Gynecological Endocrinology

ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20

Mechanism of action of levonorgestrel

contraceptive implants

V. Brache, F. Alvarez & A. Faundes

To cite this article: V. Brache, F. Alvarez & A. Faundes (2001) Mechanism of action of
levonorgestrel contraceptive implants, Gynecological Endocrinology, 15:sup2, 14-20, DOI:
10.1080/gye.15.s2.14.20

To link to this article: http://dx.doi.org/10.1080/gye.15.s2.14.20

Published online: 28 Aug 2009.

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 Gynecol Endocrinol 2001;15 (Suppl 2):14–20
Mechanism of action of
levonorgestrel contraceptive
implants
V. Brache, F. Alvarez and A. Faundes
Biomedical Research Department, Profamilia, Santo Domingo, Dominican Republic
Key words: LEVONORGESTREL IMPLANT, CONTRACEPTION, CERVICAL MUCUS, NORPLANT, TWO-ROD
SYSTEM, O VULATION INHIBITION, OVULATORY DYSFUNCTION
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ABSTRACT
Levonorgestrel implants release constant low doses of the
hormone over a period of several years. The levonorgestrel
exerts its contraceptive action by causing changes in the
cervical mucus, by inhibiting ovulation and by promoting
ovulatory dysfunction. Cervical mucus becomes viscous
and scanty. Postcoital studies and sperm penetration tests
in vitro have shown that few sperm penetrate the mucus
and that this effect persists, even in cycles with high endo-
genous estradiol production.
Ovulation is inhibited in over 85% of the cycles in the
first year of use, when the release rate of levonorgestrel is
highest. The percentage of ovulation inhibition decreases
to near 65% of the cycles in years 2 and 3, while luteal
activity occurs in around 50% of the cycles in the last 2
years of use. However, in these apparently ovulatory
cycles, a dissociation of the normal ovulatory process has
been observed. The peak of follicle stimulating hormone
present in non-users does not occur, and the luteinizing
hormone peak is blunted and of short duration. It is
known that the mid-cycle gonadotropin surge plays a
major role in the maturation of the oocyte; it is therefore
possible that, due to this inadequate gonadotropin surge,
Correspondence: Dr V. Brache, Biomedical Research Department, Profamilia, Santo Domingo, Dominican Republic
14
the oocyte may not be capable of fertilization in the event
of follicular rupture. Luteal phase defect has also been
reported.
Ultrasound evaluation of follicular activity during
levonorgestrel implant use has shown that luteinization of
unruptured follicles occurs in nearly 30% of the cycles
with luteal activity. Persistent follicles are also a common
observation among implant users. Since low-dose
progestins do not completely inhibit the gonadotropin
stimulus, follicular growth occurs. However, the positive
feedback of estradiol on the mid-cycle gonadotropin surge
is frequently blocked, thus preventing follicular rupture.
This dominant follicle remains functional for about 21
days, but the anatomic structure remains echographically
visible for around 1–2 months before spontaneously
disappearing.
Hypoestrogenism is not a concern in women with
levonorgestrel implants since mean estradiol levels in
samples taken twice weekly for 4–5 weeks were not
significantly different in women using implants from those
acting as controls.
 Mechanism of action of levonorgestrel contraceptive implants Brache, Alvarez and Faundes

INTRODUCTION following menses. Almost 90% of the samples

scored 0 or 1 on the postcoital test scale, with about
Levonorgestrel implants provide long-term,
20% having no sperm and about 70% having only
highly effective contraceptive protection, which is
immotile sperm. None of the subjects had a score
achieved with minimal hormonal doses. The
above 3 (Figure 1).
levonorgestrel is released constantly over a period
Hormonal assays (estradiol and progesterone)
of several years and exerts its action at various target
were carried out on the subjects and, retro-
organs involved in the reproductive process. The
spectively, 15 of the 34 had subsequent luteal activ-
mechanism of action of levonorgestrel has been
ity in the cycle that was studied. This means that, at
widely studied and the main effects are on the
the time the cervical mucus sample was taken,
cervical mucus, ovulation and ovulatory function.
these women had high endogenous estradiol pro-
These effects are discussed briefly and the findings
duction. The postcoital test results for this sub-
of a number of papers which have been published
group were not significantly different from those
on the subject are reviewed.
of the total group (Figure 1), indicating that, in
spite of high estradiol levels, the progestogenic
THE EFFECT OF effect of levonorgestrel on cervical mucus is
LEVONORGESTREL ON CERVICAL maintained.
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MUCUS
A continuous low dose of levonorgestrel causes
cervical mucus to become viscous and scanty, Two studies using the in vitro sperm
preventing pregnancy by interference with sperm penetration test
migration. This effect has been investigated using
The first study, by Croxatto and colleagues4, was
two different methods for assessing sperm motility.
carried out on a group of Norplant and Norplant-2
The first method1 assesses in vivo sperm motility
users, and a comparison group of women seeking
by assigning a sperm motility score to postcoital
conception. Ninety-one attempts to collect
cervical mucus samples. The samples are examined
cervical mucus samples were made on Norplant
under high power and the numbers of sperm per
and Norplant-2 subjects, of which only 27 were
high-power field are recorded. A score is assigned:
successful. Fifty-nine attempts, all successful, were
0, no sperm found; 1, immotile sperm per high-
made on control subjects. The mucus samples were
power field (HPF); 2, 1–5 migrating sperm per
then subjected to the in vitro sperm penetration test,
HPF; 3, 6–10 migrating sperm per HPF; 4, 11–20
although, when several mucus samples from a
migrating sperm per HPF; 5, > 20 migrating sperm
given cycle were available, only the best score
per HPF1.
observed was included in the analysis. The results
The second method2 uses an in vitro sperm
obtained on 16 samples from Norplant users and
penetration test. The cervical mucus sample is
aspirated into a flat glass capillary tube which is
then sealed at one end. The open end is placed in a
70
small well of semen of optimum quality and, after Norplant (n = 34)
60 Subgroup with luteal activity (n = 15)
incubation, the distance travelled by the vanguard Samples taken daily -10 to -19
sperm is observed under the microscope. 50 following menses
Percentage

40
30
A study using the postcoital test in 20
Norplant users 10
0
A study conducted in Santo Domingo, Dominican 0 1 2 3
Republic3 looked at 34 long-term Norplant users Postcoital score
with regular menses from whom cervical mucus Figure 1 Postcoital test scores in Norplant users with
samples were obtained on days -10 to -19 regular menses3

Gynecological Endocrinology 15
 Mechanism of action of levonorgestrel contraceptive implants Brache, Alvarez and Faundes

33 samples from control subjects are shown in
Figure 2.
Slightly more than 90% of the control samples
had a good sperm penetration result, with the
vanguard sperm travelling more than 2 cm during
the incubation period. On the other hand, 31% of
the Norplant user samples were so viscous and
thick that it was not possible to aspirate them
into the capillary tube. In a further 44% of samples,
the distance travelled by the vanguard sperm
was less than 0.5 cm, with the remaining 25%
being in the 0.6–2 cm range. This is in sharp
contrast with the control samples and again shows
the progestogenic effect of levonorgestrel on the
cervical mucus.
The second study, by Dunson and co-workers5,
used the in vitro test to measure the time of onset of
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needed. Norplant was inserted in the advanced
follicular phase (days 8–13 of the cycle) and
samples of cervical mucus were tested from a few
hours to 7 days after insertion. The results were
grouped according to the baseline cervical mucus
quality (spinnbarkeit, consistency, cellularity,
ferning) and in vitro sperm penetration result of the
subjects. Data for the 15 women who, at the time
of insertion, had a good cervical mucus quality are
shown in Figure 3. The baseline in vitro sperm
penetration result was very good in 80% of these
women, with the vanguard sperm travelling more
than 2 cm, and was good in the other 20%, with a
travel of 1–2 cm. Three days after insertion, 80%
of the women now had a poor penetration test
result, with a travel of less than 0.5 cm.
These data confirm that levonorgestrel has a

changes in the cervical mucus after insertion of strong and profound effect on the cervical mucus,
Norplant implants. This information is important that this effect is maintained in spite of the high
when advising users on the length of time for endogenous estradiol levels, and that it occurs fairly
which back-up methods of contraception are rapidly after Norplant insertion.

100 Norplant (n = 16)

Controls (n = 33)
80
Percentage

60

40

20

0
Not £ 0.5 0.6–1.0 1.1–1.5 1.6–2.0 > 2.0
sufficient
Distance travelled by vanguard sperm (cm)
Figure 2 In vitro sperm penetration in cervical mucus tests during
long-term Norplant use4

80 Before insertion (n = 15)

70 Day 3 post-insertion (n = 15)
60
Percentage

50
40
30
20
10
0
Not £ 0.5 0.5–1.0 1.0–2.0 > 2.0
sufficient
Distance travelled by vanguard sperm (cm)
Figure 3 Changes in cervical mucus sperm penetration test results by
day 3 post-Norplant insertion5

16 Gynecological Endocrinology
 Mechanism of action of levonorgestrel contraceptive implants Brache, Alvarez and Faundes

THE EFFECT OF alleviating any concern of hypoestrogenism among

LEVONORGESTREL ON levonorgestrel subdermal implant users7,8.
INHIBITION OF OVULATION
Ovulation inhibition in Norplant users has been THE EFFECT OF
investigated in studies by Croxatto and colleagues6 LEVONORGESTREL ON
and Brache and co-workers7. The methodology OVULATORY DYSFUNCTION
was to measure estradiol and progesterone in blood
Faundes and colleagues9 studied ovulatory dys-
samples taken twice weekly from Norplant users
function by comparing luteinizing hormone (LH),
and controls, who used non-hormonal contra-
follicle stimulating hormone (FSH) and pro-
ception, during a run of 5 consecutive weeks, the
gesterone serum levels in regularly menstruating
sampling runs being carried out each year over a
Norplant users with the levels in control subjects
5-year period.
who used non-hormonal contraception. Blood
The end-point of the investigations was to
samples were taken daily from day 8 of the cycle to
determine the frequency of cycles with luteal
day 19 and then twice a week until menses.
activity, as defined by a progesterone level above
A group of 12 Norplant users was identified
9.6 nmol/l (3 ng/ml). In the first year of Norplant
having a visible LH peak and a plasma progesterone
use, only 14% of the cycles had luteal activity. The
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level above 9.5 nmol/l during the second phase of

percentage rose steadily over subsequent years,
the cycle. This group was defined as having luteal
reaching 54% by the fifth year (Figure 4). This
activity. In Figure 6, the mean LH levels of this
increase can be expected because the release rate of
group are compared with the LH levels in the
levonorgestrel is high during the first 18 months
control group, plotted against days from the LH
of use, followed by a slow decrease throughout
the rest of the 5 years.
Another important observation in these studies 80 Mean highest progesterone
was that, even in those cycles with luteal activity, 70 Norplant: 29.0 nmol/l
the mean highest progesterone level was signifi- 60 Controls: 40.4 nmol/l 54
Percentage

cantly lower in Norplant users (29.0 nmol/l) than 50 42

40 37
32
in controls (40.4 nmol/l). This indicates that there 30
is luteal insufficiency in a significant proportion of 20 14
Norplant users. 10
Mean estradiol serum levels during the 5-year 0
1 2 3 4 5
period of Norplant use were also compared with Years of use
mean levels in the control group (Figure 5). Figure 4 Cycles with luteal activity (progesterone
Levels remained very similar to those in the con- > 9.6 nmol/l) among levonorgestrel implant users
trol group, at around 400–500 pmol/l, thus (n = 247)6,7

Figure 5 Mean estradiol serum levels during levonorgestrel implant use

and in controls

Gynecological Endocrinology 17
 Mechanism of action of levonorgestrel contraceptive implants Brache, Alvarez and Faundes

peak (day 0). There is a very distinct LH peak in the
controls, with a maximum value of about 65 IU/l.
This surge lasts for 48 h from the initiation of the
burst until the decrease of the LH peak. In contrast,
the LH peak in the Norplant users is dramatically
reduced, with a maximum value of only 15 IU/l
and a much shorter duration.
Results for FSH show a very similar pattern
(Figure 7). There is a peak of over 10 IU/l in the
controls, while this peak is almost non-existent
among Norplant users.
This mid-cycle gonadotropin surge in non-
users is important because it has been demon-
strated10 that such a surge is necessary for the
maturation of the cumulus–oocyte complex. It is
involved in the expansion of the cumulus
oophorus and is also necessary for the resumption
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The progesterone levels found during the study
confirm the findings of other studies6,7 that, among
Norplant users, there is some degree of luteal
insufficiency. In Figure 8, the area under the
progesterone–time curve is significantly lower for
Norplant users than for the controls.
ULTRASONOGRAPHIC AND
ENDOCRINE EVALUATION OF
OVARIAN FUNCTION
The advent of more sophisticated technology,
specifically vaginal ultrasound, enabled more
detailed investigations which did not rely solely
on progesterone as an indicator of luteal activity
and ovulation. The development of follicles in
the ovaries could be observed directly. Several

of meiosis and maturation of the oocyte. There- studies11–14 combined the results of vaginal
fore, in Norplant users, it is theoretically possible ultrasound observations with endocrine
that, even if the oocytes are released into the profiles, developing a classification of follicular
oviduct, they may be insufficiently mature to be development based on the following four
capable of being fertilized. categories:

80 Norplant (n = 12)
70 Controls (n = 12)
Mean LH (IU/I)

60
50
40
30
20
10
0
-8 -6 -4 -2 0 2 4 6 8 10 12 14 16
Days from LH peak
Figure 6 LH levels in Norplant users with luteal activity 9

20 Norplant (n = 12)
18 Controls (n = 12)
16
Mean FSH (IU/I)

14
12
10
8
6
4
2
0
-8 -6
2 -44 -26 0 8 10 12 14 16
Days from LH peak
Figure 7 FSH levels in Norplant users with luteal activity 9

18 Gynecological Endocrinology
 Mechanism of action of levonorgestrel contraceptive implants Brache, Alvarez and Faundes

50 Norplant (n = 12)

Mean progesterone (nmol/l)

Controls (n = 12)
40

30

20

10

0
-8 -6 -4 -2 0 2 4 6 8 10 12 14 16
Days from LH peak
Figure 8 Progesterone levels in Norplant users with luteal activity 9

(1) Ovulation: follicular development and rupture Table 1 Ultrasound and endocrine profile studies on
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occurs, followed by an increase in progester- ovarian function11–14

one levels; Levonorgestrel
(2) Luteinized unruptured follicle (LUF): follicular implants Controls
development occurs, but rupture does not Classification (n = 104) (n = 58)
occur. However, there is a rise in progester- Ovulation 34% 95%
one levels; Luteinized unruptured 13% 5%
follicle
(3) Persistent follicle: there is follicular develop- Persistent follicle 47% 0%
ment, but follicle rupture does not occur. Quiescent ovaries 6% 0%
The follicle persists and is functionally active
for about 22 days, producing increasing levels
of estradiol without a rise in progesterone.
The follicular structure may be present for data that levonorgestrel has a significant effect on
1–2 months, but it eventually disappears ovarian function.
spontaneously;
(4) Quiescent ovaries: there is an absence of CONCLUSIONS
follicles over 10 mm.
The mechanism by which levonorgestrel implants
The combined results for 104 cycles of observation inhibit fertilization is complex, and three main
with levonorgestrel implant users with regular factors have been shown to contribute. First, sperm
menses, both Norplant and the two-rod system, penetration of the cervical mucus is inhibited
are shown in Table 1 together with results for 58 because levonorgestrel causes the mucus to
control cycles. As expected, 95% of the controls become scanty and viscous. Second, anovulation
have normal ovulation, with only 5% having an occurs in 45–85% of cycles, depending on how
LUF. In contrast, only 34% of the cycles in long the implant has been in place. Third, there is a
levonorgestrel users have normal ovulation and marked degree of ovulatory dysfunction, as shown
13% have an LUF. Adding the latter two together by diminished LH and FSH peaks, a possible effect
shows that there is luteal activity in 47% of the on the oocyte and frequent luteinized unruptured
cycles, yet in just under one-third of these cycles follicles. All these mechanisms together contribute
this luteal activity is not ovulation but LUF. The to the high contraceptive efficiency that has been
remainder of the cycles are either persistent follicle observed during the use of levonorgestrel
(47%) or quiescent ovaries (6%). It is clear from the implants.

Gynecological Endocrinology 19
 Mechanism of action of levonorgestrel contraceptive implants
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Gynecological Endocrinology