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Depot medroxyprogesterone acetate for contraception
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Depot medroxyprogesterone acetate for contraception

Disclosures: Andrew M Kaunitz, MD Grant/Research/Clinical Trial Support: Agile [Contraception (investigational transdermal contraceptive patch)]; Bayer [Contraception, menopause (Levonorgestrel IUD, oral contraceptives, transdermal menopausal hormone therapy)]; Noven [Menopause (Paroxetine, transdermal hormone therapy)]; TherapeuticsMD [Menopause (investigational hormone therapy)]. Consultant/Advisory Boards: Actavis [Contraception, menopause (oral contraceptives, IUD, vaginal estrogen, generic contraceptives)]; Bayer [Contraception, menopause (Levonorgestrel IUD, oral contraceptives, transdermal menopausal hormone therapy)]; Merck [Contraception (vaginal ring contraceptives)]; Teva [Contraception (oral contraceptives, copper IUD, generic contraceptives)]. Mimi Zieman, MD Consultant/Advisory Boards: Bayer Healthcare [Contraception (LNG IUS, Essure)]. Kristen Eckler, MD, FACOG Nothing to disclose.

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Literature review current through: Apr 2015. | This topic last updated: Mar 06, 2015.

INTRODUCTION — Depot medroxyprogesterone acetate (DMPA) is an injectable, progestin-only contraceptive that provides highly effective, private, relatively long-acting (three months), reversible contraception. Use of DMPA eliminates both the need for user action daily or near the time of sexual intercourse and the need for partner cooperation.

DMPA is a good contraceptive option for the following groups of women:

Women who do not want to take a contraceptive pill daily

Women who have a contraindication to, or wish to avoid, an estrogen-containing contraceptive

Women who would like to eliminate regular menses

Adolescents who may not consistently remember to use types of contraception that require frequent administration  

Institutionalized adolescents and women who have difficulty using other forms of contraception

Wheelchair-bound adolescents and women

Other types of progestin-only contraceptives include:

Progestin pills (minipills) (see "Progestin-only pills (POPs) for contraception")

Progestin implants (eg, Nexplanon, Jadelle) (see "Etonogestrel contraceptive implant")

Intrauterine contraception (eg, Mirena, Skyla) (see "Intrauterine contraception (IUD): Overview")

FORMULATIONS AND PHARMACOLOGY — Depot medroxyprogesterone acetate (DMPA) is available in two formulations: 150 mg/1 mL for intramuscular (IM) injection and 104 mg/0.65 mL for subcutaneous (SC) injection. It can be given every 3 months (13 weeks) because low solubility of the microcrystals at the injection site allows pharmacologically active drug levels to persist and remain effective for several months [1].

Following a single intramuscular dose of DMPA, the drug level increases for approximately three weeks, reaching a peak blood concentration of up to 7 ng/mL for a few days [2,3]. The level then declines until it becomes undetectable between 120 and 200 days following injection [3], but there is considerable inter-individual variability in serum levels. Ovulation resumes at DMPA levels <0.1 ng/mL [1].

The formulation for subcutaneous injection provides slower and more sustained absorption of the progestin than conventional intramuscular DMPA. This enables a 30 percent lower dose of progestin (104 versus 150 mg) and reduces peak blood levels by half [4], but with the same duration of effect as conventional DMPA. Administration via the SC route is less painful than IM injection and potentially may allow patient self-administration [5-8]. Otherwise, the benefits and risks are similar for IM and SC administration.

Serum progesterone levels are low (<0.4 ng/mL) for several months following an injection of DMPA since ovulation is suppressed [1]. Estrogen levels vary, but most women have lower levels than normally cycling women [1,9]. Women who have used DMPA for several years have serum estradiol levels between 10 and 92 pg/mL (mean about 40 pg/mL) [1]. Although the endometrium becomes atrophic, vasomotor symptoms are uncommon and the vaginal epithelium remains moist and well rugated.

MECHANISMS OF ACTION — Progestins can prevent pregnancy via several mechanisms. Depot medroxyprogesterone acetate (DMPA) primarily acts by inhibition of gonadotropin secretion, thereby inhibiting follicular maturation and ovulation [10]. The inhibition of ovarian function results in a hypoestrogenic state, which inhibits endometrial proliferation and renders the endometrium less receptive to implantation. Progestins also cause changes in cervical mucus (thicker and less permeable to sperm) and tubal motility (reduced ciliary action) that are unfavorable to sperm migration, thus inhibiting fertilization.

EFFICACY — Depot medroxyprogesterone acetate (DMPA) is a highly effective contraceptive. For the 150 mg intramuscular (IM) injection, failure rates in clinical trials ranged from 0.0 to 0.7/100 woman-years [11]. The typical-user failure rate is 3/100 woman-years in the first year of use, which reflects pregnancies in users who do not return for their injections as scheduled (see 'Repeat injections' below) [12]. In a study assessing failure rates among women choosing various reversible contraceptives, the three-year cumulative failure rate in women who chose DMPA and returned consistently and on time for injections was 0.7 percent, a failure rate comparable to that of intrauterine devices (IUDs) and the contraceptive implant [13]. Because progestin levels are high, efficacy is not reduced by high body weight [14,15] or use of concurrent medications [16].

For the 104 mg subcutaneous (SC) injection, no contraceptive failures were reported in phase III clinical trials with a total of over 16,000 woman-cycles of use [17,18]. This formulation is relatively new; typical-user failure rates are not yet available, but are expected to be similar to the IM preparation.

ADMINISTRATION — Routine pelvic and breast examinations, blood pressure measurement, and laboratory tests are not required before initiating depot medroxyprogesterone acetate (DMPA) [19].

Medical eligibility criteria — The Centers for Disease Control and Prevention (CDC) Medical Eligibility Criteria (MEC) are listed in the table (table 1). In addition to standard contraindications to hormone use, contraindications specific to DMPA (150 mg intramuscular [IM] injection or 104 mg subcutaneous [SC] injection) include:

Current use of aminoglutethimide (usually for the treatment of Cushing's syndrome) because aminoglutethimide may increase metabolism of progestins

Pregnancy planned within the next year, because a delay in return in fertility occurs with DMPA (see 'Return to fertility after discontinuation' below)

Known fragility fracture(s) (ie, fracture caused by an injury that would be insufficient to fracture normal bone: the result of reduced compressive and/or torsional strength of bone), and known osteoporosis or strong risk factors for fracture, eg, hypothalamic amenorrhea, anorexia nervosa, rheumatoid arthritis, chronic glucocorticoid therapy, because of the effect of DMPA on bone mineral density (BMD) (see 'Reduction in bone mineral density' below)

In addition, we agree with the US Food and Drug Administration recommendation to avoid this medication in women with known breast cancer [20]. In addition, women with a strong family history of breast cancer carefully are monitored carefully if using DMPA.

Women with contraindications to estrogen therapy — Although clinicians should familiarize themselves with the contraindications listed on package labeling for all medications they prescribe, progestin-only hormonal methods appear to be appropriate contraceptive choices for many women with relative contraindications to estrogen-containing contraceptives (table 1). Many of the contraindications listed in the package insert were established for combined estrogen-progestin oral contraceptives and then extrapolated to progestin-only methods because clinical trials have not evaluated the safety of the latter in women with contraindications to estrogen. (See "Risks and side effects associated with estrogen-progestin contraceptives".)

Injection technique

Intramuscular DMPA — Both the 1 mL vial and the 1 mL prefilled syringe of DMPA should be shaken vigorously just before use to ensure that the dose being administered represents a uniform suspension; 150 mg of DMPA is administered by deep IM injection in the gluteal or deltoid muscle.

Subcutaneous DMPA — The pre-filled syringe (0.65 mL) of DMPA should be shaken vigorously just before use to create a uniform suspension; 104 mg of DMPA is administered by SC injection into the anterior thigh or abdomen.

A study of the pharmacokinetic profile of SC DMPA over one cycle after injection in the upper arm reported injection at this site provided sufficient medroxyprogesterone levels for contraceptive protection [21]. The study included 24 women with body mass index (BMI) from 18 to 40 kg/m2. Although off-label, administering SC DMPA in the upper arm is a reasonable option for women who prefer this injection site to the anterior thigh or abdomen.

Self-administration of DMPA — Although self-administration is off-label, this approach can enhance access. Several reports have documented preliminary experience with DMPA IM and DMPA SC self-administration [5,6,22].

Timing of injections — The first DMPA injection can be given at any time as long as pregnancy has been excluded. Back-up contraception, such as barrier contraception, the previously used hormonal method, or abstinence, is indicated for seven days if [19]:

DMPA is initiated more than seven days from the onset of the last menstrual period

The woman is post-abortion and DMPA was not initiated at the time of the abortion

The woman is postpartum, has not had a menstrual period, and (1) is fully breastfeeding and >6 months postpartum or (2) not fully breastfeeding and ≥21 days postpartum

Initial injection — Although pregnancy should be excluded before initiating contraception (table 2), there is no evidence that inadvertent administration of DMPA during pregnancy increases the risk of congenital anomalies [23,24]. In the United States Planned Parenthood National Database for 1994 to 1998, 402 DMPA users became pregnant and many of these women received more than one dose of DMPA while pregnant [23]. No fetal anomalies were reported; however, birth outcome data were incomplete.

First day of menses – The ideal time to initiate DMPA is within seven days of the onset of menses. This approach increases the certainty that the patient is not pregnant at the time of injection and prevents ovulation during the first month of use, so that back-up contraception is unnecessary [25]. Most women have pharmacologically active drug levels and relatively impermeable cervical mucus within 24 hours after injection.

Quick start – Several studies have initiated DMPA on the day the patient is first seen for contraception, rather than waiting until her next menses begins [26-29], as long as pregnancy can be excluded with reasonable certainty by history or pregnancy testing. This "same day" "quick start" or "Depo-now" approach facilitates DMPA initiation for many users, and thus may prevent some pregnancies [30].

If DMPA is initiated more than seven days after the first day of the woman's menstrual period and she has had unprotected intercourse during the cycle, clinicians and patients must recognize that there is a small chance of preimplantation or early pregnancy despite a negative pregnancy test prior to the injection. We suggest these women receive emergency contraception if intercourse occurred within the previous 120 hours, and we advise them to use back-up contraception for seven days after DMPA injection [31] since ovulation may occur within 24 hours of the initial injection, and we counsel them to have a repeat pregnancy test in two to three weeks.

Switching from another method – Begin DMPA while the woman is still using hormonal contraception (pill, patch, ring), and discontinue the other method seven days after the injection (table 3). Otherwise, a condom or abstinence should be used as a back-up if the first injection is not given within seven days of menses onset.

If switching from intrauterine contraception, the injection should be given seven days before removal of the intrauterine device (IUD). Otherwise, switching from an IUD requires consideration of fertilization and implantation from residual sperm in the reproductive tract. Options to prevent these pregnancies include advising the woman to [19]:

Abstain from sex or use barrier contraception for seven days before removing the IUD and receiving the first DMPA injection.

Use emergency contraception at the time of IUD removal.

Repeat injections — DMPA users should be encouraged to return every 3 months (13 weeks) for repeat injections.

Women who return late for a repeat injection – Women using injectable birth control who present late for follow-up injections should not be turned away solely because they are not on time. After a 150 mg injection, ovulation does not occur for at least 14 weeks. Therefore, a two-week "grace period" (repeat injection without pregnancy testing) is appropriate for women receiving injections every 3 months (13 weeks). In women more than two weeks late for their injection (>15 weeks from the last injection), we suggest a pregnancy test before administering DMPA and back-up contraception (or abstinence) for seven days [10]. In the United States, Centers for Disease Control and Prevention (CDC) guidelines support this approach [19]; however, the package labeling is more conservative and recommends excluding pregnancy prior to reinjection in women more than one week late for their injection or >14 weeks from their last injection.

As a result of a study showing that contraceptive efficacy is maintained with a grace period as long as four weeks [32], the World Health Organization (WHO) adopted a longer grace period in its updated guideline [12]. In this study of 2290 women in developing countries who underwent 13,608 DMPA cycles, the pregnancy risk per 100 women-years was statistically similar for users who were "on time" for their injection (0.6, 95% CI 0.33-0.92; 12,508 cycles), users who were two weeks late for their injection (0.0; 95% CI 0.0-1.88; 739 cycles), and users who were four weeks late for their injection (0.4; 95% CI 0.01-2.29; 893 cycles) [32]. A limitation of these data is that more than one third of the women in the study were lactating, placing them at low baseline risk for conception.

Because pregnancy testing may not be readily available in low resource countries, expanding the grace period to four weeks is reasonable in such settings. In high resource countries, we continue to encourage women to return on time and allow a two-week grace period, and require documentation of a negative pregnancy test in women who present more than two weeks (>15 weeks from their last injection).

Women who return early for a repeat injection – If it is necessary for a patient to move up the date of her DMPA injection, a repeat injection may be given early [19].

DISCONTINUATION — Discontinuation rates at one year range from 40 to 75 percent [33].

Return to fertility after discontinuation — Although depot medroxyprogesterone acetate (DMPA) does not permanently impact endocrine function, return of fertility may be delayed. Within 10 months of the last injection, 50 percent of women who discontinue DMPA to become pregnant will conceive; in a small proportion of women, however, fertility is not reestablished until 18 months after the last injection [34]. The persistence of ovulation suppression following DMPA discontinuation is not related to the duration of use, but is related to weight [34]. Women with lower body weights conceive sooner after discontinuing DMPA than women with higher body weights.

Before initiating DMPA contraception, clinicians should counsel candidates about the possible prolonged duration of contraceptive action. Women who may want to become pregnant within the next one or two years should choose an alternative contraceptive.

Switching from DMPA to another method — For women who wish to change from DMPA to another form of contraception, the new method should be started no later than 15 (ideally no later than 14) weeks after the previous injection. This ensures that the woman is not pregnant at the time she initiates a new contraceptive method.

With long-term use of DMPA, most users become amenorrheic. Initiation of contraception should not be delayed until resumption of menses. Amenorrhea after discontinuing DMPA injections does not mean the woman is protected against pregnancy if she has unprotected intercourse.

COUNSELING — The advantages and disadvantages of depot medroxyprogesterone acetate (DMPA) use are summarized in the table (table 4). Proactive, candid counseling on both the side effects of DMPA, especially bleeding irregularities, and the need for timed injections is important because women who are well-informed when they choose this method of contraception are much more likely to become satisfied users with high continuation rates [28,35-39]. In a randomized trial, women who received information on risks, benefits, and overall characteristics of DMPA at each visit and counseling that emphasized that potential side effects were not harmful were much less likely to discontinue the method within 12 months than the usual care group (OR 0.27, 95% CI 0.16-0.44) and much less likely to discontinue the method because of menstrual disturbances (OR 0.20, 95% CI 0.11-0.37) [37].

SIDE EFFECTS — Side effects usually decrease or stop within the first few months after starting injections. A change in uterine bleeding pattern is the best documented and most common side effect in depot medroxyprogesterone acetate (DMPA) users. Side effects associated with DMPA use were illustrated in a clinical trial in which over 3900 DMPA users were followed for up to seven years [3]. The following side effects were reported by more than 5 percent of subjects: menstrual irregularities (unscheduled bleeding or amenorrhea), weight changes, headache, abdominal pain or discomfort, nervousness, dizziness, and asthenia.

Menstrual changes — Menstrual changes occur in all women using DMPA and are the most frequent reason for discontinuation. In many cases, women become anxious over menstrual changes because of concerns that the changes are due to pregnancy or gynecologic disease. Conscientious patient education before initiation of DMPA, as well as supportive follow-up, can markedly reduce these concerns. Women who will not tolerate the menstrual changes that inevitably accompany use of DMPA should be counseled to choose an alternative contraceptive.

Unscheduled bleeding — During the first months of use, episodes of unpredictable bleeding and spotting lasting seven days or longer are common. The frequency and duration of such unscheduled bleeding decrease with increasing duration of use.

If persistent spotting or unscheduled bleeding in the first few months of use is unacceptable to a DMPA user who otherwise wishes to continue using this method, one option is to administer oral or transdermal estrogen supplements. The efficacy of supplemental estrogen for prevention or treatment of active unscheduled bleeding in DMPA users is unclear. Trials have reported discordant findings. (See "Management of unscheduled bleeding in women using contraception", section on 'Depot medroxyprogesterone acetate (DMPA)'.)

If bothersome spotting and/or unscheduled bleeding persist after several injections of DMPA, further evaluation is not necessary unless clinically indicated based on history (bleeding pattern was abnormal prior to contraceptive use), signs and symptoms (menorrhagia, pain, vaginal discharge, new abnormal findings on pelvic examination), or national cervical cancer screening guidelines, even if the unscheduled bleeding persists for the duration of contraceptive use. If a treatable abnormality is not found and the patient remains dissatisfied with the menstrual changes caused by DMPA, then she may be better served by another contraceptive method. (See "Management of unscheduled bleeding in women using contraception", section on 'General approach'.)

Amenorrhea — With increasing duration of use, amenorrhea becomes increasingly prevalent. A systematic review calculated the weighted prevalence of amenorrhea over successive 90-day periods and found rates of 12, 25, 37, and 46 percent, respectively [40]. With ongoing use, the rate of amenorrhea increases to 75 percent. As long as women understand that absence of bleeding represents an expected and reversible phenomenon associated with DMPA use, amenorrhea (along with a reduction or elimination of menstrual cramps) can be viewed as one of the advantages of using this method [28,41-45].

Weight changes — Concerns about weight gain may limit some women's choice of DMPA and other progestin-only methods. Observational studies have reported variable effects of DMPA on weight gain. These studies are difficult to interpret because individuals tend to gain weight over time irrespective of contraceptive use. Discontinuation of and changes in contraceptive methods over time, as well as variability in study design, characteristics of the participants, and endpoints also prevent using observational data to make definite conclusions about the effect of contraception on weight.

A 2013 systematic review (meta-analysis could not be performed) of studies on the effects of progestin-only contraceptives on weight concluded mean gain was <2 kg for most studies up to 12 months and usually similar to the comparison group using another contraceptive [46]. Major findings were:

DMPA versus estrogen-progestin contraception (three studies): no significant difference between groups in weight gain

DMPA versus no contraception (one study): DMPA was associated with a greater increase in body fat (mean difference 11 percent; 95% CI 3-19) and a greater decrease in percent lean body mass (mean difference -4 percent; 95% CI -7 to -1)

DMPA versus non-hormonal intrauterine device (IUD) (two studies): in one study, mean weight gain was greater for DMPA users than users of a nonhormonal IUD at one, two, and three years (mean difference 2.28 kg, 2.71 kg, 3.17 kg, respectively), while another study found no difference between groups at 10 years.

Multiple factors appear to play a role in weight gain over time, and should be considered when counseling women about this side effect. For example, one group observed that black women gain more weight over time with use of various types of contraception (implant, DMPA, copper IUD, levonorgestrel IUD) than non-black women [47]. In addition, a 2013 systematic review of three studies observed that DMPA users who gained >5 percent of baseline body weight within six months of starting DMPA appeared to be at increased risk of weight gain over the following two to three years; however, attrition and loss to follow-up was a major limitation of these studies [48].

Randomized trials, although not definitive, have not reported significant weight gain in DMPA users. One randomized trial compared the effects of intramuscular DMPA and saline injections on food intake, resting energy expenditure, and body weight [49]. DMPA did not increase appetite or weight in normal weight women observed during the two menstrual cycles before, and first menstrual cycle following, the initial injection. Two randomized trials comparing a subcutaneous formulation of DMPA and leuprolide in women with symptomatic endometriosis found no difference in the impact of these drugs on weight over 6 to 12 months of use [50,51]. However, the results of these trials are not generalizable since the first trial involved only 20 volunteers who received only 1 injection of DMPA [49] and, in the other two trials, controls were given leuprolide rather than another contraceptive drug or no contraceptive drug.

Headache — Although natural progesterone and oral progestins have been reported to reduce the frequency of migraine, DMPA appears to trigger headache as a side effect in susceptible patients [52,53]. However, a history of headache is not a contraindication to DMPA use (table 1).

Mood changes — Observational studies have not reported any consistent effects of DMPA on mood [54-57]. We feel that progestins may cause or exacerbate depressive symptoms in certain subpopulations of women, including those with a history of premenstrual syndrome or mood disorders [58-60]. Therefore, we suggest that clinicians follow such women closely when any progestin-based therapy is initiated, but we do not feel a history of depression is a contraindication to use of DMPA (table 1).

Other — Dizziness, bloating, and decreased libido are other reported side effects.

Two to 20 percent of patients using the subcutaneous formulation have reported a dent, dimple, or lump at the injection site (termed granuloma/atrophy), or other minor site reactions (redness, pruritus, bruising, or blistering) [5,6,17]. The natural history of granuloma/atrophy is unclear; resolution is possible as with other forms of lipoatrophy.

OTHER EFFECTS

Reduction in bone mineral density — A primary concern regarding the safety of long-term use of depot medroxyprogesterone acetate (DMPA) is its effect on bone density. One of the contraceptive actions of DMPA results from suppression of gonadotropin secretion [1], which in turn suppresses ovarian estradiol production [61]. In hypoestrogenic states, bone resorption exceeds bone formation [62], resulting in a decline in bone mineral density (BMD). The rate of bone loss is not linear; the greatest loss is during the first one to two years of use, after which BMD appears to plateau (figure 1) [63-68]. Compared to nonusers, BMD at the hip and spine of DMPA users decreases by 0.5 to 3.5 percent after one year of use, 5.7 to 7.5 percent after two years of use, and 5.2 to 5.4 percent after five years of use [65-67,69,70]. The subcutaneous (SC) and intramuscular (IM) formulations have similar effects [18]. (See "Drugs that affect bone metabolism".)

Observations of reduced BMD in current DMPA users have led to concerns that DMPA-induced bone loss might increase the long-term risk of fractures years after discontinuation of the drug, particularly in three groups of women [71]:

Young women, who have not yet attained their peak bone mass

Perimenopausal women, who may be starting to lose bone mass and who may have reached menopause by the time of DMPA discontinuation, with no opportunity to regain the lost bone mass

Adolescents/women who are immobilized/wheelchair-bound.

However, studies involving premenopausal women and adolescents treated with DMPA for up to five years showed that the decline in BMD associated with the drug was substantially reversed after discontinuation [50,51,64-67,69,72-82]. Reversal at the spine occurred sooner, and appeared to be more complete, than reversal at the hip. Although there is an association between current DMPA use and decreased BMD, there are few data on the effect of BMD changes in younger women on their short- or long-term fracture risk. The best available data suggest that DMPA use does not reduce peak bone mass and does not increase the risk of osteoporotic fracture in later life in women at average risk of osteoporosis [83].

We are not aware of published data addressing the skeletal safety of DMPA when used in immobilized/wheelchair-bound adolescents or women. We feel that theoretical skeletal concerns associated with DMPA use should not prevent its use in immobilized/wheelchair-bound women, given its advantages in this patient population: convenience (amenorrhea makes hygiene easier) and avoidance of the increased risk of venous thrombosis associated with both immobility and estrogen-based contraceptives.  

Although observational studies have reported an increased risk of fracture in current DMPA users compared with non-users [84-88], DMPA users differ behaviorally in a variety of ways from non-users and these differences may impact their risk of traumatic fractures, thus it is difficult to draw clinical inferences from these findings. A retrospective cohort study provided reassuring data: DMPA users had higher incident fracture risk than never users before beginning DMPA (incidence rate ratio 1.28) and after beginning DMPA (incidence rate ratio 1.23), but the fracture risk in DMPA users did not increase significantly after starting DMPA (incidence rate ratio before and after starting DMPA: 1.08, 95% CI 0.92–1.26) [88]. Long-term prospective data are not available.

Despite the lack of a proven increase in fracture rate, in 2004, the United States Food and Drug Administration (FDA) issued a black box warning on DMPA package labeling: "Women who use DMPA may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of DMPA during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. DMPA should be used as a long-term birth control method (eg, longer than two years) only if other birth control methods are inadequate." The addition of this warning to DMPA's package labeling appears to have led some clinicians in the United States to restrict the duration of DMPA use in their patients and to inappropriately order BMD testing in women using DMPA [89].

Counseling patients — We, and others, including the American College of Obstetrics and Gynecology (ACOG), the Society for Adolescent Health and Medicine (SAHM), the World Health Organization (WHO), and the Society of Obstetricians and Gynaecologists of Canada (SOGC) [90-95], believe that the advantages of DMPA use as a contraceptive generally outweigh the theoretical concerns regarding skeletal harm. Accordingly, skeletal health concerns should not restrict initiation or continuation of DMPA in adolescent girls, women 18 to 45 years of age, or older reproductive age women (age more than 45 years). The available evidence also does not justify limiting the duration of DMPA therapy, which may be continued for decades.

Given that the effect of DMPA on BMD is similar to that with pregnancy (decrease in BMD of 2 to 8 percent) or lactation (decrease in BMD of 3 to 5 percent ) [96,97], use of DMPA is not an indication for BMD testing (eg, dual-energy X-ray absorptiometry [DXA]) either before, during, or in follow-up of its administration [93,95].

Some clinicians prescribe supplemental hormone replacement doses of oral or transdermal estrogen in long-term DMPA users who have additional risk factors for low BMD. (See "Epidemiology and etiology of premenopausal osteoporosis".) This approach is based on data from randomized trials in which menopausal doses of estrogen supplements given to adolescent [98] and adult DMPA users [99] prevented declines in BMD. These studies provided evidence that the loss in BMD was estrogen-related and that the effects of estrogen on bone metabolism were not impaired by DMPA. We feel there is insufficient evidence to make specific clinical recommendations regarding estrogen supplementation for DMPA users, in part, because it appears that estrogen from an exogenous (supplemental estrogen) or endogenous (ovarian) source results in similar recovery of BMD following DMPA discontinuation.

There are no data on use of other antiresorptive agents (eg, bisphosphonates, calcitonin, selective estrogen receptor modulators) to prevent bone loss in DMPA users. We recommend not using them for this indication [100].

To promote bone health, providers should advise DMPA users to have adequate intake of calcium and vitamin D, engage in regular exercise, and avoid cigarette smoking and excessive alcohol consumption, which is good advice for all women, regardless of their contraceptive choice. Providers should also use clinical judgment when deciding whether to use DMPA versus an alternative contraceptive in women with risk factors for osteoporosis.

Beneficial effects on comorbid conditions — DMPA has been used to manage a variety of gynecologic and nongynecologic disorders:

Reduction in menorrhagia, dysmenorrhea, or iron-deficiency anemia – The tendency of DMPA to cause amenorrhea makes it a particularly appropriate contraceptive choice for women with menorrhagia, dysmenorrhea, or iron-deficiency anemia [101-104]. There are no data from randomized trials regarding the impact of DMPA on menorrhagia in women with intramural fibroids; however, the author’s substantial clinical experience over two decades and other observational data indicate that some women with menorrhagia/anemia associated with intramural fibroids become amenorrheic during use of DMPA [105].

Dysmenorrhea related to endometriosis – Progestins inhibit endometriotic tissue growth by directly causing initial decidualization and eventual atrophy and by inhibiting pituitary gonadotropin secretion and ovarian estrogen production. In randomized trials, DMPA was more effective than estrogen-progestin contraceptives and danazol [106], and as effective as leuprolide for treatment of pain associated with endometriosis [50,51].

Use in anticoagulated women – In addition to reducing menstrual blood loss, DMPA may prevent development of hemorrhagic corpus luteum cysts in women who are anticoagulated [107]. Although direct evidence is sparse, SC and IM injections do not appear to increase the risk of local hematoma formation [108].

Endometrium protection – DMPA transforms proliferative into secretory endometrium, thus it protects against development of endometrial hyperplasia.

Reduction in PID – DMPA users have a decreased risk of developing pelvic inflammatory disease (PID) [101]. This may be related to changes in cervical mucus, decreased menstrual blood flow, and/or a reduction in retrograde menstruation.

Reduction in ectopic pregnancy – Women using hormonal contraception, including DMPA, are at very low risk of conceiving ectopic, as well as intrauterine, pregnancies.

Making hygiene easier – DMPA is a useful means of suppressing menstrual bleeding and managing menstrual hygiene in individuals with special needs (eg, cognitive impairment, military personnel, those who are wheelchair-bound, and athletes) [109].

Reduction in sickle cell crisis – Use of DMPA has been associated with fewer painful crises in women with sickle cell disease [110] and appears to be a safe and effective contraceptive method in this population [111].

Possible reduction seizures – The efficacy of DMPA's contraceptive protection does not appear attenuated by the use of enzyme-inducing anticonvulsants [16], and DMPA may have intrinsic anticonvulsant properties [112,113]. For these reasons, DMPA might be a good contraceptive of choice for many women with seizure disorders (table 1).

Reduction in bothersome perimenopausal symptoms – DMPA reduces heavy anovulatory perimenopausal bleeding and is an effective treatment of menopausal vasomotor symptoms in women who need to avoid estrogen therapy [114]. (See 'Perimenopausal women' below.)

Lack of drug interactions – A benefit of DMPA use is the lack of drug interactions compared to other types of hormonal contraception (table 1). As discussed above, use of aminoglutethimide (usually for the treatment of Cushing's syndrome) is contraindicated because aminoglutethimide may increase metabolism of progestins.

Possible allergic reactions — Although allergy to any hormonal contraceptive is rare, anaphylaxis to DMPA has been reported [115].

Impact on cancer risk — Overall, studies have not identified a substantial increase in risk of malignancy with the use of DPMA. In fact, DMPA has been associated with reduced risk of endometrial cancer.

WHO examined the risk of endometrial, ovarian, liver, and cervical carcinoma in DMPA users [116-118]. In case-control studies, the prevalence of endometrial cancer decreased by 80 percent among DMPA users, and DMPA was associated with a greater protective effect against endometrial cancer than oral contraceptives. Theoretically, it is possible that prolonged ovulation suppression associated with DMPA might provide protection against ovarian cancer, as seen with oral contraceptives [41,101,119,120]. In the largest case-control study of this issue, use of DMPA was associated with protection against epithelial ovarian cancer and the magnitude of protection was similar to that seen with oral contraceptives [121]. DMPA has not been associated with an increased risk of cervical or liver cancer.

Studies evaluating the relationship between DMPA use and breast cancer risk have been generally reassuring [122-125], with the exception of two studies that suggested a 2 to 3 fold increased risk of breast cancer [126,127]. In the first of these studies [126], the authors considered their findings inconclusive given the small number of DMPA users in the study and the lack of a dose-response relationship. In the second study [127], the increase in risk was limited to current users with ≥12 months of use. The findings of this latter study, conducted in the Seattle, Washington area and based on 1028 cases of breast cancer, directly conflict with those of the Women’s Contraceptive and Reproductive Experiences (CARE) Study [124], conducted by the Centers for Disease Control and Prevention (CDC) and based on 4575 cases. In contrast with the Washington State study, the Women’s CARE study found that use of DMPA was not associated with an elevated risk of breast cancer in current/recent users or in women who had initiated DMPA five years prior. Neither study verified hormone use by review of medical records/prescriptions.

Cardiovascular risk — There is some evidence that long-term DMPA use induces moderately unfavorable changes in lipid metabolism and reduces peripheral arterial hyperemia-induced flow-mediated dilatation (FMD) [128-132], but does not increase production of coagulation factors and has no adverse effect on blood pressure [133-135]. The clinical implications, if any, of the combination of these changes in healthy young women are unproven.  Low quality evidence from epidemiological studies does not exclude the possibility of an increased risk of venous thrombosis [136,137].

ACOG [90] and the CDC (table 1) consider DMPA an acceptable contraceptive option (category 2) for women with an uncomplicated history of venous thromboembolism (VTE) in whom use of estrogen-progestin contraceptives is contraindicated. In these women, the advantages of using the method generally outweigh the theoretical or proven risks. This recommendation differs from package labeling for DMPA, which indicates that a prior history of VTE is a contraindication to DMPA use. (See "Overview of the use of estrogen-progestin contraceptives".)

For women with multiple risk factors for arterial cardiovascular disease (eg, smoking, older age, diabetes, and hypertension that is poorly controlled or associated with vascular disease) and women with a history of stroke or ischemic heart disease, WHO and the CDC classify DMPA as Category 3, indicating that the risks of use may exceed the benefits. This classification reflects theoretical concerns related to the reduction in plasma high-density lipoprotein levels associated with DMPA use and weak evidence of an increased risk of VTE in users. Although lipid changes associated with use of hormonal contraceptives have not been linked to adverse clinical cardiovascular outcomes [138], in a case-control study, women with a first episode of VTE/pulmonary embolism were twice as likely to be DMPA users than were controls in the general population (OR 2.2, 95% CI 1.3-4.0; 47 of 948 [5 percent] VTE cases and 23 of 902 [2.5 percent] controls were DMPA users) [139]. In this study, use of progestin-only pills, the levonorgestrel-releasing intrauterine device, or the progestin-only contraceptive implant was not a significant risk factor for VTE.

In the absence of accurate data on the absolute risk of VTE in DMPA users, we agree with the CDC’s conclusion that history of VTE/pulmonary embolus is “a condition for which the advantages of using the method [DMPA] generally outweigh the theoretical or proven risks” (table 1).

Lack of protection from sexually transmitted infections — Use of DMPA does not protect users from acquiring sexually transmitted infections (STIs). Whether it increases the risk of acquiring these infections is less clear.

Effect on HIV acquisition and transmission — Studies have raised concern that DMPA is associated with an increased risk of HIV acquisition, although data are mixed [140-142]. Two meta-analyses of observational studies report a small but significant increased risk of HIV acquisition for women using DMPA [141,142]. Potential limitations include observational study design mixed populations of high- and low-risk women, and possible change in sexual behavior, including decreased condom use by women using DMPA. As DMPA is an effective contraceptive option, it should remain available for women until randomized trial data are available.

In the absence of definitive data, we agree with the WHO and CDC assessments that women at high risk of and living with HIV can continue to use all existing hormonal contraceptive methods without restriction (table 5 and table 1) [143,144]. Regardless of contraceptive choice, condoms (male or female) and other HIV preventive measures should always be used to protect against transmission or acquisition of sexually transmitted infections.

Effect on chlamydia and gonorrhea acquisition — Some studies have observed an increased risk of chlamydia and gonorrhea infection in DMPA users compared to oral contraceptive users, contraceptive nonusers, or the general population [63,145-148]   However, these differences usually disappear after adjustment for relevant behavioral factors and rates of new versus existing infection.

The hypothesis that long-acting progestins promote transmission of STIs was based on two studies in Rhesus monkeys in whom progestins caused vaginal mucosal thinning, hyperplasia of cervical columnar cells, and cervical ectopy; however, these changes were not found in women given progestins [149]. Moreover, progestins thicken cervical mucus, and thickened cervical mucus may reduce the risk of ascending infection and development of PID.

Change in glucose/insulin — A study that measured fasting glucose and insulin levels over 3 years in 240 white, African-American, and Hispanic women receiving DMPA found some women experienced mild increases in fasting insulin and glucose levels (3 mg/dL and 4 units, respectively, over baseline values); however, these changes probably are not clinically important [150]. DMPA use has been associated with an increased risk of diabetes in women with increased baseline diabetes risk and in women who gain weight during use [151].

SPECIAL POPULATIONS

Adolescents — Rates of oral contraceptive failure and discontinuation can be very high among adolescents. In contrast, depot medroxyprogesterone acetate (DMPA) provides highly effective and acceptable contraception in this population [43,152-157].

A study of postpartum teens found that DMPA users were more likely to continue their contraception than oral contraceptive users (55 versus 27 percent), and had lower rates of repeat pregnancy (3 versus 24 percent) during a minimum of 12 months follow-up [158]. Some experts in adolescent gynecology suggest that long-acting progestin methods, coupled with condoms for protection against sexually transmitted infections (STIs), should be considered contraceptives of first choice for sexually active teens [153,159].

The effect of DMPA on bone mineral density (BMD) in adolescents was discussed above. (See 'Reduction in bone mineral density' above.)

Perimenopausal women — Women can safely continue use of DMPA until they become menopausal. Because long-term DMPA users are amenorrheic, perimenopausal DMPA users will not experience the irregular bleeding that characteristically accompanies the perimenopausal transition. Likewise, such women may not experience vasomotor symptoms, which are suppressed by DMPA use. (See "Menopausal hot flashes" and "Menopausal hot flashes", section on 'Options if nonhormonal therapies ineffective or not tolerated'.)

The median age of menopause (when contraception is no longer needed) is 51 to 52 years, meaning that 50 percent of women of this age are still ovulatory. By age 55 years, in contrast, at least 80 percent of women are menopausal [160,161]. Therefore, it is reasonable to continue DMPA without gonadotropin testing until the patient is in her mid-50s. At that time, contraception can be discontinued.

Although serum follicle-stimulating hormone (FSH) concentrations increase across the menopausal transition, a single elevated FSH level is not useful in determining menopausal status in any woman because FSH levels vary from cycle to cycle and may fluctuate between the normal premenopausal and postmenopausal ranges [162]. FSH testing is even less useful in DMPA users because DMPA suppresses FSH production, thus menopausal DMPA users may have FSH levels in the premenopausal range related to DMPA. These relationships were illustrated in a study of 82 amenorrheic long-term DMPA users age 40 to 55 years who had FSH testing every 90 days immediately before their DMPA injection: 41 percent of women with a high initial FSH level subsequently had a low FSH level [163]. If FSH is measured in a DMPA user ≥age 50 years, the level is most informative of menopausal status if measured immediately before the next DMPA injection is due [164] and is in the menopausal range on two consecutive occasions [163].

The effect of DMPA on BMD was discussed above (see 'Reduction in bone mineral density' above).

Postabortion and postpartum women — Use of DMPA after abortion or delivery, and in breastfeeding women, is discussed separately. (See "Postpartum and postabortion contraception".)

COST — In addition to enhancing quality of life by allowing couples to choose whether and when they wish to bear children, effective contraception saves healthcare costs. An analysis of nine contraceptive methods found that, over a five-year period, depot medroxyprogesterone acetate (DMPA) and intrauterine contraception were the most cost-effective reversible contraceptives [165].

The intramuscular DMPA formulation is available as a generic formulation, which is less costly than the subcutaneous DMPA formulation (Medi-Span $58 versus $143).

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Choosing birth control (The Basics)")

Beyond the Basics topics (see "Patient information: Hormonal methods of birth control (Beyond the Basics)" and "Patient information: Birth control; which method is right for me? (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Depot medroxyprogesterone acetate (DMPA) injection is an excellent method of contraception for women who desire a relatively long-term, reversible contraceptive method. It is highly effective for three months, private, and avoids the need for compliance daily or near the time of sexual intercourse. (See 'Introduction' above and 'Efficacy' above.)

DMPA can be initiated without a pelvic or breast examination and without any routine laboratory tests. Medical eligibility criteria are listed in the table (table 1). (See 'Administration' above and 'Medical eligibility criteria' above.)

The ideal time to initiate DMPA is within seven days of the onset of menses or before discontinuing another method of contraception, but it can be started at almost any time. The dose is repeated every three months, with a two-week grace period. We suggest performing a pregnancy test before administering DMPA in women more than two weeks late for their injection. (See 'Timing of injections' above and 'Repeat injections' above.)

Thorough counseling about side effects, particularly the high frequency of amenorrhea and unscheduled bleeding, is important to enhance continuation of the method. (See 'Counseling' above and 'Side effects' above.)

Menstrual changes occur in all women using DMPA and are the most frequent cause for discontinuation. During the first months of use, episodes of irregular bleeding and spotting lasting seven days or longer are common. The frequency and duration of such bleeding decrease with increasing duration of use. After one year of use, 50 percent of women experience amenorrhea, and with ongoing use, the rate of amenorrhea increases to 75 percent. (See 'Menstrual changes' above.)

There is an association between current DMPA use and decreased bone mineral density (BMD); losses in BMD are temporary and reverse after discontinuation of DMPA. There is no evidence of an increase in risk of fractures. We believe that, in all age groups, the advantages of DMPA use as a contraceptive generally outweigh the theoretical concerns regarding skeletal harm. We suggest not avoiding DMPA as a contraceptive option in adolescent girls and older reproductive age women (Grade 2C). (See 'Reduction in bone mineral density' above.)

In contrast to package labeling, we suggest not avoiding DMPA as a contraceptive option in women with an uncomplicated past history of venous thrombosis (Grade 2C). However, for women with multiple risk factors for arterial cardiovascular disease (eg, smoking, older age, diabetes, hypertension that is poorly controlled or associated with vascular disease), women with a history of stroke or ischemic heart disease, and women with current venous thrombosis, the risks of DMPA use may exceed the benefits. (See 'Cardiovascular risk' above.)

Return of fertility may be delayed after discontinuing DMPA, but within 10 months of the last injection, 50 percent of women who are trying to conceive will become pregnant; in a small proportion of women, however, fertility is not reestablished until 18 months after the last injection. (See 'Return to fertility after discontinuation' above.)

Women can safely continue use of DMPA without gonadotropin testing until in the mid-50s. At that time, contraception can be discontinued. Perimenopausal DMPA users will not experience the bothersome irregular bleeding that characteristically accompanies the perimenopausal transition and may not experience vasomotor symptoms. (See 'Perimenopausal women' above.)

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