AJOG REVIEWS

The mechanism of action of hormonal contraceptives and

intrauterine contraceptive devices
Roberto Rivera, MD, Irene Yacobson, MD, and David Grimes, MD
Research Triangle Park, North Carolina

Modern hormonal contraceptives and intrauterine contraceptive devices have multiple biologic effects. Some
of them may be the primary mechanism of contraceptive action, whereas others are secondary. For com-
bined oral contraceptives and progestin-only methods, the main mechanisms are ovulation inhibition and
changes in the cervical mucus that inhibit sperm penetration. The hormonal methods, particularly the low-
dose progestin-only products and emergency contraceptive pills, have effects on the endometrium that, theo-
retically, could affect implantation. However, no scientific evidence indicates that prevention of implantation
actually results from the use of these methods. Once pregnancy begins, none of these methods has an abor-
tifacient action. The precise mechanism of intrauterine contraceptive devices is unclear. Current evidence in-
dicates they exert their primary effect before fertilization, reducing the opportunity of sperm to fertilize an
ovum. (Am J Obstet Gynecol 1999;181:1263-9.)

Key words: Contraceptives, mechanism of action, family planning

An understanding of the mechanism of action of con- Combined oral contraceptives

traceptive methods is essential for the development of
new methods or the improvement of those already avail-
able. The mechanism of action also influences cultural
and individual acceptability of a contraceptive method.
Recently, some special interest groups have claimed, with-
out providing any scientific rationale, that some methods
of contraception may have an abortifacient effect.
Many contraceptive methods have several mechanisms
of action; some are primary mechanisms whereas others
are considered secondary. These methods may also have
other biologic effects on the reproductive system that are
unrelated to contraceptive action. Furthermore, the bio-
logic effects that relate to the contraceptive action can be
different from one ethnic group to another, among dif-
ferent individual women, and even for the same woman
at different stages of the reproductive cycle. Currently, we
have an incomplete knowledge of the mechanism of the
contraceptive action for most hormonal methods and in-
trauterine contraceptive devices (IUDs). However, no sci-
entific evidence supports an abortifacient effect.
Supported with funds from the US Agency for International
Development.
The views expressed in this article do not necessarily reflect those of the
funding agency.
Reprint requests: Roberto Rivera, MD, Family Health International, PO
Box 13950, Research Triangle Park, NC 27709.
Copyright © 1999 by Mosby, Inc.
0002-9378/99 $8.00 + 0 6/1/101131
The initial development of combined oral contracep-
tives in the 1950s was based on the knowledge that ovula-
tion is suppressed during pregnancy and that proges-
terone is responsible for this effect. In 1952
manufacturing of synthetic progestins led to their easy
availability for clinical experimentation. In the late 1950s
clinical trials to study the possible contraceptive efficacy
of these progestins began. These products were intended
to prevent pregnancy by inhibiting ovulation and were
referred to as anovulatories.1
Effects of combined oral contraceptives on ovarian
function. Prevention of ovulation is considered the pri-
mary mechanism of the contraceptive action of com-
bined oral contraceptives.2 The administration of com-
bined oral contraceptives inhibits follicular development,
ovulation, and, as a consequence, corpus luteum forma-
tion. This is reflected in a marked reduction of ovarian
estradiol secretion and the absence of progesterone pro-
duction. These ovarian effects are due to the inhibitory
action of combined oral contraceptives on the pituitary
production and secretion of both follicle-stimulating
hormone (FSH) and luteinizing hormone (LH), particu-
larly on the midcycle surge of these 2 hormones.3
Inhibition of pituitary gonadotropins is effected at the
hypothalamus, blocking the normal production of go-
nadotropin-releasing hormone (GnRH).4 In general, ev-
idence indicates that the FSH and LH pituitary response
to GnRH is not affected by combined oral contraceptive
administration.5 However, some studies have reported a

1263
1264 Rivera, Yacobson, and Grimes
lower pituitary response, in terms of both FSH and LH,
to the administration of GnRH in combined oral contra-
ceptive users.6 Thus combined oral contraceptives may
have a direct inhibitory effect at both the hypothalamic
and the pituitary level.
Either estrogen or progestin alone is capable of in-
hibiting FSH and LH sufficiently to prevent ovulation.
However, the combined administration of both com-
pounds greatly increases their antigonadotropic and ovu-
lation-inhibition effects.7 The progestin component of
combined oral contraceptives is particularly effective in
terms of ovulation inhibition, given its ability to block the
midcycle rise in LH secretion.8 Ethinyl estradiol in com-
bined oral contraceptives potentiates the antigo-
nadotropic effect of the progestin and prevents irregular
shedding of the endometrium.8, 9 It has also been re-
ported that important individual and ethnic differences
in the biologic effects and metabolism of synthetic estro-
gens and progestins exist, which may also influence their
contraceptive action.7
The effect of combined oral contraceptives on FSH
and LH secretion is prompt, lowering circulating FSH
and LH levels within the first day of administration.
However, at least 7 days of uninterrupted daily use of
combined oral contraceptives is necessary to suppress fol-
licular development.10 Combined oral contraceptives are
administered for a 21-day cycle followed by a 7-day pill-
free cycle, to mimic a 28-day menstrual cycle. FSH and
LH secretion resume immediately after the last day of pill
intake, which accounts for the risk of accidental preg-
nancy because of missed pills and for the rapid return of
fertility on discontinuation of combined oral contracep-
tive use.11 The development of new follicles starts during
the 7-day pill-free interval.12
In recent years combined oral contraceptives contain-
ing 1 of 3 new progestins, norgestimate, desogestrel, and
gestodene (not available in the United States), have be-
come increasingly popular. The main mechanism of ac-
tion of these newer combined oral contraceptives is also
the inhibition of ovulation. The respective daily doses of
these progestins required to inhibit ovulation are 0.20,
0.06, and 0.04 mg for norgestimate, desogestrel, and
gestodene, compared with 0.40 mg for norethindrone
and 0.06 mg for levonorgestrel.13 This potency parallels
their progestational receptor-binding affinity.14 Combined
oral contraceptives containing any of the above-men-
tioned progestins, in combination with ethinyl estradiol,
have shown the same contraceptive efficacy when com-
pared with each other and with the other pills, indicating
similar mechanisms of action.9, 15
Effects of combined oral contraceptives on cervical
mucus. In women using combined oral contraceptives,
the cervical mucus remains scanty, thick, and highly vis-
cous. In in vitro tests sperm penetration is inhibited as a
result of the progestin’s effect on mucus.11, 16-19
Effects of combined oral contraceptives on the en-
November 1999
Am J Obstet Gynecol
dometrium. The synthetic estrogens and progestins con-
tained in combined oral contraceptives have the same bi-
ologic effects on the endometrium as do their natural
parent compounds. During combined oral contraceptive
use, ovarian production of estradiol and progesterone
decreases and the endometrial changes that occur are in
response to the exogenous hormone administration.
The possibility that combined oral contraceptive admin-
istration might result in the development of an en-
dometrium not suitable for implantation was hypothe-
sized since the early trials of combined oral
contraceptives.20 A recent statement of The American
College of Obstetricians and Gynecologists (ACOG)2 in-
dicates that the “…readiness of the uterine lining for im-
plantation…” may be affected by combined oral contra-
ceptives. Although these and many other sources
mention endometrial effects as a possible mechanism of
the contraceptive action of combined oral contracep-
tives, insufficient evidence exists on whether cellular or
biochemical changes in the endometrium could actually
prevent implantation. However, the possibility of fertiliza-
tion during combined oral contraceptive use is very
small. Hence, endometrial changes are unlikely to play
an important role, if any, in the observed contraceptive
effectiveness of combined oral contraceptives.
Progestin-only methods
Progestin-only oral contraceptives. Progestin-only oral
contraceptives prevent pregnancy through a combina-
tion of actions. One of the main mechanisms is a distur-
bance of hypothalamic-pituitary function, including par-
tial suppression of ovulation. The amount of progestin in
progestin-only oral contraceptives is much less than in
combined oral contraceptives; therefore progestin-only
oral contraceptives do not prevent ovulation consistently.
Ovarian response to progestin-only oral contraceptives
varies widely among individual women. Approximately
40% of women using progestin-only oral contraceptives
ovulate.21 In other cases follicular activity occurs without
any corpus luteum development or with signs of insuffi-
cient luteal function.22 Finally, in some users ovarian
function is completely suppressed.22 When progestin-
only oral contraceptives inhibit ovulation, they do so
through the same mechanisms described for combined
oral contraceptives.3
Another important mechanism of action involves the
alteration of the cervical mucus.23 Progestin-only oral
contraceptives cause a cervical mucus that is “hostile” to
sperm, similar to mucus of the postovulatory phase.24
Progestin-only oral contraceptives greatly reduce the vol-
ume of mucus, increase its viscosity and cell content, and
alter its molecular structure. These changes result in lit-
tle or no sperm penetration. Even in the rare cases when
penetration does occur, sperm motility is reduced and
fertilization is unlikely to take place.25
Progestin-only oral contraceptives also cause changes
Volume 181, Number 5, Part 1
Am J Obstet Gynecol
in the endometrium. Some studies suggest that these
changes differ, depending on the amount of endogenous
ovarian hormones produced; this effect is superimposed
on the direct endometrial effect of the exogenous pro-
gestin.26 Other studies have indicated no correlation be-
tween changes in the endometrium, steroid hormone
levels, and histologic changes in the corpus luteum.22
The endometrial response to progestin-only oral contra-
ceptives varies between atrophy, suppressed prolifera-
tion, irregular secretion, and, sometimes, apparently nor-
mal secretory activity. The morphometric analysis of the
endometrium reveals a significantly reduced number
and diameter of endometrial glands, and in most cases
the endometrium becomes thinner. These changes may
reduce the likelihood of implantation.26 However, so far
there is no direct scientific evidence showing that im-
plantation is prevented by progestin-only oral contracep-
tives.
Progestin-only oral contraceptives are frequently used
by breast-feeding women. During the amenorrhea associ-
ated with breast-feeding, ovarian function is largely sup-
pressed, ovulation is unlikely to occur, and the cervical
mucus is hostile to the sperm. These effects greatly po-
tentiate the contraceptive effect of progestin-only oral
contraceptives during lactation.
Progestin-only injectables. The most widely used in-
jectable contraceptive is depot medroxyprogesterone ac-
etate (DMPA), a long-acting progestin. As with combined
oral contraceptives, DMPA interrupts ovulation. The con-
traceptive effect of DMPA stems primarily from its action
at the pituitary and hypothalamic levels. Specifically,
DMPA prevents the midcycle surge of LH, which is neces-
sary for ovulation.27 Thus suppression of ovulation is con-
sidered the main mechanism of action.
DMPA also has an effect on the cervical mucus. As with
combined oral contraceptives and progestin-only oral
contraceptives, the mucus becomes scanty and thick,
making sperm penetration unlikely.25 Changes in the
cervical mucus usually develop within 24 hours of injec-
tion but in some cases may take as long as 3 to 7 days.28
The changes in the endometrium associated with
DMPA use are profound. Soon after the first injection of
DMPA, proliferation of the endometrium diminishes.
The endometrium becomes thin and atrophic. These
changes stem from inhibition of ovarian function. Under
these circumstances DMPA could, theoretically, prevent
implantation.29 However, because DMPA is highly effec-
tive in inhibiting ovulation and sperm penetration, the
possibility of fertilization is negligible. No available data
support prevention of implantation as a contraceptive ac-
tion of DMPA.
Another progestin-only injectable is norethindrone
enanthate, which is given every 2 months. The mecha-
nism of action of norethindrone enanthate is the same as
that of DMPA,30 but it is effective for a shorter period of
time.
Rivera, Yacobson, and Grimes 1265
Implants. Norplant (a registered trademark of the
Population Council, Inc) subdermal levonorgestrel im-
plants are another form of progestin-only contraception.
The contraceptive effect of the levonorgestrel implant is
similar to that of progestin-only oral contraceptives.
Partial ovulation suppression is one contraceptive mech-
anism. Evidence of ovulation is found in about 10% of cy-
cles in the first year. With time, levonorgestrel blood lev-
els decline and evidence of ovulation occurs more often
by the fifth year of implant use (30% to 75% of cycles).31
However, during long-term use of Norplant implants,
progesterone production by the ovaries is low in most cy-
cles that appear to be ovulatory. This suggests that an in-
sufficient luteal phase could be at least partially responsi-
ble for the contraceptive effect in those women who do
ovulate.32, 33 Another contraceptive effect of implants
that is considered to be important is thickening of the
cervical mucus, thereby inhibiting sperm penetration.33
Implants affect the endometrium in the same manner
as was described for progestin-only oral contraceptives.
The endometrium in Norplant implant users becomes
much thinner than in untreated women and does not
show the normal phasic changes. Most endometrial biop-
sies in Norplant implant users show either suppressed or
irregular secretory changes, scarce glands with subnor-
mal or limited secretory activity, and dense stroma. This
may be the result of deficient production of estradiol and
progesterone during the luteal phase, as well as a possi-
ble local antiestrogenic action of the continuously re-
leased levonorgestrel.34 An inadequate development of a
secretory endometrium in Norplant implant users theo-
retically could prevent implantation.35 However, no di-
rect confirmation exists of this possible action.
Emergency contraceptive pills
Emergency contraceptive pills are levonorgestrel-con-
taining combined oral contraceptives or levonorgestrel-
only pills taken any time in the menstrual cycle to reduce
the risk of pregnancy after unprotected intercourse. The
regimen consists of 2 doses, administered 12 hours apart,
initiated within 72 hours of intercourse. Each of the 2
doses of combined oral contraceptives should contain
at least 100 µg of ethinyl estradiol and 0.5 mg of levo-
norgestrel. In the case of levonorgestrel-only pills, 0.75
mg per dose is used.
The mechanism of the contraceptive action for emer-
gency contraceptive pills remains unclear. As with other
hormonal methods, >1 mechanism may be involved.
These mechanisms may also vary depending on when in
the menstrual cycle emergency contraceptive pills are
used.36, 37 However, once implantation has taken place,
emergency contraceptive pills are no longer effective and
pregnancy proceeds normally. ACOG has recently indi-
cated that the contraceptive effects of these regimens
may involve inhibition of ovulation, fertilization, or steps
subsequent to fertilization.2
1266 Rivera, Yacobson, and Grimes
In a 1974 report by Yuzpe et al,38 endometrial biopsies
were obtained within 12 hours of the onset of menstrua-
tion after emergency contraceptive pill administration.
The report included 127 women with regular menstrual
cycles, 88 of whom received emergency contraceptive
pills before midcycle35 or within 3 days of what was esti-
mated as the day of ovulation. In women who received
emergency contraceptive pills before midcycle, most
biopsies showed secretory and decidual changes sugges-
tive of ovulation. The endometrium also exhibited a lag
in the development or maturity between the glands and
the stroma. The authors proposed that implantation
would be unlikely in this type of endometrium.
A series of studies conducted by Ling et al38 indicate
that different effects may account for the contraceptive
action of emergency contraceptive pills. These effects
vary according to when emergency contraceptive pills are
used in the menstrual cycle and among individual
women as well. In one report39 the administration of the
regimen of Yuzpe et al38 at or just before the LH peak
showed different degrees of ovarian effects, including di-
minished LH, estradiol, and progesterone levels sugges-
tive of ovulation inhibition or delay in some women.
Endometrial biopsies showed secretory changes, with
gland development lagging behind that in the stroma
and not coinciding with the expected day of the cycle. In
subsequent studies the regimen of Yuzpe et al38 was ad-
ministered 36 and 48 hours after the LH surge36 or on
the day after the LH surge.37 In most of these cases there
was no evidence of change in LH, estradiol, and proges-
terone levels. Some women showed reduced levels of ei-
ther estradiol or progesterone. The endometrial biopsies
showed an asynchronous development between the
stroma and the epithelium. The authors concluded that
the endometrial environment found in their studies
might inhibit normal implantation.
Rowlands et al40 administered the regimen of Yuzpe et
38
al to 14 women with a history of normal menstrual cy-
cles within 72 hours of midcycle unprotected inter-
course. After treatment, 4 women showed normal men-
strual cycles, 3 showed a suppressed or delayed LH surge,
and 7 had a shortened or “dysfunctional” luteal phase.
None became pregnant. The authors proposed that ovu-
lation was inhibited in a minority of women. No endome-
trial biopsies were obtained in this study.
More recently, Swahn et al41 reported the use of the
regimen of Yuzpe et al38 in 8 women on day 12 of the
cycle before the LH surge. A variety of hormonal pat-
terns was found, ranging from nonidentifiable LH surge
to no significant effect on LH, estrone, and pregnanediol
levels. When 8 different women were treated on day
LH+2, no effects were seen on LH, estrone, or pregnane-
diol levels. Endometrial biopsies were obtained on days
LH+6 to LH+8 only in the women treated on day LH+2,
and no difference between the chronologic and morpho-
November 1999
Am J Obstet Gynecol
logic dating was found; minor changes observed in en-
dometrial development were not considered sufficient to
prevent implantation.
With a different approach, a recent article42 reviewed
published reports on the effectiveness of the regimen of
Yuzpe et al38 as a possible source of information on its
mechanism of action. On the basis of the effectiveness of
this method, according to the menstrual cycle day when
it was administered, the authors concluded, using a theo-
retic model, that this effectiveness could not be ex-
plained if prevention or delay of ovulation were the only
mechanisms of action.42
On the other hand, a recent study43 on the use of both
the Yuzpe et al38 and levonorgestrel-only regimens has
shown that both methods are most effective when admin-
istered within 24 hours of unprotected intercourse. This
effectiveness decreases substantially and progressively
when the method is administered in the 24-48 hour and
48-72 hour intervals. These findings suggest that effects
that prevent ovulation or fertilization are likely to be the
main mechanism of action of emergency contraceptive
pills. If endometrial effects that would prevent implanta-
tion played an important role, the same level of effective-
ness of emergency contraceptive pills should continue
beyond 24 hours, possibly until implantation is estab-
lished.
Little information exists on the mechanism of action
of levonorgestrel-only pills for emergency contraception.
A recent study from China44 reported the use of two 0.75-
mg doses of levonorgestrel, given 12 hours apart, within
72 hours of unprotected intercourse, on day LH+2 of the
cycle. Morphologic endometrial changes indicated a
delay of endometrial development. Expression of the
progesterone receptor increased, whereas Dolichos bi-
florus agglutinin and α1 and α2 integrin expression de-
creased. The authors44 proposed that these endometrial
effects might hinder implantation, although no evidence
was presented to support this statement.
The use of postcoital levonorgestrel, as a means of reg-
ular contraception, was studied in the 1970s.45 The
mechanism of action for this approach appears to be in-
fluenced by the number of doses received and the day(s)
of the menstrual cycle when administered, and impor-
tant individual variation exists from woman to woman.
Kesserü et al46 reported suppression or delay in the mid-
cycle LH surge, after the use of 1 to 4 doses of norgestrel
0.4 mg on days 10 to 18 of the cycle. However, all women
showed urinary pregnanediol levels suggestive of ovula-
tion. In this study 85 women received a single dose of
norgestrel after coitus, timed at the anticipated ovulatory
phase of the cycle. There was a rapid decline in sperm re-
covery from the uterine cavity after 4 hours and an im-
portant reduction of forward sperm motility 9 to 10
hours after norgestrel administration. These findings
support the possibility that direct effects on the sperm
Volume 181, Number 5, Part 1
Am J Obstet Gynecol
might play a role in the mechanism of action of emer-
gency contraceptive pills. Other studies have shown ei-
ther no effect or inhibition or delay of ovulation after ad-
ministration of 0.4 mg norgestrel on either day 10 or day
12 of the cycle.47, 48
A more recent study reported the effects on ovarian
function and endometrial morphologic characteristics
resulting from the repeated administration of 0.75 mg
levonorgestrel on different days of the menstrual cycle.49
Administration on days 2, 4, 6, and 8 had no effect on
ovarian function. Administration on days 9, 11, 13, and
15 or on days 11, 12, 16, and 19 resulted in either normal
ovulation, ovulation inhibition, or corpus luteum insuffi-
ciency. Administration on days 16, 18, 20, and 22 showed
no effects on ovarian function. No women who received
levonorgestrel between days 9 and 19 showed a normal
secretory endometrium, which, the authors suggested,
might account for the contraceptive effect.
IUDs
Despite decades of study, the precise mode of contra-
ceptive action of copper-containing IUDs remains un-
clear, because of difficulties in carrying out relevant in-
vestigations in humans and the limitations of
extrapolating findings from animal studies. The high ef-
ficacy of these types of IUDs in humans may stem from >1
mechanism of action.
Effects on sperm. IUDs prevent fertilization by imped-
ing ascent of sperm to the fallopian tubes or by reducing
the ability of sperm to fertilize an ovum. Several studies
have shown that IUDs influence the number of sperm
reaching the uterine cavity and fallopian tubes. The ster-
ile foreign body reaction in the uterine cavity causes both
cellular and biochemical changes that may be toxic to
sperm. 50, 51 In studies in which the uterine cavity and fal-
lopian tubes were flushed after exposure to semen,
women using IUDs had lower concentrations of sperm
than women not using IUDs.52 In addition, the sperm
found in women using copper IUDs were likely to be
damaged (eg, head-tail separation) and were no longer
able to fertilize.
Chemical evidence of early developmental events. Most
studies of early pregnancy rates have relied on sensitive
measurements of serum β-hCG, which is produced by the
fertilized ovum near the time of implantation. By use of
this marker, a number of studies show that implantation
of an embryo is much less frequent in IUD users than in
women attempting to achieve pregnancy. One study53
using a sensitive assay found a transient rise and fall of
β-hCG in 1% of IUD users. Among couples trying to con-
ceive, early embryonic loss is very high, ranging from 8%
to 57%.52 Whether the early embryonic loss rate among
IUD users with a contraceptive failure is higher than in
other women is unknown.54
Microscopic evidence of fertilization. Microscopy has
Rivera, Yacobson, and Grimes 1267
provided further evidence of the preimplantation contra-
ceptive effect of IUDs. Fertilized ova are found in the fal-
lopian tubes and in the uterine cavity with predictable
frequencies in women who are sexually active and not
using contraception. Investigators can flush the uterine
cavity through the cervix or flush the fallopian tubes at
the time of sterilization surgery and look for fertilized
ova under a microscope.55 The rate of recovery of fertil-
ized ova from the fallopian tubes of copper IUD users is
lower than that in women not using contraception who
are sexually active. Stated alternatively, the number of
normally dividing, fertilized ova that reach the uterine
cavity is markedly decreased in women using copper
IUDs. Indeed, when all the studies searching for ova in
IUD users were combined, only 3 fertilized ova had been
found, and none was developing normally.52
Is the IUD an abortifacient? Some hold that the princi-
pal mechanism of action of IUDs is prevention of im-
plantation of fertilized ova.54 Even if this were true, it still
would not constitute early abortion. However, because
some believe pregnancy begins with fertilization, the
issue is important.
As noted by the World Health Organization scientific
group,50 “It is unlikely that the contraceptive efficacy of
IUDs results, mainly or exclusively, from their capacity to
interfere with implantation; it is more probable that they
exert their antifertility effects beyond the uterus and in-
terfere with steps in the reproductive process that take
place before the ova reaches the uterine cavity.” Similarly,
ACOG56 has reviewed the evidence and concluded that
“…as such, the IUD is not an abortifacient.”
Unintended pregnancies occur with all contraceptive
methods, including IUDs. This provides incontrovertible
evidence that fertilization and implantation can occur, al-
beit rarely, with modern methods of contraception.57
The more relevant question, however, is the principal
mode of action that averts pregnancy in nearly all users.
The evidence does not support the theory that the usual
mechanism of action of IUDs is destruction of fertilized
ova in the uterus. The IUD appears to work at an earlier
stage of human reproduction. Prevention of fertilization
seems to be the dominant mode of action.
In summary, even though the precise mechanism of ac-
tion of modern contraceptives is not yet fully known, sci-
entific evidence suggests the main mechanisms of action
for each method. Inhibition of ovulation and effects on
the cervical mucus are the primary mechanisms of the
contraceptive action of hormonal methods. Evidence in-
dicates that the primary mechanism of action of IUDs is
the prevention of fertilization. All these methods, di-
rectly or indirectly, have effects on the endometrium that
might prevent implantation of a fertilized ovum.
However, so far, no scientific evidence has been pub-
lished supporting this possibility. No scientific evidence
supports an abortifacient effect.
1268 Rivera, Yacobson, and Grimes
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