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Injectable Long-Acting Contraceptives

Kaunitz, Andrew M. MD

Clinical Obstetrics and Gynecology: March 2001 - Volume 44 - Issue 1 - p 73-91
CONTRACEPTION FOR THE 21st CENTURY

Injectable long-acting contraception offers users convenient, safe, and reversible birth control as effective as surgical sterilization. American women have two available options: Depo-Provera (DMPA), (Pharmacia, Peapack, NJ) a 3-month progestin-only formulation containing 150 mg medroxyprogesterone acetate (MPA) per injection, 1 and Lunelle (MPA/E2C), a 1-month combination containing 25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate (E2C) per injection. 2 Both were developed by Upjohn (Peapack, NJ) during the 1960s.

Although DMPA was approved in several countries in the late 1970s, it was not approved for contraception by the Food and Drug Administration (FDA) until 1992, after publication of reassuring data from a 9-year World Health Organization (WHO) study that examined the risks of cancers of the breast, endometrium, ovary, and cervix in women using DMPA. 3,4 After initial studies, further development of MPA/E2C by the WHO led to its approval in 18 foreign countries. 5 FDA approval of MPA/E2C occured in late 2000, and the product is marketed in the United States by Pharmacia (Pharmacia, Kalamazoo, MI). This chapter reviews pharmacologic and epidemiologic data and provides clinicians with clinical insights pertaining to counseling, selection, initiation, and maintenance to facilitate successful use of injectable contraceptives.

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Formulations

Depo-Provera contraceptive injection is provided as an aqueous microcrystalline suspension. In the United States, DMPA is marketed as a 150-mg/ml contraceptive solution in individual ampules or prefilled syringes and as a 400-mg/ml solution for the treatment of inoperable, recurrent, and metastatic endometrial or renal carcinoma. Because its use is associated with more injection site pain and reduced bioavailability, the high-strength DMPA solution should not be used for contraception. 6 Lunelle is marketed in the United States as single-use ampules of an aqueous suspension containing 25-mg medroxyprogesterone acetate and 5-mg estradiol cypionate in a 0.5-ml volume. Ampules of DMPA and MPA/E2C are stored at room temperature and should be shaken vigorously before drawing up into an appropriate syringe. Deep intramuscular injection through a 1 to 1.5-inch, 21 to 23-gauge needle in the gluteus or deltoid is appropriate for either DMPA or MPA/E2C. The anterior thigh is also suitable for injection of MPA/E2C.

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Pharmacokinetics

In 1996, Mishell 7 reviewed the pharmacokinetics of MPA after an intramuscular injection of 150-mg DMPA. Pharmacologically active levels (>0.5 ng/ml) of MPA are achieved within 24 hours after injection, and serum concentrations of MPA of approximately 1.0 ng/ml are maintained for approximately 3 months. Thereafter, MPA levels decrease to approximately 0.2 ng/ml during the fifth or sixth month, becoming undetectable (<0.02 ng/ml) between 7.5 and 9 months. 8 Ovulation returns when concentrations of MPA decrease to <0.1 ng/ml. 8 Lunelle pharmacokinetics in women after repeated intramuscular administration of MPA/E2C monthly contraceptive injections were reviewed by Kaunitz in 2000. 9 In US women receiving MPA/E2C injections, MPA and estradiol (17 β-E2) attain steady-state conditions after the first injection, with no further accumulation of either component after subsequent injections. 10 After three monthly injections, mean serum concentrations of MPA peak at 3.5 days (range, 1–10 days), and those of 17 β-E2 peak at 2.1 days (range, 1–7 days). Peak levels are 1.25 ng/ml for MPA and 247 pg/ml for 17 β-E2, and the mean terminal half-lives are 14.7 days and 8 days, respectively, indicating prolonged absorption from the injection site after administration of MPA/E2C. The observed peak level of 17 β-E2 is similar to levels observed in the nontreated preovulatory range and returns to baseline by approximately 14 days after injection. This may explain why bleeding episodes resembling normal menses tend to occur 2 to 3 weeks after each injection of MPA/E2C. 11–13 Levels of MPA decrease to less than 10 pg/ml (the lower limit of quantitation) 2 to 3 months after the third injection of MPA/E2C. 10

No adjustment of the dose of MPA/E2C is necessary based on body weight or injection site. 14 Individual MPA concentrations at the end of the 28-day dosing interval exceed 0.2 ng/ml in all users studied, confirming that the 28 to 30-day dosing interval recommended for MPA/E2C provides an adequate margin of contraceptive protection, regardless of a woman’s body weight or the injection site used.

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Mechanism of Contraceptive Action and Efficacy

Depo-Provera acts by inhibiting ovulation. Injection of 150 mg of DMPA every 3 months provides extremely high contraceptive efficacy. In clinical trials, failure rates ranging from 0.0 to 0.7 per 100 woman-years have been reported. With typical use, the failure rate of DMPA is 0.3 per 100 woman-years, which is comparable with that of levonorgestrel implants, copper intrauterine devices (IUDs), or surgical sterilization. 15,16 Neither varying weight nor use of concurrent medications has been noted to alter efficacy, apparently because of high circulating levels of progestin. 17,18

The MPA component of MPA/E2C suppresses ovulation and provides high contraceptive efficacy, whereas the E2C component contributes to bleeding patterns similar to those of women not receiving hormonal methods of contraception. 11,19 The contraceptive efficacy and tolerability of MPA/E2C was established in 15,614 women who participated in trials conducted by the WHO during the 1980s and 1990s, and by a 60-week US multicenter study of MPA/E2C in 782 women completed in February 1999. 11,20–23 During 1 year of use (13 cycles of 28 days) by US women, no pregnancies occurred in 782 MPA/E2C users and 1 pregnancy occurred in 321 OC users (norethindrone [NET] 0.5, 0.75, 1.0 mg/0.035 mg ethinyl estradiol [EE] triphasic OC, Ortho-Novum 7/7/7), for life table rates of 0 and 0.3, respectively. Similar 1-year failure rates substantially less than 1% have been reported in other clinical trials of combination OCs and in the WHO clinical trials of MPA/E2C. 9

Based on extensive clinical and introductory trial experience in the US and abroad, the failure rate of MPA/E2C can be estimated at 0.1 failures per 100 women-years. 9 This extremely low failure rate compares favorably with other highly effective contraceptives including OC, implants, progestin-only injectables, intrauterine devices, and tubal sterilization. 15,16 In addition, body weight does not appear to impact the contraceptive efficacy of MPA/E2C.

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Timing of Initial and Subsequent Injections

Recommendations for timing of the initial injection of DMPA and MPA/E2C in women who are postabortion, postpartum, or who are switching from other hormonal or intrauterine methods of contraception are provided in Table 1. Repeat injections of DMPA are administered every 12 weeks or 3 months. Because ovulation does not occur for at least 14 weeks after a 150-mg injection of DMPA, there is a 2-week grace period for women receiving injections every 3 months. Although the 2-week grace period is supported by published literature, the manufacturer recommends excluding pregnancy before proceeding with reinjection in women who return more than 13 weeks after the previous injection. 24 Repeat injections of MPA/E2C are administered every 28 days or monthly, and the manufacturer has proposed a grace period of 5 days (ie, 23–33 days). Studies have shown that the earliest return of ovulation in women who have received multiple injections of MPA/E2C is approximately 60 days after the last injection. 9 Nonetheless, pregnancy should be excluded before reinjection in women who return for reinjection after 33 days.

Table 1

Table 1

Although clinicians should take precautions to avoid any unnecessary exposure to drugs during pregnancy, inadvertent administration of DMPA during pregnancy does not increase the risk of congenital anomalies. 25 Evidence to suggest that either OCs or injectable progestins are teratogenic or mutagenic is lacking, and there have been no published reports of adverse fetal outcomes in the offspring of women who became pregnant during use of MPA/E2C injections. 9

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Return to Fertility

Use of DMPA has no permanent impact on fertility. Return of fertility may be delayed, however, regardless of the duration of DMPA use. Within 10 months of the last injection, 50% of women who discontinue use of DMPA to become pregnant will have conceived; in a small proportion of women, however, fertility is not reestablished until 18 months after the last injection. 26 Clinicians should counsel candidates about the possible prolonged duration of action before initiating DMPA contraception. Women who may want to become pregnant within the next 1 or 2 years should choose an alternative contraceptive method in the interim.

In contrast to DMPA, return to fertility occurs rapidly after discontinuation of MPA/E2C. A pharmacodynamic study evaluated the effects of MPA/E2C on ovarian function as reflected by changes in serum progesterone concentrations in 16 surgically sterile women with regular menstrual cycles. 27 Using a progesterone level threshold of 4.7 ng/ml or greater, normal ovulatory cycles resumed between 63 and 112 days after the third and final injection of MPA/E2C. A prospective study found rates of conception in former users of MPA/E2C within 6 and 12 months of discontinuation to be 53% and 83%, respectively. 28 With pregnancy rates within 60 days after the last injection (or 30 days after MPA/E2C discontinuation) similar to those of other women attempting to conceive, 29 no correlation was noted between return to fertility and either duration of MPA/E2C use or patient weight. 28 No congenital anomalies were reported among 55 subsequent live births.

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Side Effects

Contraceptive satisfaction and continuation rates are highest in users who are well informed about their method’s side effects. Therefore, before initiating DMPA or MPA/E2C for birth control, clinicians should ensure that candidates recognize common side effects and implications of the method that they have selected.

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MENSTRUAL CHANGES

Menstrual changes commonly are reported by women using either DMPA or MPA/E2C. After 3 months’ use, almost one half of women receiving DMPA injections report amenorrhea, with most of the remainder noting irregular bleeding/spotting. 30 By 1 year of use (4 injections), some three quarters of women using DMPA will experience amenorrhea. 31 Some women view amenorrhea (along with reduction or elimination of menstrual cramps) as a potential benefit of DMPA use. 32 Adolescent users of DMPA may be more accepting of amenorrhea than adults. 33 Like some adults, many teens actually welcome amenorrhea. 34

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Depo-Provera

Clinical experience indicates that menstrual disturbances are the most frequent cause for dissatisfaction with and discontinuation of not only DMPA but also OCs. 9 DMPA users who experience menstrual changes may be concerned that pregnancy or gynecologic disease is present. Clinicians can markedly reduce patients’ discontent and enhance contraceptive continuation by candid patient education before initiation, as well as supportive follow-up measures. 35,36 Women clearly uncomfortable or persistently dissatisfied with the menstrual changes that inevitably accompany use of DMPA may be better served by MPA/E2C, OCs, or other contraceptive methods.

When persistent bleeding or spotting causes DMPA users to consider contraceptive discontinuation, and lower genital tract infection and neoplasia have been excluded as a cause of such symptoms, use of continuous oral or transdermal supplemental estrogen can be considered. Results of a large, carefully conducted study by the WHO that used short courses of high-dose estrogen, however, provided little support for the use of estrogen supplementation to reduce bleeding among DMPA users. 37 A study of lower dose supplemental estrogen (eg, conjugated estrogen or estrone sulfate [estropipate] 1.25 mg daily) used for longer periods (1–3 months or indefinitely) might provide information useful in the management of bleeding experienced by women using DMPA.

Although some clinicians administer early reinjections (eg, each 8–10 weeks) with the intent of reducing DMPA-associated bleeding, a controlled cohort study noted that early reinjection did not reduce bleeding. 38

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Lunelle

In contrast to DMPA, the majority of long-term users of MPA/E2C report regular menses. As demonstrated in the US multicenter study, most women using MPA/E2C experience regular menses after the first cycle of use, with an average cycle length of 28 days. 11 Users of MPA/E2C experience more bleeding/spotting days than OC users, but both the overall number of days of bleeding/spotting and the number of bleeding/spotting episodes for MPA/E2C users are similar to or less than those observed in healthy, nonpregnant, nonlactating women not using hormonal contraception. 19

In the US study, cycle length was more variable in MPA/E2C users than in OC users, which was not unexpected in view of the variation in injection intervals (23–40 days). Bleeding patterns, however, were more predictable in women who received all MPA/E2C injections at evenly spaced intervals. Importantly, only 2.5% (19/775) of the women discontinued treatment because of irregular bleeding. 11 The predictable pattern of users experiencing shorter and more regular bleeding episodes with ongoing use seen in both the WHO studies and the US multicenter trial underscores the importance of candidly counseling MPA/E2C candidates and users about likely menstrual changes caused by this method. 9

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WEIGHT CHANGES

Depo-Provera

Weight gain is a major concern of women of all ages and a factor cited by many who discontinue hormonal methods of contraception. Although users of DMPA and MPA/E2C (as with OCs) often report weight changes, few controlled clinical studies addressing this issue have been conducted in developed countries. Recent controlled studies in US and Thai women do not indicate that long-term use of DMPA causes an increase in body weight. 39 These studies, however, do not rule out the possibility that subgroups of DMPA users may be predisposed to weight gain.

Studies in adolescents suggest that certain DMPA users in this age group will greatly benefit from specific counseling about weight management. Among 130 predominantly white teen users of contraceptives attending an urban family planning clinic, mean weight gain after adjusting for expected weight changes during 1 year was 2.1 kg in DMPA users and 0.6 kg in OC users, a difference not found to be statistically significant. 40 These findings differ from those of a prospective 30-month study of mostly African-American adolescents, nearly three quarters of whom had at least one previous pregnancy. 41 Although some of these adolescents lost weight during DMPA use, most tended to gain more weight than demographically similar female patients not using hormones. 41 Previous pregnancy and the sedentary lifestyle of adolescent mothers may have contributed to the weight changes seen in these DMPA users. Moreover, in this study the first two DMPA injections were administered 6 to 8 weeks apart to try to increase menstrual regularity, a practice that was associated with a greater change in body mass index in another study of adolescents followed after discontinuation of either DMPA (n = 35) or levonorgestrel implants (n = 31). 33

Clearly, clinicians can enhance continuation of DMPA use by providing specific counseling about effective weight management strategies. This can be especially beneficial for adolescent mothers using DMPA, who often express frustration at their inability to lose weight gained during pregnancy and who commonly report increased hunger and weight gain with DMPA. 42

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Lunelle

No studies specifically designed to assess weight changes during use of MPA/E2C have been conducted. Multicenter clinical trials conducted by the WHO found that body weight tended to increase among users of MPA/E2C, but that after 12 months’ use, the mean change was less than 1 kg at most centers. 5 In the recent US multicenter study, median body weight in MPA/E2C users increased 1.8 kg, or approximately 0.3 kg per month during the first 7 months of use. 11 At 60 weeks (study completion), median weight gain was 2.25 kg. Among the 321 OC users, weight generally remained unchanged throughout the study. The findings in OC users cannot be compared directly with those in MPA/E2C users, however, because the two groups of participants varied with respect to ethnicity, parity, and previous use of other hormonal contraceptives.

Neither the studies by the WHO nor the US multicenter trial included women not using hormonal contraception for comparison. Additionally, because the participants in all trials to date were 18 years of age or older, there are no data at this time about weight changes associated with use of MPA/E2C in adolescents.

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MOOD CHANGES

Available published data indicate that neither DMPA nor MPA/E2C causes depressive symptoms. 9,39 Nonetheless, the product labeling for DMPA includes depression as a side effect reported in clinical trials or postmarketing experience. 43 The overall incidence of depression was low in a U.S. clinical trial of DMPA conducted between 1965 and 1971; only 1.7% of 3,857 women using DMPA reported depression. 1,44 Two recent U.S. studies have specifically examined the issue of depressive symptoms and use of DMPA. 45,46 An initial evaluation of 80 DMPA users attending an inner city family planning clinic found no worsening in depression scores during 2 to 3 months. 46 Likewise, a large prospective cohort study at three large urban family planning clinics assessed depressive symptoms in 393 women before and after 1 year of DMPA use. 45 The 170 women who continued to use DMPA had lower depressive symptoms scores at baseline than the 218 who discontinued the method. Among those who continued to use DMPA at 1 year, however, depressive symptoms improved slightly. Moreover, no increase in depressive symptoms was evident in those who continued to use DMPA or those who did not. These carefully designed studies clarify that DMPA does not cause depressive symptoms. Further, the presence of depression or other mood disorders should not be considered a contraindication to the contraceptive use of DMPA.

There were no reports of depression with MPA/E2C use in either the clinical trials or introductory studies conducted by the WHO. 9 In the 60-week US multicenter clinical study, 6.5% (50 of 775) of MPA/E2C users and 4.4% (14 of 318) of the triphasic NET/EE OC users reported depression at some point during treatment, but only 1% and 0.6%, respectively, cited depression as a reason for discontinuing treatment (Roger J. Garceau, MD, personal communication, June 1999).

Another effect reported by users of DMPA in some studies is reduced libido. In the U.S. multicenter trial in 3,857 women who used DMPA for a median of 12 months, 5.4% (207) reported decreased libido. 1 In New Zealand, a population-based study of 252 women who had used DMPA at some time during a 20-year period found that only 2.3% (seven women) reported loss of libido. 47 It is interesting to note that there were no reports of loss of libido in two US studies following more than 1,000 women during the first 12 months of DMPA use. 30,48 In the US multicenter evaluation of MPA/E2C monthly injections, decreased libido was cited as a reason for contraceptive discontinuation by 0.6% of MPA/E2C users and 0.9% of OC users (Roger J. Garceau, MD, personal communication, June 1999).

Libido represents a complex entity; a woman’s relationship with her sexual partner as well as endocrine factors can impact sexual desire. Women reporting reduced libido during use of any hormonal method of contraception should be reassured that this is not unusual and that it does not mean that anything is wrong with them or their relationship. For many hormonal contraceptive users with this concern, such reassurance will facilitate ongoing contraceptive use.

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Benefits and Potential Risks

NONCONTRACEPTIVE BENEFITS AND THERAPEUTIC USES

Use of DMPA provides a variety of noncontraceptive benefits including prevention of endometrial cancer, iron-deficiency anemia, pelvic inflammatory disease, ectopic pregnancy, and hysterectomy in women with uterine leiomyomas. 3,49–52 For endometrial cancer, a case-control study by the WHO published in 1991 found an 80% reduction in risk among women who had used DMPA for more than 1 year before diagnosis, which is greater than the reduction of 50% associated with use of combination OCs. 49,53

Depo-Provera also has been successfully used in the treatment of a variety of gynecologic, menopausal, and oncologic conditions (see Table 2). Clinical experience suggests that for some women, use of DMPA reduces premenstrual syndrome symptoms. 54 Because DMPA tends to cause amenorrhea, it may be a particularly appropriate contraceptive choice for women with menorrhagia, dysmenorrhea, and iron deficiency anemia. 50 Use of DMPA or other progestins effectively treats menorrhagia and dysmenorrhea associated with uterine fibroids in many cases, and a recent epidemiologic study found lower hysterectomy rates for uterine fibroids in DMPA users than in other women. 52,55

Table 2

Table 2

Progestins have been used in the management of endometriosis for decades, and a well-controlled clinical trial confirmed DMPA’s effectiveness in treating pain associated with this disease. 56 DMPA is also appropriate for mentally handicapped women suffering from menstrual hygiene problems. 57 DMPA use also has been associated with hematologic improvement in women with sickle cell disease and reduced seizure frequency in women with seizure disorders. 58,59 Overall, the broad array of therapeutic uses of DMPA (Table 2) suggests that this injectable progestin may be appropriate for a diverse group of women, including contraceptive candidates as well as those with a variety of gynecologic and nongynecologic disorders. Clinicians should recognize, however, that use of DMPA for indications other than contraception or metastatic endometrial cancer represents off-label use not approved by the FDA.

Functional ovarian cysts, which cause symptoms in some women, represent a common cause of hospital admission and surgery among young women. Follicular ovarian cysts occur in women using contemporary OC formulations and Norplant. 60 A recent randomized clinical trial found that use of MPA/E2C monthly injections suppresses follicular cysts significantly more than use of a 20-μg ethinyl estradiol OC. 60 No published data address the impact of DMPA use on follicular cysts; however, sustained MPA levels are higher in DMPA users than in MPA/E2C users. 7,10 Accordingly, it is likely that use of DMPA suppresses ovarian follicular cyst activity at least as much as MPA/E2C. These observations suggest that both MPA/E2C and DMPA may be particularly useful for women with a history of symptomatic ovarian cysts.

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IMPACT ON BREAST AND REPRODUCTIVE TRACT CANCER RISK

Large case-control studies by the WHO found that use of DMPA does not increase the risks of breast, endometrial, ovarian, or cervical carcinoma. 9 As noted earlier (see Noncontraceptive Benefits), the protection against endometrial cancer provided by DMPA use is even more profound than that associated with OC use. 9 For breast cancer, risk in DMPA users was increased within the first 4 years of initiating use, mainly in women younger than 35 years of age. 61 There was no increase in risk after use of DMPA, however, and risk was not increased in women who had used DMPA for more than 5 years. The effect of DMPA on the risk of breast cancer appears to be similar to that for combination OC users in that the slight increase in risk is limited to recent users. 62 Based on these findings, clinicians can reassure women that long-term use of DMPA will not increase their risk of breast cancer.

In contrast to DMPA, there are limited epidemiologic data about cancer risks associated with use of monthly combined injectable contraception. The available studies were reviewed by Skegg in 1994. 63 More extensive worldwide use of monthly injectable contraceptives and additional epidemiologic studies should clarify MPA/E2C’s impact, if any, on risk of reproductive tract cancer. Prevention of ovarian and endometrial cancers represents a well-documented noncontraceptive benefit of OC use. Accordingly, it would not be surprising if similar protection is noted with use of MPA/E2C injections when this monthly contraceptive becomes more widely used in developed countries.

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IMPACT ON CARDIOVASCULAR RISK FACTORS AND OCCURRENCE OF EVENTS

Lipids

Both DMPA and MPA/E2C produce changes in plasma lipid levels that are consistent with their steroid component(s). Westhoff 64 recently reviewed the data from 11 studies of DMPA users. In the 10 studies that measured triglycerides and total cholesterol, use of DMPA had no overall impact on mean plasma levels of these lipids; however, all seven studies in which high density lipoprotein (HDL) cholesterol was measured reported decreased levels in DMPA users, and three of five studies found an increase in mean levels of low density lipoprotein (LDL) cholesterol. A cohort study not included in Westhoff’s review compared the impact of DMPA and levonorgestrel implants after 6 months’ use by groups of 25 women who previously had not used a hormonal contraceptive for at least 3 months. 65 Mean total cholesterol in users of levonorgestrel implants was significantly lower than in DMPA users, but there were no significant differences in HDL cholesterol, triglycerides, or the total cholesterol/HDL cholesterol ratio in the two groups.

Use of MPA/E2C does not appear to cause clinically important changes in lipid metabolism. A WHO multicenter prospective trial studied MPA/E2C’s impact on lipid metabolism during 9 months’ use and 3 months after discontinuation of use. 66 After 3 months of MPA/E2C use, there were small (2–6%) but statistically significant decreases in total cholesterol, HDL cholesterol, and apo A-I that were maintained at 9 months, and a small decrease (2%) in apo A-II was noted at 9 months. Three months after MPA/E2C injections were discontinued, all lipid parameters returned to baseline values. No statistically significant increases in triglyceride levels were associated compared with baseline after 9 months use of MPA/E2C. This is notable, in that use of combination OCs is associated with substantial increases in triglyceride levels. 44,67 Likewise, among U.S. women initiating hormonal contraception, use of MPA/E2C was associated with stable or reduced triglyceride levels in contrast to a triphasic NET/EE OC, which increased them. Both MPA/E2C and NET/EE were associated with stable total cholesterol/HDL cholesterol ratios. 68

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Coagulation

Medroxyprogesterone acetate use does not increase globulin production in the liver; thus, in contrast to combination OCs, use of DMPA is not associated with increases in procoagulant factors. 9 Little data, however, address the impact of DMPA use on specific coagulation factors.

MPA/E2C differs from low-dose combination OCs and resembles DMPA in that it does not appear to cause procoagulant changes. A prospective WHO trial compared the effects of a low-dose OC (35 μg EE/1 mg NET) and MPA/E2C on various coagulation parameters. 23,69 In contrast to the findings in OC users, no significant prothrombotic changes in fibrinogen, Factors VII and X, plasminogen, or the activated prothrombin time were noted among MPA/E2C users. These observations suggest that MPA/E2C has less procoagulant impact than low-dose OCs.

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Blood Pressure

Studies in both adults and adolescents have found that long-term use of DMPA has no unfavorable impact on blood pressure. 9 Likewise, in 1-year clinical trials of MPA/E2C by the WHO and the US multicenter study, 9,11 no clinically significant blood pressure trends were noted.

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Cardiovascular Events

A recent analysis of data from the case-control WHO Collaborative Study evaluated the risks of cardiovascular disease (CVD) associated with use of oral and injectable progestin-only and combined injectable contraceptives. 70 All 37 patients in the progestin-only group used DMPA, and 11 of 13 in the combined injectable group used dihydroxyprogesterone acetophenide 150 mg/estradiol enanthate 10 mg. No users of MPA/E2C were included in the analysis. None of these hormonal contraceptives was associated with an increase in overall CVD risk. Likewise, there was no increased risk of stroke, acute myocardial infarction, or venous thromboembolism among users of combined injectable contraceptives, and only a small, nonsignificant increase in risk of venous thromboembolism was noted in users of progestin-only injectable contraceptives. The WHO concluded that although their analysis was based on a small number of cases and controls, little or no increased risk of venous or arterial events is associated with use of injectable progestin-only, combined injectable or oral progestin-only methods. Accordingly (and in contrast to package labeling), DMPA represents an appropriate choice for women for whom use of combination OCs is contraindicated because of increased cardiovascular risk (Table 3). 71,72

Table 3

Table 3

In other WHO trial experience to date in more than 15,000 MPA/E2C users and in the US multicenter experience with 775 users, no cases of thromboembolic disease, myocardial infarction, or cerebral vascular events have been reported. 9 In view of the low-dose estrogen component (5 mg) in MPA/E2C, it is anticipated that this monthly combined injectable will be at least as safe as combined OCs in terms of cardiovascular disease risk.

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IMPACT OF DEPO-PROVERA ON BONE DENSITY

Because use of DMPA in contraceptive doses suppresses ovarian production of estradiol, there has been concern that women using DMPA for contraception might develop osteopenia, potentially increasing their risk for postmenopausal osteoporotic fractures. To date, 14 studies (described in 15 publications) have assessed the impact of current or past use of DMPA on bone mineral density. 9,73 In the majority of these studies, bone mineral density was assessed using dual energy x-ray absorptiometry. With the exception of one randomized, controlled trial and one prospective cohort study, these were cross-sectional studies, although one had a cohort component.

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Current Users

Among premenopausal and perimenopausal women currently using DMPA, eight cross-sectional studies found decreased bone mineral density compared with DMPA nonusers, women using no hormones, or those using levonorgestrel (LNG) implants or OCs. 9 Two studies found no relation between bone mineral density and duration of DMPA use, and another found that loss of bone mineral density in DMPA users increased with age. 9 It also was noted in one study that DMPA had less impact on bone mineral density in women who initiated use after the age of 20 years and in those who used DMPA for 15 years or less. 9 In contrast to these studies, three other studies failed to find lower bone mineral density in DMPA users. 9

Because adolescence is a critical period for bone mineralization, there is concern about use of any drug that may impact bone density in this population. To date, only two studies have specifically examined the effects of DMPA use on bone mineral density in adolescents. 74,75 A small, prospective cohort study found that, after 1 year, lumbar vertebral bone density decreased in DMPA users and increased in users of OCs, implants, and no hormones. 74 After 2 years, bone density showed a total decrease of 3.1% in DMPA users and total increases of 9.5% and 9.3%, respectively, in nonhormone users and implant users. Likewise, a cross-sectional comparison found that DMPA users had lower age-adjusted bone mineral density at all sites (spine, femoral neck, greater trochanter, and whole body) compared with nonusers of similar age. 75 The most prominent differences in bone density between DMPA users and nonusers across all sites and a dose–response in terms of duration of DMPA use were found in the youngest age group (18–21 yrs). These two studies suggest that DMPA use may, at least transiently, impair bone mineralization in adolescents.

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Former Users

On examining the long-term impact of previous DMPA on bone density and the risk of postmenopausal osteoporosis, one New Zealand cross-sectional study found increases in bone mineral density in a cohort of eight former DMPA users at 12 and 24 months after discontinuation. 76 A second cross-sectional study of bone density assessed former DMPA users in three regions of the developing world. 73 No significant differences were noted in bone density between former and never-users of DMPA. In the only study assessing postmenopausal women, 10% of 346 healthy postmenopausal women were former DMPA users (mean age, 60 years; median age at DMPA initiation, 41 years; median duration of use, 3.0 years). 77 Postmenopausal bone mineral density in former DMPA users was not significantly different from that of never-users at any site. 77 These observations provide reassuring evidence that the decreases in bone mineral density seen in current and recent DMPA users are indeed reversible and that they are therefore unlikely to have clinical importance. DMPA’s impact on bone density appears similar to that of lactation in that both lactation and DMPA use lower ovarian production of estradiol, leading to reversible decreases in bone mineral density. 9

A prospective US multicenter study comparing bone density in DMPA users and nonusers was initiated in 1994 and will conclude early in this century. 39 Results of this study should clarify the long-term impact of DMPA use, if any, on bone mineral density. Until results of this and other studies become available, clinicians should individualize treatment of long-term DMPA users. Clinicians concerned about the potential for osteopenia in high-risk long-term DMPA users, including teenagers, may choose to prescribe “add-back” estrogen, using oral (eg, conjugated equine or esterified estrogen or estropipate 1.25 mg daily) or transdermal (eg, estradiol 0.1 mg daily) formulations during DMPA use. No data, however, address the impact of such an “add-back” regimen on bone mineral density in users of DMPA.

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Contraindications

Contraindications in the DMPA product labeling and those proposed to the US FDA for MPA/E2C are listed in Table 4. Progestin-only contraceptives, including DMPA, may be used safely by smokers aged 35 years and older and by other women at increased risk for arterial or venous events (see Impact on Cardiovascular Risk Factors and Occurrence of Events). 70–72 Similarly, use of DMPA has not been associated with clinically significant alterations in hepatic function, even in a population of Danish intravenous drug users in whom viral hepatitis was endemic. 78,79 A small clinical trial of oral MPA in adults with chronic liver disease suggests that DMPA may be a safe contraceptive choice for women with liver ailments. 80 The author has had favorable clinical experience providing DMPA contraception to women at high risk for vascular events, as well as for those with liver disease.

Table 4

Table 4

Contraindications for MPA/E2C parallel those listed for combination OCs. Given MPA/E2C’s minimal impact on coagulation, and the reassuring findings of the WHO for other monthly injectable combination contraceptives, it may be possible in the future to liberalize these contraindications with respect to venous and arterial vascular disease. 69,70

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Use With Concomitant Medications

Anticonvulsants and antiinfectives that induce hepatic enzymes (Table 3) can reduce the contraceptive efficacy of OCs and implants. 9 The contraceptive efficacy of DMPA in women taking hepatic enzyme inducers has not been explicitly studied; however, physicians with substantial experience prescribing DMPA (150 mg every 3 months) for women taking anticonvulsants have not reported contraceptive failure among such patients. 18 Given DMPA’s intrinsic anticonvulsant activity, as well as its efficacy despite the use of concomitant enzyme-inducing anticonvulsants, DMPA may be considered the contraceptive of choice in women with seizure disorders. 59,72 No pharmacokinetic studies assessing sex steroid levels in women using MPA/E2C and concomitant enzyme inducers have been conducted to date; however, it is not anticipated that contraceptive efficacy will be affected by the use of concurrent medications.

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Helping Women Successfully Use Injectable Contraception

Initial experience with use of DMPA in the US has found discouragingly low continuation rates. 9 The most common reasons contributing to DMPA discontinuation have been nonmenstrual side effects, mainly weight gain and headaches, followed by changes in menstrual bleeding. These observations underscore the importance of candid counseling about DMPA side effects for women considering use of this contraceptive method and supportive follow-up measures for those women who have chosen to use DMPA. 9,36 Facilitation of access to repeat contraceptive injections should be emphasized.

One-year MPA/E2C continuation rates in the WHO trials and the U.S. multicenter trial range from lows of 28.2% and 28.6% in Tunisia and Mexico, respectively, to highs of 73.6% and 74.3% in China and Vietnam, respectively. 9 These wide variations reflect cultural and service provision differences between countries. In Mexico, the MPA/E2C continuation rate was higher than that noted with other hormonal methods such as OCs, which may be as low as 15%, according to data from the Ministry of Health’s National Family Planning Program. 22 The continuation rate of 55.5% seen in the US multicenter clinical trial is similar to those reported for introductory trials in Jamaica, Brazil, Chile, and Peru. 11,21

Clinicians can enhance continuation of MPA/E2C use by counseling those initiating use of monthly injections about side effects and by facilitating access to subsequent injections. Where applicable, student and employee health service nurses can administer reinjection. Nurses based at pharmacies may also be able to administer contraceptive reinjection. Development of subcutaneous formulations for self-administration at home would go a long way toward expanding use of these safe and effective birth control methods.

Table 5 compares DMPA, MPA/E2C, OCs, implants, and the copper IUD for a variety of parameters. These comparisons are intended to facilitate the clinician’s task of helping candidates make sensible contraceptive choices.

Table 5

Table 5

There is a high rate OC discontinuation among teenagers, which has been reported to approach 50% within 3 months of initiating use. 81 In contrast, DMPA can provide highly effective and acceptable contraception in adolescent populations. 9 Some experts in adolescent gynecology suggest that long-acting progestin methods, coupled with condoms for protection against sexually transmitted diseases, should be considered contraceptives of first choice for sexually active teens. 82 A recent study of postpartum teens found greater continuation rates (55% vs 27%) and fewer repeat pregnancies (3% vs 24%) in DMPA users than in OC users at 12 months after childbirth. 83

As mentioned earlier, DMPA represents an appropriate choice for lactating women and others for whom use of combination OCs is contraindicated because of increased cardiovascular risk (Table 3). 71,72 DMPA is also a contraceptive option for women with other conditions in which estrogen is contraindicated, such as diabetes with vascular disease, lipid disorders (including overt hypertriglyceridemia), and systemic lupus erythematosus. Women with psychiatric illness and those who are mentally handicapped also may benefit from the convenience associated with use of injectable or implantable contraceptives. Both DMPA and MPA/E2C provide high contraceptive efficacy that is not user dependent, in contrast to OCs. Users of DMPA are protected against pregnancy for 3 months, generally do not experience regular menstrual bleeding, and experience a delayed return to fertility after cessation of injections. Those using MPA/E2C are protected against pregnancy for 1 month, experience regular menstrual cycles, and have a rapid return of fertility after discontinuation. Other reasons that some women choose an injectable method such as DMPA or MPA/E2C include concerns about daily pill taking and the privacy associated with its use no one other than health care providers need know it is being used. 32

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Conclusions

Both DMPA and MPA/E2C offer women safe, effective, convenient, and reversible birth control choices. DMPA, a 3-month injectable, is characteristically associated with amenorrhea. This progestin-only birth control method can be used by lactating women and by others in whom contraceptive doses of estrogen are contraindicated. Return of fertility can be delayed in women discontinuing DMPA to become pregnant. In some cases, use of DMPA also confers important noncontraceptive and therapeutic benefits.

MPA/E2C, a monthly estrogen/progestin injectable contraceptive, should appeal to women who are concerned about daily pill taking, who prefer regular cycles to amenorrhea, and who find monthly injections acceptable and accessible. MPA/E2C, like OCs, also represents an appropriate choice for women who prefer a rapidly reversible contraceptive method. Currently, the contraindications for MPA/E2C parallel those for combined OCs. As clinicians gain experience with MPA/E2C contraception, they will learn how to best include this new method among the array of contraceptive choices.

By individualizing contraceptive selection, counseling, and management approaches based on relevant behavioral and medical considerations reviewed here, clinicians can help their patients successfully use injectable contraceptives. The more innovative that clinicians, family planning agencies, and insurers can be in facilitating access to care (including reinjection), the more women will take advantage of safe, effective, reversible methods of contraception. In addition to the physician’s office or health clinic, other sites at which women might receive contraceptive injections include employee health nurses, college health clinics, or perhaps the pharmacy where the prescription is filled. If subcutaneous formulations become available, self-administration may become an appropriate option for some users of injectable contraception.

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