Clinical Review


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Subcutaneous depot medroxyprogesterone acetate for birth control and endometriosis pain.


Since it was approved more than 10 years ago, depot medroxyprogesterone acetate (DMPA; Depo-Provera) has gained popularity among US women, largely because it requires minimal user participation and has a failure rate of only 0.3% per year.1,2 The main limitation, from the patient’s point of view, has been the intramuscular (IM) route of injection, which requires an office visit every 12 to 14 weeks for administration.

Now a subcutaneous version of the drug is available (Depo-subQ Provera 104) that delivers a lower dose of medroxyprogesterone acetate (MPA) (104 mg versus 150 mg for the IM formulation). The subcutaneous route opens the possibility for home self-injections, and the lower dose could decrease suppression of pituitary function and ovarian estradiol production, though further study is needed.

This article reviews the indications, benefits, risks, and potential adverse reactions of subcutaneous DMPA, a pharmacologically unique formulation with 16% weight/volume and a final dose of 104 mg MPA/0.65 mL. The dose was selected after study showed 100 mg to be the lowest dose to effectively suppress ovulation for at least 91 days.

The formulation and composition of subcutaneous DMPA cannot be duplicated by diluting the original IM formulation.

A potent contraceptive

Tw o large open-label, phase 3 studies assessed the 1-year efficacy, safety, and patient satisfaction of subcutaneous DMPA.3 These studies, conducted in North and South America, Europe, and Asia, reported zero pregnancies in 16,023 women-cycles of exposure.

Women in these studies had a broad range of body weights, ranging from 86 to 364 lb in the Americas and 77 to 249 lb in the European/Asian trial. The absence of pregnancies across all categories of body mass index (BMI) suggests that no dosage adjustments are necessary for higher BMIs.

Noncontraceptive benefits

Besides the high efficacy and long duration, which free women from daily attention to contraception, DMPA protects against endometrial cancer. The fact that it contains no estrogen makes it suitable for women who cannot or will not take estrogen products. It also is safe for breastfeeding mothers.

Perhaps most important is its ameliorative effect on endometriosis-associated pain.

Adverse effects

Many women stop using DMPA during the first year due to problems with irregular uterine bleeding, such as spotting and prolonged bleeding, which are especially common during the first 3 months of use. However, this problem usually diminishes over time, with most users becoming amenorrheic. This is true of both IM and subcutaneous DMPA. In a study of the latter, amenorrhea increased from 26% during month 3 to 55% during month 12.

The bleeding abnormalities associated with progestin-only contraceptives are not fully understood. We do know that suppression of circulating estradiol and the potent effect of MPA on the endometrium lead to varying degrees of endometrial disruption and atrophy, which ultimately manifest as irregular bleeding and amenorrhea. Subcutaneous DMPA likely involves the same processes, even though it contains 30% less MPA than the IM formulation.

Importance of counseling about bleeding effects

Two studies have shown that women are more likely to continue DMPA if they are counseled about bleeding effects when they start the medication.4,5 Since many patients would prefer less frequent or no menses, they may be encouraged by the prospect of becoming amenorrheic.

Risk of breast cancer

It will be several years before the effect of the lower-dose MPA on breast cancer risk is known.

DMPA and bone loss: Should we worry?

Subcutaneous DMPA, like its IM counterpart, is associated with changes in bone mineral density and carries a “black box” warning regarding this risk.6 Because DMPA suppresses circulating estradiol levels, it causes reductions in bone mineral density (BMD) that have aroused concern among the lay and medical media, although studies suggest BMD levels generally change little and recover when the drug is discontinued— except during perimenopause.

A metaanalysis of 12 studies involving 1,039 DMPA users (IM formulation) and 2,086 controls found that the average Z-score in DMPA users decreased less than 1 standard deviation, compared with nonusers.7 These BMD reductions stabilized after 3 to 4 years of DMPA use, and the bone loss was reversed when the drug was discontinued.8,9 Thus, it appears that, in time, BMD returns to levels similar to those in women who have never used the drug.

IM versus subcutaneous DMPA

In a comparison of both formulations of DMPA, both caused decreases in BMD at the end of 1 and 2 years of treatment.10 Women using subcutaneous DMPA experienced smaller decrements in total hip, lumbar spine, and femoral neck BMD after 1 and 2 years of treatment. However, these differences were significant only in the lumbar spine at 1 year.


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