanon1 on menstrual bleeding patterns Mansour et al.

Table 4 Bleeding parameters for the first two years for subjects who completed (continuers), subjects who
discontinued prematurely because of bleeding irregularities other than amenorrhoea, and for all subjects included (RP
Analysis Group)

Discontinuers for bleeding Total (continuers þ

irregularities other than discontinuers
Continuers* amenorrhoea for any cause){

Number of subjects 588 55 780

Number of RPs 2774 142 3315
B-S days, mean{ 16.5 45.2 17.7
Bleeding days, mean{ 6.7 19.5 7.2
B-S episodes, mean{ 2.3 3.50 2.4
Amenorrhoea, % 23.1 0.7 22.2
Infrequent B-S, % 33.2 37.3 33.6
Frequent B-S, % 6.4 18.3 6.7
Prolonged B-S, % 15.5 61.3 17.7

B-S ¼ bleeding-spotting; RP ¼ reference period.

*Continuers ¼ 2-year completers (subjects with treatment duration 720 d).
{
Note that the total does not equal the sum of the first two columns because it also includes discontinuation due to
reasons other than bleeding irregularities.
{
Mean over RPs 2–6.

Figure 2 Mean + SEM number of bleeding-spotting days per RP and geographic region (RP analysis group).
RP ¼ reference period. SEM ¼ standard error of the mean

20 The European Journal of Contraception and Reproductive Health Care

Effects of Implanon1 on menstrual bleeding patterns Mansour et al.

frame of the bleeding pattern analysis, 28% of women bleeding irregularities. The incidence of 0 to 14 B-S
discontinued Implanon1 use prematurely, but only days gradually declined from 100% in RP 1.1 to 46%
9% did so because of bleeding irregularities. The in RP 8, the majority (95% to 62% across the RPs)
discontinuation rate for bleeding irregularities of the stayed within an acceptable bleeding pattern of fewer
women experiencing 50 B-S days in RP 1.1 was than 28 days. Most discontinuers from this group
substantially elevated (26%) through each successive (68%) also had 14 B-S days in the RP that preceded
RP. However, more than 50% of the women their interrupting treatment.
experiencing 50 B-S days in RP 1.1 completed Among women having 15 to 28 B-S days in RP 1.1
two years of Implanon1 treatment. (Figure 4B), 26.9% discontinued Implanon1 use
Of the women experiencing 0 to 14 B-S days in RP prematurely, but only 4.6% did this because of
1.1 (Figure 4A), 21.8% discontinued Implanon1 use bleeding irregularities. Most discontinuers from this
prematurely, but only 2.3% stopped because of group (77%) also had 28 or fewer B-S days in the RP
that preceded their discontinuation.
Of women who had 29 to 49 B-S days in RP 1.1
Table 5 Number of B-S days experienced in RP 1.1 (days
29–118) (Figure 4C), 24.6% discontinued Implanon1 use
prematurely, but only 7.0% because of bleeding
B-S days, n Subjects, n (%) irregularities. Most discontinuers (79%) also had
49 B-S days in the RP that preceded their stopping
0–14 303 (37.5) treatment.
15–28 175 (21.7)
The women who experienced 50 to 90 B-S days
29–49 171 (21.2)
behaved somewhat differently from the other groups.
50 159 (19.7)
Total 808 (100)
Among women having 50 to 90 B-S days in RP 1.1
(Figure 4D), 44.0% discontinued Implanon1 use
B-S ¼ bleeding-spotting; RP ¼ reference period. prematurely; 26.4% discontinued Implanon1 because

Figure 3 Discontinuation rate as a function of B-S days in RP 1.1. B-S ¼ bleeding-spotting. RP ¼ reference period. For
each category, the number of B-S days experienced in subsequent RPs was analysed

The European Journal of Contraception and Reproductive Health Care 21

22
Effects of Implanon1 on menstrual bleeding patterns

Figure 4 Progression of B-S days as a function of number of B-S days in RP 1.1. (A) 0–14 B-S days in RP 1.1. (B) 15–28 B-S days in RP 1.1. (C) 29–49 B-S days in RP

The European Journal of Contraception and Reproductive Health Care

Mansour et al.

1.1. (D) 50–90 B-S days in RP 1.1

Effects of Implanon1 on menstrual bleeding patterns Mansour et al.

of bleeding irregularities. The proportion experien-
cing 550 B-S days in subsequent RPs varied between
48% and 58%. In RP 2 48% had already shifted to a
lower B-S days category. Across the RPs, a small
group (18–34%) experienced a further improvement
to 529 B-S days. Half of the discontinuers in this
group had 50 to 90 B-S days in the RP that preceded
their discontinuation.
For all categories, it can be concluded that across
the RPs an increase in B-S days compared with RP
1.1 occurs in a small proportion of subjects. For the
bleeding categories 29–49 and 449 B-S days, a
moderate decrease in B-S days occurred across RP 2
through RP 8 when compared with RP 1.1. The
group of women with favourable bleeding patterns in
the first RP tended to continue with this pattern
throughout the first two years of use, whereas the
group with unfavourable patterns had at least a
50% chance that the patterns would subsequently
improve.
Dysmenorrhoea
Changes from baseline to end of treatment in
dysmenorrhoea intensity are presented in Table 6. At
baseline, 48.7% of subjects reported dysmenorrhoea.
Among this cohort of women, 77% reported that their
symptoms resolved, and 6% reported decreased
severity. Dysmenorrhoea developed or became worse
in 5.5% of women.
Haemoglobin
To assess whether blood loss associated with the use of
Implanon1 resulted in anaemia, haemoglobin blood
levels were measured at baseline and at the end of
treatment in several studies. The mean haemoglobin
concentration was 133 g/l (n ¼ 504, SD ¼ 9.8) at
baseline and 129 g/l (n ¼ 68, SD ¼ 9.2) at end of
treatment.
DISCUSSION
Summary of results
Bleeding irregularities constituted an important reason
for discontinuation of treatment with this progesto-
gen-only implant. In the United States and Europe/
Chile, 13.1% and 13.6% of subjects, respectively,
discontinued because of bleeding-related reasons;
amenorrhoea was a quantitatively unimportant con-
tributor to this figure, accounting for approximately
1% of discontinuations. In Southeast Asia, the
discontinuation rate for bleeding irregularities was
low, accounting for only 5.1% of discontinuations.
Implanon1 use was almost always associated with
change in the menstrual pattern. The average number
of B-S days and that of B-S episodes were lower than
in normal menstrual cycles – as indicated by relatively
high incidences of infrequent bleeding (33.6%) and
amenorrhoea (22.2%). Variability in bleeding pattern
with Implanon1 was reflected in relatively high
incidences of, in particular, infrequent bleeding
(33.6%) and prolonged bleeding (17.7%); frequent
bleeding (6.7%) was less common.
Analyses of continuers and discontinuers for bleed-
ing irregularities other than amenorrhoea revealed that
the latter usually experience much more B-S,
especially prolonged and frequent bleeding, whereas
amenorrhoea was a rare cause of discontinuation.

Table 6 Dysmenorrhoea intensity shift from baseline to implant removal assessment (all treated subjects)

Implant removal assessment

Baseline None Mild Severe Very severe

n (%) n (%) n (%) n (%) n (%)

None 332 (51.3) 310 (47.9)* 19 (2.9) 3 (0.5) 0 (0.0)

Mild 219 (33.8) 182 (28.1) 24 (3.7)* 12 (1.9) 1 (0.2)
Severe 95 (14.7) 60 (9.3) 18 (2.8) 17 (2.6)* 0 (0.0)
Very severe 1 (0.2) 0 (0.0) 0 (0.0) 1 (0.2) 0 (0.0)*
Total 647 (100) 552 (85.3) 61 (9.4) 33 (5.1) 1 (0.2)

*No change reported (total 54.3% of subjects).

The European Journal of Contraception and Reproductive Health Care 23

Effects of Implanon1 on menstrual bleeding patterns
From these observations it appears that users of
Implanon1 in all the cultures that were studied found
amenorrhoea and infrequent bleeding to be highly
acceptable.
From the analyses of continuers versus those who
discontinued because of bleeding irregularities other
that amenorrhoea, it is clear that discontinuers have a
less favourable bleeding pattern (i.e., far more B-S
days). Therefore, the prognosis of bleeding patterns
based on RP 1.1 characteristics is hampered by the fact
that those discontinuing early do not contribute any
more RP data to the analysis, which leads to a more
favourable pattern with time. Nevertheless from these
analyses, it can be concluded that across the RPs an
increase in B-S days compared with RP 1.1 occurs in a
small proportion of subjects. For the bleeding
categories 29–49 and 50 B-S days, a moderate
decrease in B-S days occurred across RP 2 through
RP 8 when compared with RP 1.1. The group of
women with favourable bleeding patterns in the first
RP tended to continue with this pattern throughout
the first two years of use, whereas the group with
unfavourable patterns had at least a 50% chance that
the patterns would subsequently improve.
Comparison with other contraceptive methods
A recent RP analysis11 of a large database of normal
menstrual cycle patterns in women aged 18 to 40 years
initiated by Dr Alan Treloar12 was characterized by a
median value of 20 B-S days in a 90-day RP, with
about 90% of women experiencing 13 to 25 B-S days.
The only clinically important bleeding disturbance
recorded in these women (according to the original
WHO concept of clinically important bleeding
patterns2,8) was infrequent B-S (*10% of subjects);
amenorrhoea, frequent B-S, and prolonged B-S were
all rare (50.5%). Hence, Belsey and colleagues11
defined new clinically important bleeding patterns
based on medians and confidence interval (CI) data.
We chose to work with the original concept based on
subject perception and discontinuation rate data2,8.
We also chose to combine B-S days in all analyses
because of the recognized difficulties of assessing
changes in the volume of menstrual loss and because
many women do not tolerate prolonged or frequent
spotting or bleeding well.
The median number of B-S days associated with
Implanon1 use is slightly lower than the number
24 The European Journal of Contraception and Reproductive Health Care
Mansour et al.
reported for natural cycles and comparable with that of
a combined oral contraceptive (COC). This feature is
shared with other long-acting progestogen-only
methods, like the levonorgestrel-releasing intrauterine
system (LNG-IUS) and injectable contraceptives
containing depot medroxyprogesterone acetate
(DMPA). For Implanon1, the median number of B-
S days per RP is relatively constant (13–16 d) over its
three-year lifetime, whereas for the LNG-IUS,
initially high numbers of B-S days are followed by a
decrease to a level of about 7.5 B-S days per RP13,14.
DMPA injectables result in the most profound
suppression of B-S from three months of use onward,
with medians of only two to three B-S days per RP.
Consequently, amenorrhoea is particularly frequent
among these users (approaching 50% at the end of year
1)15. Implanon1 and the LNG-IUS are associated
with a comparable overall incidence of amenorrhoea,
but the pattern evolves differently. For Implanon1,
amenorrhoea occurs in 19% to 25% of subjects in the
first year and decreases in the third year to 12%. With
the LNG-IUS, the incidence of amenorrhoea in-
creases over time: 22.2% at 6 months, 43.8% at one
year, and 57.1% at the end of three years16. The
acceptability of the bleeding pattern seems comparable
between the products, as judged from published
discontinuation rates17.
Users of classic cyclic COCs experience 12 to 14 B-
S days per 90-day RP, most of which concern
scheduled B-S in the pill-free period18. Although
quantitatively comparable to Implanon1, this predict-
ability is a clearly distinctive feature of COCs.
Recently a continuously used COC containing
90 mg levonorgestrel and 20 mg ethinyl oestradiol has
become available; it aims to reduce menses by
omitting the pill-free period. As apparent from a large
phase III clinical trial19, the proportion of users
experiencing amenorrhoea during a 28-day period
increases from 25% after three months to almost 60%
after one year; those not amenorrhoeic experience on
average about 13 B-S days (at three months) and 9 B-S
days (at one year) per 28-day period. With 28 days
rather than 90 days being the basis for the analysis,
these data are difficult to compare with the afore-
mentioned progestogen-only methods. For example,
the extent to which amenorrhoea experienced during
28 days is maintained over 90 days (the length of the
RP in the analyses presented in this article) cannot be
assessed. The reported figures19 reveal a substantial
Effects of Implanon1 on menstrual bleeding patterns
proportion of users (40% after one year) who
experienced B-S in one third to one half of their
28-day cycle, which is much more than reported for
any of the progestogen-only methods. Also, the
reported discontinuation rate from the trial, amount-
ing to 57% at one year, suggests limited acceptability,
and further research on this continuous COC
approach is required.
Determinants of number of bleeding-spotting
days
Regional differences in B-S experience were noted,
with women from Southeast Asia experiencing
significantly fewer B-S days than women from the
United States and Europe/Chile. This could be related
to body weight, which on average was 7.7 kg higher
among the non-Asian women. A positive correlation
was found between numbers of B-S days and body
weight, with lower numbers of B-S days in those of
low body weight. The differences in BMI were less
pronounced between the regions. BMI appeared to be
negatively related to B-S days, which might be related
to increased oestrogen production in adipose tissue
and/or lower sex hormone-binding globulin levels20.
These findings are in agreement with those of Belsey
et al.15,21 who found similar regional differences and a
negative correlation with ponderal index (similar to
BMI). It should be added that in addition to body
composition, many other factors may contribute to
the observed regional differences.
Mechanisms and treatments
Breakthrough bleeding arises from abnormal endo-
metrial vessels embedded in an abnormal endometrial
environment. Although in normal menstrual cycles
bleeding appears to originate from spiral arterioles,
breakthrough bleeding during progestogen use arises
from a dense network of small, thin-walled, dilated
superficial veins and capillaries5. The integrity of
these vessels is compromised by alterations in their
basement membranes and pericytes. Alterations in
several angiogenic factors suggest that abnormal
endometrial angiogenesis may be the common
denominator to those changes. Endometrial haemos-
tasis may also be impaired owing to changes in
several vasoactive substances (endothelins, tissue
factor, nitric oxide) and a bleeding-prone superficial
The European Journal of Contraception and Reproductive Health Care
Mansour et al.
vascular network results. This network is embedded
in an endometrial environment that provides less
structural support, partly because of the changed
proportions between vascular and structural compo-
nents but also because of impaired stromal integrity.
The latter may be the result of increased levels of
cytokines and matrix metalloproteinases (MMPs)
derived from an increased number of endometrial
leukocytes, resulting in a loss of extracellular
matrix5,22. Among Implanon1 users, endometrial
histology assessed after one and two years of use
revealed mainly inactive or weakly proliferative
endometrium and an endometrial thicknesses of less
than 4 mm as determined by ultrasound23. Immuno-
histochemistry for progesterone receptor (PR), oes-
trogen receptor (ER) and vascular endothelial growth
factor (VEGF) on endometrial biopsies of Implanon1
users after one year of treatment revealed a reduction
in glandular VEGF without a change in endothelial
cell density and an increase in glandular PR.
However, no relationship was observed in individual
subjects between PR, ER, and endothelial cell
density and vaginal bleeding pattern24. In an ovarian
and endometrial ultrasound study25, subjects with
bleeding disturbances appeared more likely to have
increased follicular diameter and endometrial thick-
ness, which suggests that incomplete ovarian suppres-
sion with associated increased ovarian oestradiol levels
may contribute to bleeding disturbances. However,
similar correlations were not studied in the clinical
trials discussed in this article.
There is a rich and diverse body of literature
available on treatment or prevention of progestogen-
induced irregular bleeding26. Varying results have
been reported with oestrogens, COCs27, additional
progestogen28, PR modulators29–31, selective ER
modulators (tamoxifen)32, vitamin E, nonsteroidal
anti-inflammatory drugs33, and doxycycline (as an
MMP inhibitor)31. Some of these are effective short-
term therapies for stopping a particular bleeding
episode, but none provide useful medium- or long-
term benefits. Therefore, the evidence obtained so
far with any treatment is not sufficiently strong to
recommend the routine use of any of these. In fact,
effective patient counselling on the likely changes in
the vaginal bleeding pattern still appears to be the
most effective method to increase continuation
rates on progestogen-only contraception2, including
Implanon1.
25
Effects of Implanon1 on menstrual bleeding patterns
Recommendations for user counselling
Clear and accurate counselling before the insertion of
Implanon1 is pivotal to improving a woman’s
satisfaction with this contraceptive method. About
18% of users will discontinue use of Implanon1 in the
first year and 7.5% because of bleeding irregularities.
Therefore, new information presented in this article
provides healthcare professionals with up-to-date
advice regarding bleeding patterns in Implanon1
users. Acceptance and continuation may further
improve if these points are incorporated into the
preinsertion counselling discussion.
. The advantages and limitations of Implanon1
should be covered, emphasizing the alteration in
menstrual bleeding pattern.
. A woman’s menstrual pattern will invariably
change and be less predictable when using
Implanon1. This also occurs with other progesto-
gen-only contraceptives.
. In general, the mean numbers of B-S days and
bleeding episodes are fewer than the number
reported in natural menstrual cycles.
. A significant proportion of women will have
relatively little bleeding. For example, in about
34% of the reference periods women experienced
infrequent bleeding and in 22% amenorrhoea. This
pattern appeared to be acceptable, as indicated by
high continuation rates in such women.
. A small number of women experienced frequent
irregular bleeding (2–8%) and/or prolonged men-
strual flow (14–21%) and were more likely to
prematurely discontinue using Implanon1.
. The majority of Implanon1 users will experience
an equal or a slightly lower number of B-S days
over time than they experienced during the first
three months.
. Many women (44%) who experienced between
50 to 90 B-S days in the first three months dis-
REFERENCES
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26
Mansour et al.
continued using Implanon1 in the first two
years.
. Ethnicity, body weight, and BMI may affect
menstrual bleeding patterns in women using
Implanon1. Women from Asian countries, those
with low body weight, and those with higher
BMIs were likely to experience fewer B-S days.
Amenorrhoea was also more common in Asian
women. Discontinuation due to bleeding pro-
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. Dysmenorrhoea was improved in almost all the
women using Implanon1.
ACKNOWLEDGEMENTS
Declaration of Interest
Diana Mansour has received honoraria for attending
Organon (part of Schering-Plough) Advisory Boards
and financial support for lectures and travel to
Organon- (part of Schering-Plough)-sponsored sym-
posia. She has also been involved in a number of
Organon (part of Schering-Plough)-sponsored re-
search studies. Ian S. Fraser has acted as an occasional
consultant to Organon (part of Schering-Plough)
International, Organon (part of Schering-Plough)
Australia, and Bayer Schering Pharma and has received
honoraria and travel support for lectures and symposia
from Organon (part of Schering-Plough), Bayer
Schering Pharma, and Daiichi Pharmaceuticals. Tjeerd
Korver and Maya Marintcheva-Petrova are employees
of Organon, part of Schering-Plough and manufac-
turer of Implanon1.
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28 The European Journal of Contraception and Reproductive Health Care