CLINICAL OBSTETRICS AND GYNECOLOGY

Volume 50, Number 4, 898906

r 2007, Lippincott Williams & Wilkins

Injectable Contraception
SADIA HAIDER, MD, MPH* and PHILIP D. DARNEY, MD, MScw
*Department of Obstetrics and Gynecology, Beth Israel Deaconess Hospital,
Harvard Medical Center, Boston, Massachusetts; and w Obstetrics,
Gynecology and Reproductive Sciences, San Francisco General Hospital,
University of California, San Francisco, California

Abstract: Injectable contraceptive methods are safe,

highly efficacious, and commonly used worldwide.
Depo-Provera (depot-medroxyprogesterone acetate)
is the most commonly used injectable in the United
States. It is a convenient, discrete, and low-maintenance method, and is ideal for patients with contraindications to estrogen use and certain medical
conditions. In addition, there are many noncontraceptive benefits to Depo-Provera use. Side effects with
this method including irregular bleeding, breast tenderness, weight gain, and the impact on bone mineral
density should be taken into consideration when
prescribing the method. Other injectables such as
Mesigyna and norethindrone enanthate are widely
used outside the United States.
Key words: injectable contraceptive, Depo-Provera

Depot-Medroxyprogesterone
Acetate
According to the 2002 National Survey of Family Growth, 5.3% of all US women between
the ages of 15 and 44 currently use depotmedroxyprogesterone acetate (DMPA or
Depo-Provera) as their chosen method of contraception.1 A higher proportion of women in
younger age groups use DMPA with 13.9% of
women aged 15 to 19 using DMPA compared
with 10.1% between the age of 20 and 24, and
1.6% between the ages of 40 and 44. A decline in
adolescent pregnancy rates between 1995 and
2002 has been attributed to increased use of
contraception in general, including DMPA use
by younger women.
Correspondence: Philip D. Darney, MD, MSc, Professor and Chief, Obstetrics, Gynecology and Reproductive Sciences, San Francisco General Hospital,
University of California, San Francisco, 1001 Potrero
Avenue 6D, San Francisco, CA 94110. E-mail: darneyp
@obgyn.ucsf.edu
CLINICAL OBSTETRICS AND GYNECOLOGY

898

Depo-Provera is one the most widely used

and thoroughly studied contraceptive methods.
It has been available in many countries other
than the United States since the 1960s. Evidence
about the safety, efficacy, and acceptability of
DMPA comes from other countries including Sri
Lanka, Indonesia, Thailand, and Mexico where
DMPA has been used and studied for decades. It
was approved for use as contraception in the
United States in 1992. It is composed of microcrystals suspended in an aqueous solution. Studies comparing 100-mg intramuscularly (IM)
doses compared with 150 mg IM doses found
that 150 mg IM dose (gluteal or deltoid) is
required to effectively prevent pregnancy with
a first-year pregnancy rate of 0.3%.2
Other injectables including Mesigyna (50 mg
norethindrone enanthate and 5 mg estradiol
valerate), and norethindrone enanthate (200 mg
every 2 mo) are widely used outside the United
States. A new formulation of DMPA, 104 mg,
has recently been approved for subcutaneous
administration in the United States.

Mechanism of Action
Depo-Provera, like other progestin-only methods, alters the endometrial lining, thickens the
cervical mucus, and blocks the luteinizing hormone surge to prevent ovulation. After method
discontinuation, ovulation resumes at 14 weeks,
but can take up to 18 months. In comparison to
combined hormonal methods DMPA does not
impact follicle-stimulating hormone as consistently or as intensely. Thus, for one-third of
DMPA users, estradiol levels remain unchanged
from early-to-mid-follicular phase levelsapproximately 40 to 50 pg/mL. For most DMPA
users, estradiol levels vary throughout the injection period and may reach postmenopausal
VOLUME 50

NUMBER 4

DECEMBER 2007

Injectable Contraception
levels of <20 pg/mL, but vasomotor symptoms
such as hot flashes and vaginal atrophy are
uncommon in DMPA users. Absence of these
symptoms is likely due to the fact that progestins, like estrogens, also suppress them. Onset of
contraceptive efficacy of Depo-Provera is within
24 hours after injection and is maintained for at
least 14 weeks providing a margin of protection
if reinjection typically scheduled at 12 weeks is
delayed. If reinjection is delayed beyond 14
weeks, women should be questioned regarding
unprotected intercourse since they were due for
their injection and should be evaluated for emergency contraception.3 Because there is an association between higher neonatal and infant
mortality rates associated with initial DMPA
injection at the time of early pregnancy, the
timing of the first injection is important. The
first injection should be administered within the
first 5 days of the menstrual cycle. DMPA
(150 mg) can be given IM into the deltoid or
gluteal muscle using a z-track technique; the area
should not be massaged postinjection. A new
subcutaneous formulation is now available in
the United States. DMPA (104 mg/0.65 mL) is
administered subcutaneously every 3 months.
The 30% lower dose of progestin in the subcutaneous formulation is because it provides
slower and more sustained absorption of the
progestin; the duration of the effect is unchanged.4 The risks of using the IM injection
and the subcutaneous injection are similar. The
subcutaneous formulation is less painful for
patients and has the potential for allowing patient self-administration whereas the IM formulation is available in the generic form, and thus is
less costly.
DMPA takes 6 to 8 months after the last
injection to disappear and clearance is slower in
heavier women. Approximately half of women
who discontinue Depo-Provera can expect norTABLE 1.

Failure Rates During the First Year

of Use, United States6 (Percent of
Women With Pregnancy)

Method
Combination pill
Progestin only
IUDs
Progesterone IUD
Levonorgestrel IUD
Copper T 380A
Implants
Injectable

Lowest
Expected

Typical

0.1%
0.5%

7.6%
3.0%

1.5%
0.1%
0.6%
0.05
0.3%

2.0%
0.1%
0.8%
0.2
3.1%

899

mal menses to return in 6 months after the last

injection, but 25% will wait a year before resumption of a normal pattern. This delay should
be taken into consideration when counseling
patients about method choice5 (Table 1).

Efficacy
The efficacy of DMPA is equal to that of sterilization and better than that of oral hormonal
contraceptive methods. The theoretical effectiveness is 99.7% with a lowest expected rate of
pregnancy of 0.3%.6 Serum concentrations of
DMPA are high so efficacy of the method is not
compromised by increasing body weight or medication-induced increased hepatic enzyme activity patients with contraindications to estrogen
use, DMPA, a progestin-only method, is a safe
and effective alternative.
Indications for DMPA use:

1. At least 1 year of birth spacing desired.

2. Highly effective long-acting contraception
not linked to coitus desired.
3. Private, coitally independent method desired.
4. Estrogen-free contraception needed.
5. Breastfeeding.
6. Sickle cell disease.
7. Seizure disorder.
Absolute Contraindications:

1.
2.
3.
4.

Pregnancy.
Unexplained genital bleeding.
Severe coagulation disorders.
Previous sex steroid-induced liver adenoma.

1.
2.
3.
4.
5.

Liver disease.
Severe cardiovascular disease.
Rapid return to fertility desired.
Difficulty with injections.
Severe depression.

Relative Contraindications:

Advantages
Depo-Provera is an especially good choice for
contraception in women who find it challenging
to use contraception regularly. It is a convenient,
discrete, and low-maintenance method. These
characteristics make it ideal for adolescents
seeking contraception. Furthermore, the efficacy of DMPA does not rely on daily compliance. The intramuscular and subcutaneous
injections of DMPA are required only once
every 3 months and it does not depend on

900

Haider and Darney

partner cooperation or user action at the time of

intercourse. The availability of the newer subcutaneous injection of DMPA provides an even
more convenient option for women who cannot
make a clinic visit for reinjection every 3 months.
Compared with the oral contraceptive pill
DMPA continuation rates are increased and
repeat pregnancy rates are reduced in teenagers.
DMPA as a progestin-only method can be
used in patients with contraindications to estrogen such as women over age 35 who are at risk
because of smoking, hypertension, or diabetes.
DMPA can also be used safely in women with
seizure disorder, sickle cell anemia, congenital
heart disease, migraines with aura, and a previous history of venous thromboembolism. Observational data from epidemiologic studies and
a World Health Organization (WHO) casecontrol study have not shown increased risks
of stroke, myocardial infarction, or venous
thromboembolism.7
Depo-Provera is a good contraceptive option
for women with a history of seizure disorder and
sickle cell anemia. In patients with seizure disorder antiepileptic drugs increase hepatic enzyme
activity and the metabolism of contraceptive
steroids. Oral contraceptives are not recommended in patients on antiepileptic drugs per
WHO guidelines. However, DMPA hormone
levels are high enough that contraceptive efficacy
is not compromised by increased metabolic activity of hepatic enzymes. Furthermore, DepoProvera can have a beneficial effect on seizure
control as it is thought that progestins increase
the seizure threshold in patients with seizure
disorders. In patients with sickle cell anemia,
there is evidence that DMPA results in decreased
sickling of red blood cells, and a reduction in the
frequency and intensity of sickle cell crisis.
Noncontraceptive benefits of DMPA include
a decreased risk of endometrial cancer.8 Reduction in risk of endometrial cancer is similar to
that observed with oral contraceptive pills. In
addition, like oral contraceptive pills, DMPA
decreases the risk of pelvic inflammatory disease, endometriosis, and uterine fibroids.

Lactation
The physiologic changes required for breastfeeding are dependent on the drop in serum concentrations of progesterone after the delivery of the
placenta. This mechanism causes some concern
regarding the use of DMPA during breastfeeding.
A prospective cohort study evaluated the effect of
early administration of DMPA on initiation of

breastfeeding. This study found no adverse effects

on breastfeeding. However, the mean time of
initiation of DMPA was 50 hours postpartum.9
This delay should be kept in mind when initiating
DMPA postpartum as there is a theoretical risk of
decreasing breastfeeding if progesterone is introduced too soon after delivery not allowing for the
natural physiologic drop in progesterone to occur
for initiation of milk production. Studies have
shown no adverse effect on breastfeeding in women who receive DMPA at postpartum follow-up
visits. In particular, there was no effect on the
quantity and quality of milk production while on
Depo-Provera. Thus, DMPA can safely be administered at the 2-week or 6-week postpartum visit.
This schedule will provide full contraceptive protection for lactating mothers in whom ovulation
does not occur until at least 12 weeks after delivery.
Use of DMPA does not affect the duration of
breastfeeding. The concentration of DMPA in the
breast milk is negligible, and no effects of the drug
on infant growth and development have been
observed. One group of women, obese Latina
women with prior gestational diabetes who used
DMPA postpartum require extracaution when
prescribing DMPA. In this group of breastfeeding
women who were taking the progestin-only oral
contraceptive pill, a 3-fold increased risk of noninsulin-dependent diabetes was observed.10 It is
unknown whether other progestin-only methods
might pose a risk in obese Latinas who have a
history of gestational diabetes.

Summary of Advantages
1. Long-acting contraceptive benefit is not
dependent on daily user action or partner
cooperation at time of intercourse.
2. Discrete, use not detectable.
3. No serious health side effects.
4. Highly effective, efficacy is comparable to
sterilization, intrauterine contraception, and
implant contraception.
5. Multiple noncontraceptive benefits.
6. Good alternative for women with contraindications to estrogen.
7. Safe for breastfeeding mothers.
8. Positive impact on sickle cell anemia and
seizure disorders.

Disadvantages
There are a few major side effects associated with
Depo-Provera use. These include irregular menstrual bleeding, breast tenderness, weight gain,

Injectable Contraception
depression, acne, and headache. These side effects combined resulted in over 70% discontinuation at 1 year in 1. One-quarter of women
initiating DMPA use discontinue it due to irregular bleeding in the first year.11 If bleeding
occurs shortly after beginning DMPA, patients
should be counseled and advised that irregular
bleeding decreases with use of DMPA for a few
more cycles. Overall incidence of irregular bleeding is 70% in the first year with a decrease in
irregular bleeding with each reinjection, and
rates as low as 10% after the first year. Fifty
percent of the patients report amenorrhea by 1
year with 10% becoming amenorrheic by the
first injection interval, 40% reporting amenorrhea by the fourth injection cycle, and 80%
reporting amenorrhea at 5 years.5
Irregular bleeding which begins several
months after initiation is due to decidualization
of the endometrium and can be treated with
exogenous estrogen such as 1.25 mg conjugated
estrogens, or 2 mg estradiol, given daily for 7 to
14 days. In addition, nonsteroidal anti-inflammatory drugs given for a week or oral contraception pill supplementation during the first 1 to
3 months of DMPA injection, which is when
irregular bleeding tends to be worst, can be used
for treating it.
Studies of exogenous estrogens including
supplementation with 50 mcg ethinyl estradiol,
2.5 mg estrone sulfate, or transdermal estrogen
have shown limited effect on bleeding with no
change in continuation rates of DMPA.12 Overall continuation of DMPA at year 1 is about
33%, 50% at year 2, and as low as 20% at the
end of 3 years.13
Weight gain is a common complaint among
DMPA users with approximately 2.1% of users
discontinuing the method due to weight increase. As is the case with other hormonal contraceptive methods, weight gain while using
DMPA may be a result of dietary changes and
aging and not hormonally induced. Studies of
weight gain and DMPA use have shown mixed
results. Prospective controlled studies evaluating weight gain in normal weight women showed
no relationship between DMPA use and food
intake, energy expenditure, or body weight.
However, in certain subgroups DMPA use has
been correlated with weight gain. Obese adolescent DMPA users gained significantly more
weight when compared with obese adolescents
using oral contraceptive pills or nonhormonal
contraception. Similarly, it has been show that
Navajo women using DMPA have significant
weight gain.14 Weight change should be taken

TABLE 2.

901

Most Common Reasons for Discontinuing Depo-Provera in the First 2

Years of Use15

Headaches
Weight gain
Dizziness
Abdominal pain
Anxiety

2.3%
2.1%
1.2%
1.1%
0.7%

into consideration when counseling patients

about using DMPA (Table 2).

Cancer
Evidence from animal data indicates that
estrogens and progestins could be carcinogenic,
and that progestins could serve as tumor promoters.
Concerns about Depo-Provera use and increased risk of liver, breast, ovarian, and cervical
cancer have not been confirmed in humans.
Earlier population-based case-control studies
indicate a possible association between breast
cancer and DMPA. These studies had small
numbers with only 19 cases in a study conducted
in Costa Rica. Another earlier study in New
Zealand did not find an increased relative risk
in those who had ever used DMPA, but did find
an increased risk among those who recently
initiated the method and were under age 25.
Given the fact that these studies demonstrated
increased risk on the basis of a small number of
cases it is not clear whether the risk, which seems
to be small, is actually due to confounding
variables.16 Other data suggesting a possible link
between DMPA use and breast cancer come
from a large, hospital-based case-control study
conducted by the WHO over 9 years in 3 developing countries. This study found that exposure
to DMPA is associated with a very slight increase risk in breast cancer in the first 4 years of
use, but there was no evidence for an increase in
risk with duration of use.17 The limitation of this
study was that the number of cases in recent
users was small and limited the interpretation of
conclusions. As is the case with oral contraceptive pills and hormone replacement therapy, it is
possible that DMPA accelerated the growth of
an already present tumor or that detection of the
tumor occurred earlier because of study-related
surveillance. More recent data from a population-based multinational case-control study,
qthe Womens Contraceptive and Reproductive

902

Haider and Darney

Experiences Study of the National Institute

of Child Health and Human Development,
assessed the association between exposure to
injectable contraceptives and risk of breast
cancer. The use of injectable contraceptives
was not associated with an increased risk
of breast cancer [odds ratio (OR) = 0.9, 95%
confidence interval (CI) = 0.7, 1.2], and risk was
not increased in current users (method used
within 1 y of the reference date) (OR = 0.7,
95% CI = 0.4, 1.3), or in those initiating the
method within 5 years of the reference date
(OR = 0.9, 95% CI = 0.5, 1.4).18
These studies did not find an increased risk
for breast cancer or increase in risk with duration of use. However, there is some evidence
suggesting that recent use maybe related to
breast cancer development, thus clinicians
should consider counseling patients that DMPA
might accelerate the growth of an already present cancer rather than cause a new disease.
If such cases occur, disease would likely be
detected earlier and result in better outcomes.
Earlier detection is the probable explanation for
lower breast cancer mortality rates in women
who use oral contraceptive pills.

Other Cancers
Increased risk of cervical cancer while on DepoProvera has not been confirmed. The WHO
Collaborative Study of Neoplasia and Steroid
Contraceptives conducted a hospital-based casecontrol study in Thailand, Mexico, and Kenya.
This study did not find a statistically significant
increase in invasive cervical cancer with DMPA
use. Furthermore, there was no association with
increasing risk with duration of use.19 In one
study conducted in New Zealand, a slight increase in the risk of cervical dysplasia among
users of Depo-Provera was noted, but could be
attributed to an increased prevalence of known
risk factors (ie, multiple sexual partners, history
of sexually transmitted infections) for dysplasia.20 Although there is no increase in overall risk
of invasive cervical cancer with DMPA use,
clinicians should provide recommended cervical
cytologic surveillance in all users of contraception including DMPA users, but Pap smears
should not be required before initiation of
DMPA or other methods.
As with oral contraceptive use, there is no
evidence for increased risk of liver cancer with
use of Depo-Provera. Strong evidence supports
a reduction in risk of endometrial cancer in
DMPA users at least as great as that seen with

oral contraceptive users relative risk = 0.21

(95% CI = 0.06, 0.79) in women who had ever
used DMPA in a Thai study.21 There is no
evidence for increased risk of ovarian cancer
with DMPA use, and potentially a modest decrease in overall risk.

Depression
Although DMPA labeling suggests that depression may worsen with use of the method, studies
regarding DMPA use and depression are inconclusive. No significant increase in depressive
symptoms were observed among young, poor,
Hispanic inner city women who are known to
have a high prevalence of depression. There is
little evidence for increasing depression with
short-term or long-term DMPA use and it is
not a contraindication to DMPA use.22 A prospective study set in an urban clinic compared
adolescents on DMPA to controls and used 2
standardized questionnaires, the Beck Depression Inventory (BDI) and the Multiple Affect
Adjective Checklist-Revised (MAACL-R), and
found no statistically significant differences
in depressive symptoms when using DMPA
as a contraceptive agent over a period of
12 months and no significant changes in negative
or positive affect.23 Depression should not be a
reason to withhold DMPA administration in
patients for whom DMPA is an ideal contraceptive method.

Metabolic Effects
The overall impact of Depo-Provera on lipoproteins remains uncertain. There seems to be no
clinically significant alterations in lipoprotein
profiles while on Depo-Provera. It is thought
that there may be no impact on lipoproteins due
to the avoidance of a first-pass metabolism
through the liver. However, there does seem to
be a theoretical risk of increased total cholesterol
and low-density lipoprotein-cholesterol and a
decrease in high-density lipoprotein-cholesterol
during the initial period after initiation of
DMPA. A multicenter clinical trial by the
WHO found a transient adverse impact in the
first few weeks after injection when hormonal
levels in the blood were high.24 The clinical
significance of these findings is unclear. It seems
that following lipid profiles of patients with
hyperlipidemia or with a family history of
it would be prudent. Depo-Provera does not
affect carbohydrate metabolism or coagulation
factors.

Injectable Contraception

Effect on Bone Density

Owing to the decrease in endogenous serum
estradiol levels secondary to DMPA, a relative
hypoestrogenic state exists among users that is,
associated with increased bone resorption. Given this physiologic change in DMPA users,
there has been increasing concern about the
impact of DMPA on bone health. In 2004, the
US Food and Drug Administration (FDA)
added a black box warning to DMPA labeling
which stated that women who use DMPA might
lose significant bone mineral density (BMD).
The warning also cautioned providers that bone
loss increases with greater duration of DMPA
use and may not be completely reversible.
Furthermore, the warning stated that it is unknown whether use of DMPA during adolescence or early adulthood will reduce peak bone
mass or increase risk for osteoporotic fracture
later in life. The FDA then concluded that
DMPA should be used as birth control for longer than 2 years only if other contraceptive methods are not advisable.
The BMD effects of DMPA are equivalent to
those of pregnancy and lactation. A hypoestrogenic state occurs in women after their deliveries
and is known to result in a decline in BMD.
During lactation breastfeeding women experience progressive declines in BMD compared
with non-breastfeeding women and are known
to regain BMD after cessation of breastfeeding.
Similarly, in the case of Depo-Provera use, most
studies have found a decrease in BMD in adults
compared with their own baseline BMD or
compared with nonusers. There were similar
findings among adolescent DMPA users compared with nonusers. Only some of these studies
found a statistically significant difference in
bone density changes between DMPA users
and nonusers whereas others did not. Available
data do not suggest that DMPA will reduce peak
bone mass and increase the risk of osteoporotic
fracture rate. A systematic review of DMPA
studies revealed that longitudinal data from
adult DMPA users had results that differed
about the rates of BMD reduction and seemed
to change over time. Most studies showed reduction in BMD of less than 1% per year of
use.25 In addition, most of the decrease in BMD
occurs in the first 2 years of DMPA use, with
little incremental BMD loss during additional
years of use.26 There are no data on postmenopausal fracture rates in women who used DMPA
as adolescents or adults thus, the clinical significance of DMPA associated decline in BMD is
unknown. Furthermore, most of the evidence

903

currently available indicates that women regain

BMD after discontinuation of DMPA use. A 7year prospective study found at 96 weeks (1.8 y)
after DMPA was discontinuous, total hip BMD
had returned almost to baseline levels, only
0.20% lower than baseline, and BMD measurements at the lumbar spine showed partial
recovery ( 1.19%).27 After discontinuation of
DMPA in adult women users, BMD recovery
differed by anatomic site and length of
DMPA use. All women had return to levels
comparable to nonuser controls by 76 months
and return to baseline levels by 92 months.
Two years after discontinuation of long-term
(median 10 y; range: 3 to 17 y) DMPA use,
BMD in the lumbar spine increased significantly
(P<0.002), with mean increases overall of 3%
(0.4% to 5.6%) at 1 year and 6.4% (3.4% to
9.4%) at 2 years.28
Because adolescence is a period of critical
bone formation, there has been even more concern about the use of DMPA in adolescent users.
Evidence regarding DMPA use in adolescents
and BMD recovery is similar to that in adults,
and is overall reassuring. The only study to look
at BMD changes in adolescents after DMPA
discontinuation is a population-based prospective cohort study of users age 14 to 18, the mean
BMD at all anatomic sites reached or exceeded
the levels of never-users by 12 months after
DMPA discontinuation, a faster rate of recovery
than that seen in the adult studies.29
After the FDA black box warning resulted in
changes in Depo-Provera labeling, many professional organizations including the American
College of Obstetrician Gynecologists (ACOG),
the Society for Adolescent Medicine (SAM), and
the WHO reviewed the existing evidence and
endorsed guidelines differing from DMPA product labeling. All 3 of these organizations stated
that there should be no restriction on initiation
or duration of Depo-Provera use in adult women
who are eligible to use this method as the risk of
osteoporotic fractures is only theoretical, and
does not warrant alteration in current practice
patterns. Furthermore, adolescents should not
be denied DMPA as the risk of unintended
pregnancy far outweighs the theoretical concerns about fracture risk. Overall risks and
benefits for continuing DMPA use should be
reconsidered over time with individual adolescent users.
The decline in BMD in Depo-Provera users is
similar to that associated with lactation. There is
no evidence of clinically significant adverse outcomes (ie, increased fracture rates) associated

904

Haider and Darney

with current, past, or prolonged DMPA use.

Bone densitometry testing or antiresorptive
agents should not be used in otherwise healthy
adolescents or adults using Depo-Provera. All
users of contraception, including DMPA users
should be encouraged to perform weight-bearing exercise, not to smoke, and have a sufficient
amount of dietary calcium (1300 mg) and vitamin D (400 IU) daily in order for adolescents to
attain peak bone mass, and adults to decrease
osteoporotic risk. Concerns about skeletal
health in adults and adolescents should not
restrict initiation, continuation, or duration of
DMPA use.

Effect on Future Fertility

Despite concern about the delay in becoming
pregnant after cessation of DMPA use, DepoProvera does not permanently suppress ovarian
function, and the pregnancy rate in women with
a desire to become pregnant after discontinuing
DMPA is normal. By 18 months after discontinuation of the method 90% of Depo-Provera
users have become pregnant which is the same
proportion as other methods.30 There is a delay
in conception after DMPA. This delay is approximately 9 months after discontinuation of
the method and there is no increase in the delay
with duration of use. Need for pregnancy planning should be taken into consideration when
counseling patients as those patients wanting to
conceive immediately after stopping the method
should not use DMPA. If menstrual function
remains suppressed beyond 18 months after
discontinuation further evaluation of other
etiologies unrelated to DMPA administration
should be pursued.

Short-term Injectable
Contraceptives
Short-term injectable contraception of estrogen
and progestin administered on a monthly or
alternate month basis has been available around
the world for some time. These injections are
popular methods in China, Latin America, and
Eastern Asia.

Lunelle (or Cyclofem)

Lunelle, a monthly injectable, consists of 25 mg
of DMPA and 5 mg estradiol cypionate, and is
administered every 28 to 30 days (not to exceed
33 d) as a deep intramuscular injection. Lunelle
was taken off the market in the United States in

2002 by the manufacturer because of concerns

that there may not have been enough medication
in the syringe containing the medication, but is
still available in other countries. Lunelle is as
efficacious as DMPA, but has a better bleeding
profile with less irregular bleeding and amenorrhea.31 In addition, fertility rates after discontinuation of the method are similar to oral
contraceptives due to rapid reversibility of the
method. Owing to the estrogen and progestin
components of the method, the same risks,
benefits, and contraindications as oral contraceptive pills apply to Lunelle.

Norethindrone Ethanate
Another progestin-only injectable, norethindrone ethanate, is given in a dose of 200 mg IM
every 2 months. This progestin has the same
mechanism of action as DMPA as well as the
same advantages and disadvantages.

Mesigyna
Mesigyna is a combination of norethindrone
ethanate (50 mg) and estradiol valerate (5 mg)
given monthly. It has a better bleeding
profile than even Lunelle, provides effective
contraception and cycle control, and rapid return to fertility within 1 month after discontinuation.

Dihydroxyprogesterone
Acetophenide and Estradiol
Enanthate
A combination injectable, 150 mg dihydroxyprogesterone acetophenide with 10 mg estradiol
enanthate is the most commonly used injectable
in Latin America. It is also given monthly like
Mesigyna and Lunelle and has similar bleeding
profiles.

References
1. Mosher WD, Martinez GM, Chandra A, et al.
Use of contraception and use of family planning services in the United States: 1982-2002.
Adv Data. 2004;350:135.
2. World Health Organization. A multicentered
phase III comparative clinical trial of depotmedroxyprogesterone acetate given threemonthly at doses of 100 mg or 150 mg: I.
Contraceptive efficacy and side effects.
Contraception. 1986;34:223.

Injectable Contraception
3. Mishell DR Jr. Pharmacokinetics of depot
medroxyprogesterone acetate contraception.
J Reprod Med. 1996;41:381390.
4. Jain J, Dutton C, Nicosia A, et al. Pharmacokinetics, ovulation suppression and return to
ovulation following a lower dose subcutaneous
formulation of Depo-Provera. Contraception.
2004;70:1118.
5. Gardner JM, Mishell DR Jr. Analysis of bleeding patterns and resumption of fertility following discontinuation of a long-acting injectable
contraceptive. Fertil Steril. 1970;21:286.
6. Fu H, Darroch JE, Haas T, et al. Contraceptive failure rates: new estimates from the 1995
National Survey of Family Growth. Fam Plann
Perspect. 1999;31:58.
7. WHO. Cardiovascular disease and use of oral
and injectable progestogen-only contraceptives and combined injectable contraceptives.
Results of a an international, multicenter,
case-control study. Contraception. 1998;57:
315324.
8. WHO. Depot-medroxyprogesterone acetate
(DMPA) and risk of endometrial cancer. The
WHO Collaborative Study of Neoplasia and
Steroid Contraceptives. Int J Cancer.
1991;49:186190.
9. Truitt ST, Fraser AB, Grimes DA, et al. Combined hormonal versus nonhormonal versus
progestin-only contraception in lactation. Cochrane Database Syst Rev. 2003:CD003988.
10. Kjos SL, Peters RK, Xiang A, et al. Contraception and the risk of type 2 diabetes in Latino
women with prior gestational diabetes. JAMA.
1998;280:533.
11. Cromer BA, Smith RD, Blair JM, et al.
A prospective study of adolescents who choose
among levonorgestrel implant (Norplant),
medroxyprogesterone acetate (Depo-Provera),
or the combined oral contraceptive pill as
contraception. Pediatrics. 1994;94:687.
12. Goldberg AB, Cardenas LH, Hubbard AD,
et al. Post-abortion depomedroxyprogesterone
acetate continuation rates: a randomized trial
of cyclic estradiol. Contraception. 2002;66:
215.
13. Said S, Sadek W, Rocca M. Clinical evaluation
of the therapeutic effectiveness of ethinyl oestradiol and oestrone sulphate on prolonged
bleeding in women using depot medroxyprogesterone acetate for contraception. Hum
Reprod. 1996;11(suppl 2):113.
14. Smith RD, Cromer BA, Hayes JR, et al. Medroxyprogesterone acetate (Depo-Provera) use
in adolescents: uterine bleeding and blood
pressure patterns, patient satisfaction, and
continuation rates. Adolesc Pediatr Gyencol.
1995;8:24.

905

15. Espey E, Steinhart J, Ogburn T, et al. DepoProvera associated with weight gain in Navajo
women. Contraception. 2000;62:55.
16. WHO. Multinational comparative clinical evaluation of two long-acting injectable contraceptive steroids: norethisterone enanthate and
medroxyprogesterone acetate. Contraception.
1983;28:1.
17. Paul C, Skegg DC, Spears GF. Depot-medroxyprogesterone (Depo-Provera) and risk of
breast cancer. Br Med J. 1989;299:7591.
18. WHO. Collaborative study of neoplasia and
steroid contraceptives, breast cancer and depot-medroxyprogesterone acetate: a multinational study. Lancet. 1991;338:833.
19. Strom BL, Berlin JA, Weber AL. Absence
of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of
breast cancer. Contraception. 2004;69:353360.
20. WHO. Depot-medroxyprogesterone acetate
(DMPA) and risk of invasive squamous cell
cervical cancer. The WHO Collaborative
Study of Neoplasia and Steroid Contraceptives. Contraception. 1992;45:299312.
21. The New Zealand Contraception and Health
Study Group. History of long-term use of depot-medroxyprogesterone acetate (DMPA) in
patients with cervical dysplasia; case-control
analysis nested in a cohort-study. Contraception. 1994;50:443.
22. WHO. Depot-medroxyprogesterone acetate
(DMPA) and risk of endometrial cancer. Int
J Cancer. 1991;49:186190.
23. Westoff C, Truman C, Kalmuss D, et al.
Depressive symptoms and Depo-Provera.
Contraception. 1995;51:351.
24. Gupta N, OBrien R, Jacobson LJ, et al. Mood
changes in adolescents using depot-medroxyprogesterone acetate for contraception: a
prospective study. J Pediatr Adolesc Gynecol.
2001;14:71.
25. WHO. A multicentre comparative study of
serum lipids and apolipoproteins in long-term
users of DMPA and a control group of IUD
users. Contraception. 1993;47:177.
26. Curtis KM, Martins SL. Progestogen-only
contraception and bone mineral density: a
systematic review. Contraception. 2006;73:
470487.
27. Scholes D, Lacroix AZ, Ott SM, et al. Bone
mineral density in women using depot medroxyprogesterone acetate for contraception.
Obstet Gynecol. 1999;93:233238.
28. Kaunitz AM, Miller PD, Rice VM, et al. Bone
mineral density in women aged 25-35 years
receiving depot medroxyprogesterone acetate:
recovery following discontinuation. Contraception. 2006;74:9099.

906

Haider and Darney

29. Cundy T, Cornish J, Roberts H, et al.

Menopausal bone loss in long-term users of
depot medroxyprogesterone acetate contraception. Am J Obstet Gynecol. 2002;186:
978983.
30. Scholes D, Lacroix AZ, Ichikawa LE, et al.
The association between depot medroxyprogesterone acetate contraception and bone
mineral density in adolescent women. Contraception. 2004;69:99104.

31. Schwallie P, Assenze J. The effect of depomedroxyprogesterone acetate on pituitary

and ovarian function, and the return to fertility
following its discontinuation. Contraception.
1974;10:181.
32. Kaunitz AM, Garceau RJ, Cromie MA, et al.
Comparative safety, efficacy, and cycle control
of Lunelle monthly contraceptive injection
and Ortho-Novum 7/7/7 oral contraceptive.
Contraception. 2000;62:289.