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.
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.
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.
Uncertain value for adolescents
DMPA should be carefully considered for use in adolescent girls—and this proviso includes the subcutaneous formulation.
Adolescence is a critical period for bone mineralization. Thus, any agent that limits bone accretion should be prescribed only after weighing all the other options.
A prospective cohort study in adolescents found a 3.1% decrease in BMD after 2 years of DMPA use, versus a 9.5% increase among nonusers.11 More recent reports indicate significant gains in BMD and reversal in bone loss once the drug is discontinued.12
What the “black box” warning means
Based in part on results from these studies, the Food and Drug Administration (FDA) and the drug’s manufacturer issued a black box warning for both the IM and subcutaneous formulations of DMPA. This step was taken to highlight the fact that users of DMPA may lose significant BMD, and that this loss may increase with duration of use and may not be entirely reversible.
The warning recommends that the drugs be used as long-term birth control only if other methods are inadequate. It emphasizes the general lack of certainty about the effect of these drugs on peak bone mass (when used in adolescence or early adulthood) and the risk of osteoporotic fracture (later in life).
How to counsel patients
I discuss the black box warning with each patient in the larger context of contraceptive counseling. The lower efficacy and other problems associated with daily birth control methods must be weighed against the risk of bone loss in both adolescents and adults.
It also is important to consider other risk factors for osteoporosis, such as chronic alcohol or tobacco use, eating disorders, or chronic use of corticosteroids. Adolescents who have poor eating habits or who use alcohol or tobacco may be at heightened risk of BMD loss.
Once a woman chooses DMPA, she should be encouraged to maintain a healthy lifestyle, including adequate calcium intake, weight-bearing and musclestrengthening exercises, smoking cessation, and moderate to no alcohol intake.
BMD measurements are not recommended since they do not predict fracture risk in premenopausal women.
Other side effects
Though rare, serious thrombotic events have been reported in women using the IM formulation.
Also rare are ocular disorders (loss of vision, proptosis, diplopia, or migraine) and ectopic pregnancy.
Other possible side effects include injection site reactions, decreased libido, acne, headache, fatigue, gastrointestinal disorders (distention, abdominal pain, diarrhea, nausea), infection, arthralgia, back pain, limb pain, dizziness, insomnia, anxiety, depression, breast pain and/or tenderness, and hot flushes.
Return to ovulation
DMPA is associated with a prolonged return to ovulation once it is discontinued. In a large US study of women who discontinued intramuscular DMPA to become pregnant, 68% conceived within 12 months, 83% conceived within 15 months, and 93% conceived within 18 months of the last injection, with a median time to conception of 10 months.13
Though no studies have determined the median time to conception for subcutaneous DMPA, it is likely to be similar to the 10-month interval seen with the IM formulation.
Comparing drugs head to head
The IM and subcutaneous formulations were compared prospectively at a single US center.14 The study defined return to ovulation as the first time serum progesterone levels reached at least 4.7 ng/mL. At the end of 12 months (postinjection), the cumulative rate of ovulation was 97.4% for subcutaneous DMPA and 94.7% for the IM formulation.
Ovulation occurred at a median of approximately 7 months (subcutaneous route) and 6 months (IM).
Early ovulation is possible
One subject in the subcutaneous DMPA group ovulated 14 weeks after her last injection. Thus, it is important to adhere to the recommended dosing schedule of 12 to 14 weeks.
Weight gain: 0 to 7.5 lb
Reports of weight gain with DMPA have been highly variable. Many women who discontinue hormonal contraceptives cite weight gain as the reason. With one third of US women meeting the criteria for obesity—a number that is likely to rise—and with ethnic variations, it is difficult to determine the exact impact of DMPA.
A well-designed, placebo-controlled trial by Pelkman and colleagues15 found DMPA to have no effect on resting energy expenditure, food intake, or body weight. Three large clinical trials of subcutaneous DMPA found a mean weight gain of 3.5 lb during the first year of use, and a small 2-year study comparing IM and subcutaneous DMPA found mean weight gains of 7.6 and 7.5 lb, respectively.
Combating endometriosis pain
With the FDA’s approval of subcutaneous DMPA for treatment of endometriosis-associated pain, the drug expands the pharmacologic choices for endometriosis pain relief for the first time in 15 years, with less frequent side effects than the other widely used drug, leuprolide acetate.
In an 18-month clinical trial comparing the 2 drugs, researchers found similar efficacy, with DMPA causing less bone loss and less frequent and severe menopausal symptoms. The trial involved 274 women and measured pain across the following categories: pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration.
Clearing a woman for use
The manufacturer recommends that all women undergo an annual history and physical examination. The physical exam should include a blood pressure check; examination of the breasts, abdomen, and pelvic organs; cervical cytology; and any relevant laboratory studies.
Subcutaneous DMPA offers women the same advantages as the IM formulation. Since we have long-term experience with MPA as a contraceptive agent, we know it offers many noncontraceptive benefits, safety, and excellent contraceptive efficacy.
As we gain experience specific to subcutaneous DMPA , and as data accumulate from additional trials, we will be able to further define its role as a contraceptive option.
Dr. Jain has disclosed that he has received grant/research support from Ferring, Organon, Pfizer, Serono, and TA P.
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