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Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits

Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits
Literature review current through: May 2024.
This topic last updated: May 21, 2024.

INTRODUCTION — Depot medroxyprogesterone acetate (DMPA) is an injectable, progestin-only contraceptive that provides highly effective, private, three-month-long, reversible contraception. Careful counseling for those considering DMPA, particularly around issues of menstrual changes, helps improve patient satisfaction and method continuation. Other counseling points include the need to return on time for repeat injections, possible extended duration of contraceptive efficacy, risk of sexually transmitted infection acquisition, metabolic effects of the medication, and noncontraceptive benefits.

This topic will review the various counseling points pertinent to DMPA use. Related information on DMPA formulations, patient selection, and drug administration, as well as information on other progestin-only contraceptives and contraceptive selection, is presented elsewhere. This topic will not discuss norethisterone enanthate injections, which are not available in the United States.

(See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

(See "Contraception: Etonogestrel implant".)

(See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)

(See "Contraception: Progestin-only pills (POPs)".)

(See "Contraception: Counseling and selection".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

EFFICACY — For individuals who return on time for repeat injections, DMPA is a highly effective contraceptive (figure 1) [1]. During the first year of starting DMPA, an unintended pregnancy rate of 6 percent has been reported with typical use [2]. This typical-use failure rate likely reflects individuals who returned late for the next injection. In a study of individuals using DMPA who returned consistently and on time for injections, the three-year cumulative failure rate for DMPA was 0.7 percent, which is comparable to the failure rate for those using intrauterine devices and the contraceptive implant, as well as the perfect use rate for DMPA [1]. (See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration", section on 'Repeat injections'.)

The unintended pregnancy rate for the first year of perfect use of DMPA has been estimated at 0.2 percent (table 1) [2]. This estimate is a weighted average derived from seven trials of the 150 mg intramuscular dose and two trials of the 104 mg subcutaneous dose. Of note, no pregnancies occurred in clinical trials of individuals using the 104 mg subcutaneous injection [3,4].

Because DMPA results in high progestin levels, efficacy is not reduced by high body weight [5,6] or use of concurrent medications [7].

(See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration", section on 'Overweight and obese women'.)

(See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration", section on 'Drug interactions'.)

SIDE EFFECTS — Proactive, candid counseling on both the side effects of DMPA, especially bleeding changes which occur in all users, and the need for timed injections is important because well-informed patients are much more likely to become satisfied users with high continuation rates [8-13]. In a randomized trial, those 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 (odds ratio [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) [11].

Local — Although DMPA is injected into musculoskeletal or subcutaneous tissue, the occurrence of injection site reactions is low. In the initial trials of IM injection, 1 to 5 percent of users reported only nonspecific musculoskeletal and skin changes, including leg cramps, arthralgias, acne, no hair growth or alopecia, and rash [14]. 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) [3,15,16]. The natural history of granuloma/atrophy is unclear; resolution is possible as with other forms of lipoatrophy.

Menstrual changes — Menstrual changes occur in all patients using DMPA and are the most frequent reason for discontinuation (approximately 8 percent of DMPA users in the initial trial discontinued the medication because of bleeding changes) [14]. Changes in menstrual patterns can raise concerns about possible pregnancy or gynecologic disease. Proactive patient education before initiation of DMPA, as well as supportive follow-up, can markedly reduce these concerns. Individuals who are not accepting of the menstrual changes that accompany use of DMPA should be offered 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. As an example, in the initial trials, episodes of unscheduled bleeding decreased from 57 percent at 12 months of use to 32 percent at 24 months of use [14].

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 "Evaluation and management of unscheduled bleeding in individuals using hormonal contraception", section on 'Depot medroxyprogesterone acetate'.)

If bothersome spotting and/or unscheduled bleeding persist after several injections of DMPA, we evaluate for other causes of abnormal uterine bleeding. The purpose of such evaluation is to exclude cervicitis (including that caused by chlamydial or gonococcal infection), cervical neoplasia, and uterine/endometrial pathology (including fibroids, adenomyosis, endometrial polyps, and endometritis). (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis".)

Once these conditions have been excluded, further evaluation for repeat bleeding episodes is not necessary unless the patient develops new signs or symptoms (eg, heavy bleeding, pain, vaginal discharge, new abnormal findings on pelvic examination). DMPA users are educated that unscheduled bleeding can persist for the duration of contraceptive use. If a treatable cause of the unscheduled bleeding is not found and the patient remains dissatisfied with the menstrual changes caused by DMPA, then another contraceptive method may be preferred. (See "Evaluation and management of unscheduled bleeding in individuals using hormonal contraception", section on 'Evaluation'.)

Amenorrhea – Amenorrhea becomes increasingly prevalent with increasing duration of DMPA use. Approximately 50 percent of patients will achieve amenorrhea after one year of use [3,17] and over 70 percent will report amenorrhea with longer duration of use [18]. We counsel that absence of bleeding represents an expected and reversible phenomenon associated with DMPA use and that amenorrhea (along with a reduction or elimination of menstrual cramps) is viewed by many users as one of the advantages of using this method [19-21].

Weight changes — Concerns about weight gain may limit some people from using 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. In response to the conflicting data, as discussed below, we counsel patients that individuals who have a tendency to gain weight may struggle with weight gain while using DMPA [22].

A 2016 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 [23]. Major findings included:

DMPA versus estrogen-progestin contraception (three studies): No significant difference between groups in weight gain [24-26].

DMPA versus nonhormonal contraception (two studies): In one study comparing adolescents using DMPA with those using a nonhormonal method, DMPA use 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) [24]. However, a different study that compared postpartum patients using DMPA with those who had elected to receive surgical sterilization reported no significant differences in weight gain after one year [27].

DMPA versus nonhormonal copper intrauterine device (IUD) (six studies): For the retrospective studies (three), results ranged from no differences in weight gain between DMPA and copper IUD users after 10 years of uninterrupted use to a 3 kg greater mean weight gain for DMPA users compared with copper IUD users at three years of use [28-30]. For the three prospective studies, outcomes similarly ranged from no significant differences in weight change between groups to an increase in total fat mass (but not percent body fat) for DMPA users only [31-33].

Multiple factors appear to play a role in weight gain over time, and should be considered when counseling about this side effect. For example, one United States study observed that Black women gain more weight over time with use of various types of contraception (implant, DMPA, copper IUD, levonorgestrel IUD) than women of other ethnic and racial groups [31]. 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 were major limitations of these studies [34].

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 [35,36]. In the initial clinical trials for DMPA that followed over 3900 self-reported women for up to seven years, approximately 17 percent reported headache [14]. However, a history of headache is not a contraindication to DMPA use [37].

Mood changes — Observational studies have not reported any consistent effects of DMPA on mood [38-42]. We believe that progestins may cause or exacerbate depressive symptoms in certain subpopulations, including those with a history of premenstrual syndrome (PMS) or mood disorders [43-45]. Therefore, we suggest that clinicians follow such patients closely when any progestin-based therapy is initiated; however, we do not believe a history of depression represents a contraindication to use of DMPA [37].

Other

General – In clinical trials including over 3900 self-reported women, other noted side effects included dizziness (6 percent), bloating (2 percent), and decreased libido (6 percent) [14].

Hair loss – While hormonal medications can result in hair loss, hair loss does not appear to be a common adverse event with use of DMPA. A clinical trial of nearly 1800 self-reported women receiving DMPA 104 mg for one year did not note the occurrence of hair loss [3]. In a cohort study comparing 219 users of DMPA 150 mg with 171 users of nonhormonal contraception, the DMPA users were more likely to report hair loss than nonhormonal contraception users, but this difference did not achieve statistical significance [46].

Anaphylaxis – Although allergy to any hormonal contraceptive is rare, anaphylaxis to DMPA has been reported [47].

Meningioma – Epidemiologic data and observational studies suggest progesterone and exogenous progestins may be associated with increased risk of meningioma [48,49]. However, the data on impact are mixed and the absolute increase in risk, if real, would be small. We neither counsel nor advise against use of hormonal contraceptives based on potential concern for meningioma development. These issues are discussed in detail in related content. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Hormonal factors'.)

RISK OF STI ACQUISITION — DMPA does not protect users from acquiring sexually transmitted infections (STIs). Whether it increases the risk of acquiring these infections has been less clear. Regardless of contraceptive choice, condoms (male or female) and other HIV preventive measures should always be used to protect against transmission or acquisition of STIs. (See "Prevention of sexually transmitted infections".)

Effect on HIV acquisition and transmission – The body of evidence supports both that DMPA is a highly effective contraceptive option and that individuals at high risk of HIV infection can be safely offered DMPA (table 2) [37,50-53]. The impact of DMPA use on risk of HIV acquisition has been unclear because of conflicting observational data [54-57]. In 2019, a large multicenter trial of nearly 7800 HIV-seronegative self-reported women in high-risk regions reported similar rates of HIV acquisition over an 18-month period for DMPA users compared with copper intrauterine devices (IUD) or levonorgestrel (LNG) implant users (DMPA versus IUD: hazard ratio [HR] 1.04, 95% CI 0.82-1.33; DMPA versus LNG implant: HR 1.18, 95% CI 0.91-1.53) [58]. While rates of serious adverse events were similar across the groups, individuals using the IUD or LNG implant were more likely to discontinue these methods because of adverse events compared with DMPA users. Of the 255 pregnancies that occurred, 71 percent occurred after method discontinuation. A subsequent 2020 systematic review that included the 2019 trial data plus 35 other studies concluded that "high-quality randomized controlled trial data comparing use of DMPA, LNG implant, and Cu-IUD do not support previous concerns from observational studies that DMPA-IM increases the risk of HIV acquisition" [59].

Unlike norethisterone (norethindrone) and LNG, DMPA acts on glucocorticoid receptors [60]. Although glucocorticoid-like effects, specifically suppression of pDC and T-cell function and suppression of specific regulators of cellular and humoral immunity, might provide a pathway by which DMPA could increase the risk of HIV acquisition, the clinical implications of these observations (if any) are uncertain.

Effect on chlamydia and gonorrhea acquisition – Some studies have observed an increased risk of chlamydia and gonorrhea infection in DMPA users compared with oral contraceptive users, contraceptive nonusers, or the general population [61-65]. 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 human females given progestins [66]. Moreover, progestins thicken cervical mucus, and thickened cervical mucus may reduce the risk of ascending infection and development of pelvic inflammatory disease.

METABOLIC EFFECTS

Reduction in bone mineral density

Review of data — We, and others, including the American College of Obstetrics and Gynecology (ACOG), the Centers for Disease Control and Prevention (CDC), the Society for Adolescent Health and Medicine (SAHM), the World Health Organization (WHO), and the Society of Obstetricians and Gynaecologists of Canada (SOGC) [37,67-73], 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 adolescents, patients 18 to 45 years of age, or older reproductive age individuals (age more than 45 years). The available evidence also does not justify limiting the duration of DMPA therapy, which may be safely continued for decades.

Impact on bone density – Concerns regarding DMPA's impact on bone density have generated substantial controversy. One of the contraceptive actions of DMPA results from suppression of gonadotropin secretion (including prevention of luteinizing surges associated with ovulation) [74], which in turn suppresses ovarian estradiol production [75]. In hypoestrogenic states, bone resorption exceeds bone formation [76], 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 2) [61,77-81]. Compared with 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 [78-80,82,83]. The subcutaneous and intramuscular formulations have similar effects [4]. (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 patients [84]:

Young females, who have not yet attained their peak bone mass.

Perimenopausal individuals, 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.

Those who are immobilized or use a wheelchair.

However, studies involving premenopausal females and adolescents treated with DMPA for up to five years reported that the decline in BMD associated with the drug was substantially reversed after discontinuation [77-80,82,85-97]. 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 limited data on the effect of BMD changes in younger individuals 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 those at average risk of osteoporosis [98].

Fracture risk – Although observational studies have reported an increased risk of fracture in current DMPA users compared with nonusers [99-104], DMPA users differ behaviorally in a variety of ways from nonusers, 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 that included over 1.7 million person-years of follow-up provided reassuring findings: 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: 1.01 [95% CI 0.92-1.11]) [103,105]. A different retrospective study of over 308,000 self-reported women age 12 to 45 years who initiated a hormonal contraceptive or intrauterine device (IUD) similarly confirmed a small increase in fracture risk for current DMPA users compared with nonusers (relative risk 1.15, 95% CI 1.01-1.31), but a low absolute risk (5.5 per 1000 person-years) [104]. However, DMPA users were also more likely to have behavior-related risk factors for fracture, including alcohol use disorder and being a current or former smoker. Thus, it is unclear if the small increased relative risk was related to differences in behavior or other unmeasured biases. Past DMPA use was not associated with an increase in fracture risk. Long-term prospective data are not available. Given the lack of compelling data suggesting an elevated risk of fractures in DMPA users, the author does not counsel that DMPA may increase fracture risk. However, the author does discuss that the US Food and Drug Administration (FDA) black box warning, reviewed below, is not supported by strong evidence, and accordingly does not advise patients to limit their duration of DMPA use based on skeletal health concerns. (See 'Approach to bone health' below.)

Despite the lack of a proven increase in fracture rate, in 2004, the FDA issued a black box warning on DMPA package labeling: "Women who use DMPA may lose significant BMD. 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 not be used as a long-term birth control method (eg, longer than two years) unless other birth control methods are considered inadequate" [14]. 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 patients using DMPA [106].

Use in patients with limited mobility – A chart review of 102 female patients with cerebral palsy (CP) reported similar BMD for patients with and without DMPA exposure [107]. The BMD of the patients in both CP groups was low compared with healthy age-matched control individuals, but use of DMPA did not further lower it. Study limitations included small sample size, retrospective review, and lack of long-term follow-up. Despite these limitations, we believe that theoretical skeletal concerns associated with DMPA use should not prevent its use in patients who are immobilized or who use a wheelchair, 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.

Approach to bone health — To promote bone health, we 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 patients, regardless of their contraceptive choice. Providers should also use clinical judgment when deciding whether to use DMPA versus an alternative contraceptive in those with risk factors for osteoporosis. Given that the effect of DMPA on BMD is similar to that with pregnancy (decrease in BMD from 2 to 8 percent) or lactation (decrease in BMD from 3 to 5 percent) [108,109], 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 [71,73].

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. This approach is based on data from randomized trials in which menopausal doses of estrogen supplements given to adolescent [110] and adult DMPA users [111] 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. (See "Epidemiology and etiology of premenopausal osteoporosis".)

There are no data supporting use of other antiresorptive agents (eg, bisphosphonates, calcitonin, selective estrogen receptor modulators) to prevent bone loss in DMPA users. We advise not using them for this indication [112].

Cardiovascular and thromboembolic risk — While concerns have been raised that DMPA use may increase venous thromboembolism (VTE) risk, including deep venous thrombosis and pulmonary embolism, definitive conclusions are limited by the observational nature of the available data. We educate DMPA candidates and users about the possibly increased risk of VTE, and thus cardiovascular risk, and avoid DMPA use in patients with additional cardiovascular risk factors.

Metabolic and physiologic changes with DMPA use – In general, lipid changes associated with use of hormonal contraceptives have not been linked to adverse clinical cardiovascular outcomes [113]. However, 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 [114-118], but does not increase production of coagulation factors and has no adverse effect on blood pressure [119-122]. The clinical implications, if any, of the combination of these changes in healthy individuals are unproven and clinicians are not advised to obtain lipid profiles on patients prior to starting DMPA unless there are other clinical indications for such testing.

Concern for increased VTE risk – While earlier studies could not exclude the possibility of increased VTE risk with DMPA use [123,124], subsequent larger case-control studies have reported approximately double the risk of VTE for DMPA users compared with nonusers [125,126]. However, while observational data raise concerns for increased risk, study limitations include healthy-user bias and confounding by indication. Causation has not been definitively established.

In a US case-control study performed between 2010 and 2018 comparing patients aged 15 to 49 years with acute VTE (n = 21,405) with control patients (n = 107,025), current use of DMPA was associated with more than double the risk of acute VTE compared with nonuse (adjusted odds ratio 2.37, 95% CI 1.95-2.88) [126]. Lower-dose progestogens (levonorgestrel intrauterine device, oral norethindrone, etonogestrel implant, or oral progesterone) were not associated with VTE risk. Exclusion criteria included a nonqualifying VTE diagnosis (eg, pregnancy), prior anticoagulation prescription, conditions that could be treated with ultra-high dose progestogens (eg, breast cancer, endometrial hyperplasia), and pregnancy or postpartum status. Study results could have been confounded by indication as included patients may have had contraindications to estrogen use or other conditions that conferred risk.

In a Swedish case-control study performed between 2003 and 2009 that compared 948 patients with VTE with 902 control individuals (age range for both groups 18 to 54 years), patients with a first episode of VTE/pulmonary embolism were twice as likely to be DMPA users than the general control population (odds ratio 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) [125]. In this study, use of progestin-only pills, the levonorgestrel IUD, or the etonogestrel implant were not significant risk factors for VTE.

Clinical recommendations based on cardiovascular risk

Average risk – There are no restrictions to DMPA use for patients at average risk of cardiovascular disease or VTE [37,51]. Individuals older than 45 years are thought to receive benefits that outweigh potential risks of DMPA use [37].

Moderate risk – In the absence of definitive data on the absolute risk of venous thromboembolism (VTE) in DMPA users, we agree with other health organizations that DMPA is an acceptable contraceptive option (Category 2) for individuals with adequately controlled hypertension, known thrombogenic mutations, or a history of DVT/PE, particularly those individuals with uncomplicated events in whom use of estrogen-progestin contraceptives is contraindicated [37,51,68]. We counsel patients that use of DMPA has been associated with elevated VTE risk in some studies, but causation has not been established and the advantages of using the method are thought to generally outweigh the theoretical or proven risks [126]. However, this recommendation differs from package labeling for DMPA, which indicates that a prior history of VTE is a contraindication to DMPA use; we discuss this warning with patients [14].

Multiple risk factors – We advise patients with multiple risk factors for, existing, or history of cardiovascular disease or stroke against using DMPA. The WHO and the CDC classify DMPA as category 3, indicating that the risks of use may exceed the benefits for those with multiple risk factors for arterial cardiovascular disease (eg, smoking, older age, diabetes, and hypertension that is poorly controlled or associated with vascular disease) or patients with a history of stroke or ischemic heart disease [37,51]. 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.

Change in glucose/insulin — DMPA use has been associated with an increased risk of diabetes in individuals with increased baseline diabetes risk and in those who gain weight during use [127]. However, baseline glucose testing is not advised prior to starting DMPA [67]. Patients with known diabetes who elect to use DMPA should carefully monitor their blood glucose levels [14]. Individuals at risk for diabetes should be screened according to guidelines regardless of DMPA use.

In normal-risk individuals, use of DMPA has also been associated with increased insulin resistance parameters. In a prospective study comparing 31 self-reported women using DMPA with 25 individuals using copper IUDs over 12 months, DMPA users had significant increases in body mass index, waist circumference, fasting insulin levels, and homeostasis model assessments of insulin resistance (HOMA-IR) [128]. A larger study that measured fasting glucose and insulin levels over three years in 240 White, African American, and Hispanic self-reported women receiving DMPA reported mild increases in fasting insulin and glucose levels (3 mg/dL and 4 units, respectively, over baseline values) in some; however, these changes are likely not clinically important [129].

NONCONTRACEPTIVE BENEFITS

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

Reduction in heavy menstrual bleeding (HMB), dysmenorrhea, or iron-deficiency anemia – The high amenorrhea rates with continued DMPA use makes it a particularly appropriate contraceptive choice for individuals with HMB, dysmenorrhea, or iron-deficiency anemia [130-133]. There are no data from randomized trials regarding the impact of DMPA on HMB in patients with intramural fibroids; however, the author's clinical experience and other observational data indicate that some patients with HMB/anemia associated with intramural fibroids become amenorrheic during use of DMPA [134].

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 [135], and as effective as leuprolide for treatment of pain associated with endometriosis [85,86].

Use in anticoagulated patients – In addition to reducing menstrual blood loss, DMPA may prevent development of hemorrhagic corpus luteum cysts in individuals who are anticoagulated [136]. Although direct evidence is sparse, subcutaneous and intramuscular injections do not appear to increase the risk of local hematoma formation in this patient population [137].

Reduction in size of fibroidsDMPA use has been associated with lower risk of fibroid formation, reduced growth when fibroids do occur, and increased loss of fibroids that do develop [138,139].

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

Reduction in pelvic inflammatory disease (PID)DMPA users have a decreased risk of developing PID [130]. This may be related to changes in cervical mucus, decreased menstrual blood flow, and/or a reduction in retrograde menstruation.

Reduction in ectopic pregnancy – The unintended pregnancy rate (ie, failure rate) for DMPA is low. Therefore, while ectopic pregnancies can occur in those using DMPA, the risk of ectopic pregnancy is reduced in DMPA users because the risk of any pregnancy is greatly reduced.

Improved menstrual hygieneDMPA 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 mobility-limited, and athletes) [140].

Reduction in sickle cell crisis – Use of DMPA has been associated with fewer painful crises in those with sickle cell disease [141] and appears to be a safe and effective contraceptive method in this population [142].

Possible reduction in seizures – The efficacy of DMPA's contraceptive protection does not appear attenuated by the use of enzyme-inducing anticonvulsants [7], and DMPA may have intrinsic anticonvulsant properties [143,144]. For these reasons, DMPA might be a good contraceptive choice for individuals with seizure disorders [37].

Impact on cancer risk — DMPA has been associated with reduced risk of endometrial cancer and does not appear to substantially increase the risk of other malignancies.

The World Health Organization (WHO) examined the risk of endometrial, ovarian, liver, and cervical carcinoma in DMPA users [145-147]. 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 [19,130,148,149]. 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 [150]. 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 generally been reassuring [151-155], with the exception of two studies that suggested a two- to threefold increased risk of breast cancer [156,157]. In the first of these studies [156], 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 [157], 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 [153], 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 those who had initiated DMPA five years prior. Neither study verified hormone use by review of medical records/prescriptions.

Data on the use of DMPA in breast cancer survivors, particularly those who are progestin-receptor negative, are lacking. Package labeling for estrogens and progestins indicates these medications are contraindicated in breast cancer survivors. Nonhormonal contraceptive methods are generally preferred for these patients. (See "Approach to the patient following treatment for breast cancer", section on 'Contraception after breast cancer'.)

COMPARISON WITH OTHER PROGESTIN-ONLY CONTRACEPTIVES — Other progestin-only contraceptives include the daily oral pill, etonogestrel implant (commercial name Nexplanon), levonorgestrel (LNG) implant (commercial name Jadelle), and LNG-releasing intrauterine devices (IUDs, commercial names Mirena, Liletta, Kyleena, and Skyla).

Compared with progestin-only pills (POPs), DMPA has [67]:

Higher contraceptive efficacy (typical use unintended pregnancy rates of 6 versus over 9 percent).

Ease of dosing (every 13 weeks compared with daily dosing within a three-hour time interval).

Slower return of fertility. Fertility returns rapidly with discontinuation of POPs, but not DMPA.

Comparisons with the etonogestrel implant and LNG IUDs:

Compared with the etonogestrel implant and LNG-releasing IUDs, both of which are long-acting reversible contraceptives, some users may find that DMPA is more private, in that the implant rod(s) and intra-vaginal IUD strings can be sometimes be felt, and in some users, the implant is visible.

With one year of continued use, amenorrhea will be achieved in approximately 50 percent of DMPA users, 6 to 20 percent of LNG-releasing IUD users (rate varies with LNG dose), and approximately 20 percent of etonogestrel implant users [67].

Upon discontinuation, ovulation typically occurs within a few cycles for patients previously using the etonogestrel implant and IUDs, while fertility return following DMPA use is less predictable and often takes longer. (See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration", section on 'Return to fertility after discontinuation'.)

Detailed discussions of alternate progestin-only contraceptives are available elsewhere.

(See "Contraception: Progestin-only pills (POPs)".)

(See "Contraception: Etonogestrel implant".)

(See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)

RESOURCES FOR PATIENTS AND CLINICIANS

World Health Organization Family Planning: A Global Handbook for Providers

Planned Parenthood – A nonprofit organization dedicated to reproductive health with resources for patients and clinicians

Bedsider.org – A free website developed by the National Campaign to Prevent Teen and Unplanned Pregnancy, a private nonprofit group

CHOICE Project – A free website sponsored by the Washington University School of Medicine in St. Louis that provides resources on contraceptive options and training resources for clinicians

Center for Young Women's Health – A free website run by Boston Children's Hospital that addresses reproductive health needs of teens and young adults

Beyond the Pill – A free website run by the University of California San Francisco

SexualityandU.ca – An educational site run by the Society of Obstetricians and Gynaecologists of Canada that includes descriptions of various methods and a tool to help with selection of birth control

ACOG Contraceptive FAQs – American College of Obstetricians and Gynecologists addresses frequently asked questions (FAQs) about progestin-only contraception

ACOG LARC Program – American College of Obstetricians and Gynecologists Long-Acting Reversible Contraception Program

United States Medical Eligibility Criteria for Contraceptive Use

United States Selected Practice Recommendations for Contraceptive Use

World Health Organization Medical Eligibility Criteria for Contraceptive Use

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Contraception".)

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 email 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 education: Choosing birth control (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

Efficacy – For patients who return on time for repeat injections, depot medroxyprogesterone acetate (DMPA) is a highly effective contraceptive (figure 1). During the first year of starting DMPA, an unintended pregnancy rate of 6 percent has been reported with typical use. (See 'Efficacy' above.)

Changes in bleeding pattern – Menstrual changes occur in all DMPA users and, as with all progestin-only contraceptives, 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 (see 'Menstrual changes' above). The universal menstrual changes caused by DMPA use underscore the importance of proactive counseling prior to DMPA initiation and during DMPA use.

Risk of sexually transmitted infection (STI)DMPA does not protect users from acquiring STIs. Whether it increases the risk of acquiring these infections is less clear. Individuals at risk for STI acquisition are advised to use condoms (male or female) and other HIV preventive measures. (See 'Risk of STI acquisition' above.)

Impact on bone mineral density – 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 subsequent 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. (See 'Review of data' above.)

To promote bone health, we 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 patients, regardless of their contraceptive choice. (See 'Approach to bone health' above.)

Risk of venous thromboembolism (VTE) – In the absence of definitive data on the absolute risk of VTE in DMPA users, we agree with the American College of Obstetricians and Gynecologists, the Centers for Disease Control and Prevention Medical Eligibility Criteria for Contraceptive Use, and the World Health Organization Medical Eligibility Criteria for Contraceptive Use that DMPA is an acceptable contraceptive option (Category 2) for patients with known thrombogenic mutations or a history of DVT/PE, particularly those with uncomplicated events in whom use of estrogen-progestin contraceptives is contraindicated. (See 'Cardiovascular and thromboembolic risk' above and 'Change in glucose/insulin' above.)

Additional progestin-only contraceptives – Other progestin-only contraceptives include the daily oral pill, etonogestrel implant, levonorgestrel (LNG) implant, and LNG-releasing intrauterine devices. (See 'Comparison with other progestin-only contraceptives' above.)

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Topic 118540 Version 37.0

References

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