This chapter should be cited as follows:
Kaunitz, A, Glob. libr. women's med.,
(ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10393
This chapter was last updated:
May 2008

Injectable Contraception

Andrew M. Kaunitz, MD
Professor and Assistant Chair, Department of Obstetrics and Gynecology, University of Florida Health Science Center, Jacksonville, Florida, USA

INTRODUCTION

Injectable contraception offers women convenient, safe, and reversible birth control that is as effective as sterilization. This chapter describes two injectable contraceptives of interest to United States clinicians. Depot medroxyprogesterone acetate (DMPA) (Depo-Provera; Pfizer, New York, NY, USA), a 3-month progestin-only contraceptive, has been widely used in the United States since it was approved by the Food and Drug Administration (FDA) for birth control in 1992. Medroxyprogesterone acetate/estradiol cypionate (MPA/E2C) (Lunelle; Pfizer, New York, NY, USA), a 1-month combination estrogen–progestin contraceptive, was approved by the FDA in October 2000 but has not been available in the United States since February 2003 as the result of manufacturing concerns. The contraceptive selection and management approaches detailed in the text and clinical cases included at the end of this chapter should help clinicians assist their patients in making prudent decisions regarding injectable contraception. Such informed choices should result in high rates of birth control efficacy, satisfaction, and continuation.

DEPOT MEDROXYPROGESTERONE ACETATE

History

Depo-Provera, developed by Upjohn, was first studied in clinical trials in the 1960s. Although an application for contraceptive use was submitted decades earlier, concerns, including the finding of tumors after animal testing, prevented FDA approval for contraception until 1992. Approval occurred after publication of reassuring World Health Organization (WHO) studies regarding gynecologic cancer risk.1, 2 DMPA has been used by more than 68 million women in more than 114 countries worldwide.3

 

Pharmacology, Mechanism of Contraceptive Action, and Efficacy

Please verify all doses and dosages. The low solubility of the microcrystals at the injection site results in pharmacologically active levels of medroxyprogesterone acetate (MPA) that persist for at least 3–4 months after a 150-mg injection.4 DMPA is marketed in the United States as a 150-mg/mL contraceptive solution in individual ampules or prefilled syringes.

DMPA inhibits ovulation. When 150 mg DMPA is injected every 3 months, contraceptive efficacy is extremely high. Failure rates in clinical trials have ranged from .0 to .7 per 100 woman-years. The typical failure rate of DMPA is .3 per 100 woman-years, which is comparable with that of implantable contraceptives, copper intrauterine devices (IUD), or surgical sterilization.5 The efficacy of DMPA apparently is not reduced by high body weight or use of concurrent medications,6 likely reflecting high circulating levels of progestogen associated with DMPA use.

 

Timing of Initial and Repeat Injections

The ideal time to initiate DMPA is within 5 days of the onset of menses (Table 1). This approach ensures that the patient is not pregnant and prevents ovulation during the first month of use. After a 150-mg injection, ovulation does not occur for at least 12 weeks. Therefore, a 2-week grace period exists for women receiving injections every 3 months. For women more than 2 weeks late for their DMPA injection, pregnancy testing should be performed before administering DMPA.2 Although published literature supports a 2-week grace period, the package labeling recommends excluding pregnancy in women more than 1 week late for reinjection.

 

Table 1. Timing of first injection and subsequent injections


Method DMPA MPA/E2C
First Injection
Spontaneous menstrual cycle Within 5 days of menses onset Within 5 days of menses onset
Spontaneous or elective first-trimester abortion Within 7 days Within 7 days
Term delivery Within 3 weeks postpartum if not lactating; within 6 weeks postpartum if lactating Between 21 and 28 days postpartum if not lactating
Switching from combination OC While using active pills or within 7 days after taking the pill pack's last active tablet While using active pills or within 7 days after taking the pill pack's last active tablet
Switching from combination contraceptive patch (Ortho Evra™) While using weekly patch or within 7 days after patch removal While using weekly patch or within 7 days after patch removal
Switching from combination contraceptive vaginal ring (NuvaRing®) While ring is in place or within 7 days after ring removal While ring is in place or within 7 days after ring removal
Switching from DMPA Within 13 weeks after last DMPA injection
Switching from MPA/E2C Within 33 days after previous injection
Switching from levonorgestrel IUD (Mirena®) First injection should occur before IUD removal and within 5 years after IUD insertion; if patient is menstruating, a condom should be used as a back-up if the first injection is not administered within 5 days of menses onset First injection should occur before IUD removal and within 5 years after IUD insertion; if patient is menstruating, a condom should be used as a back-up if the first injection is not administered within 5 days of menses onset
Switching from First injection should occur before IUD removal and within 10 years after IUD insertion; a condom should be used as a back-up if the first injection is not administered within 5 days of menses onset First injection should occur before IUD removal and within 10 years after IUD insertion; a condom should be used as a back-up if the first injection is not administered within 5 days of menses onset
Copper T 380A IUD    
Subsequent Injections
Injection interval Every 12 weeks or 3 months; earlier reinjections are acceptable Every 28 days or 4 weeks or monthly; reinjection earlier than 23 days may cause unpredictable bleeding
Grace period 2 weeks; after 1 week manufacturer recommends pregnancy testing before repeat injection ±5 days (23–33 days); thereafter, pregnancy testing needed before repeat injection

DMPA, depot medrovxyprogesterone acetate; MPA/E2C, medroxyprogesterone acetate and estradiol cypionate; OC, oral contraceptives; IUD, intrauterine device.

 

Inadvertent administration of DMPA during pregnancy does not increase the risk of congenital anomalies.7 In the Planned Parenthood database, 46% of 402 DMPA users who became pregnant from 1994–1998 had a pregnancy diagnosed after the first trimester.8 No fetal anomalies were reported among the offspring of 77 women (19.1%) who received an additional DMPA injection during pregnancy.

 

Return to Fertility

Although DMPA does not have any permanent impact on endocrine function, return of fertility may be delayed. The persistence of ovulation suppression after DMPA discontinuation is not related to the duration of use. Within 10 months of the last injection, 50% of women who discontinued DMPA to become pregnant will conceive; in a small proportion of women, however, fertility is not reestablished until 18 months after the last injection.9 Before initiating DMPA contraception, clinicians should therefore counsel candidates about the possible prolonged duration of action. Women who may want to become pregnant within the next 1 or 2 years should choose an alternative contraceptive.

 

Side Effects

Users who are well informed regarding their method's side effects have the highest contraceptive satisfaction and continuation rates.10, 11, 12, 13 Hence, before initiation of DMPA contraception, clinicians should ensure that candidates recognize this method's most common side effects. As with all long-acting progestin contraceptives, menstrual changes constitute the most important side effects of DMPA use.

Menstrual changes occur in almost all women using DMPA. Episodes of unpredictable, irregular bleeding and spotting lasting 7 days or more are common during the first months of use. With increasing duration of use, the frequency and duration of these episodes decrease. After 1 year of DMPA use (four injections), 50% of women experience amenorrhea.14 With ongoing use, the rate of amenorrhea increases to 75%.

These menstrual changes are the most frequent cause for dissatisfaction with and discontinuation of DMPA. In many cases, DMPA users experiencing anxiety over menstrual changes may be concerned that pregnancy or gynecologic disease is present. Candid patient education before initiation and supportive follow-up measures can markedly reduce patients' discontent. Women clearly uncomfortable with the menstrual changes that inevitably accompany use of DMPA should be counseled to choose an alternative contraceptive.

When persistent spotting or bleeding becomes unacceptable to a DMPA user who otherwise wishes to continue using injection, then oral or transdermal estrogen supplementation (e.g. 1.25 mg of oral conjugated estrogen, estropipate, or esterified estrogens; 1 mg of oral estradiol; .1-mg estrogen patches) can be considered. Bleeding may recur after discontinuing estrogen. Although some clinicians treat irregular spotting or bleeding in DMPA users by administering follow-up injections at intervals more frequent than 3 months, I am unaware of any data demonstrating the efficacy of this practice. If bothersome spotting and/or bleeding persists after several injections of DMPA, evaluation with sonography, sonohysterography, or hysteroscopy may reveal the presence of anatomic causes of abnormal bleeding unrelated to DMPA use, including uterine fibroids (intramural or submucous) or endometrial polyps. Patients persistently dissatisfied with the menstrual changes caused by DMPA and not found to have the uterine/endometrial pathology detailed here may be better served by combination oral, patch, ring, monthly injectable (when available), or intrauterine contraceptive methods. In contrast to the patient dissatisfaction that unpredictable bleeding or spotting can cause, many women using DMPA view amenorrhea (along with a reduction or elimination of menstrual cramps) as a favorable aspect of their contraceptive choice.15, 16, 17, 18

A variety of other side effects are reported by women using DMPA, including weight gain, headaches, bloating of the abdomen or breasts, mood changes, and reduced libido. One HMO-based study suggested that depressive symptoms were more common in DMPA users than in nonusers.19 However, studies that have compared depressive symptoms at baseline with those during DMPA use indicate that DMPA does not, in general, cause depressive symptoms in either adolescents or adults.20, 21, 22

Notwithstanding these overall reassuring observations, clinicians should be aware that progestins (whether in contraceptive or menopausal therapy) may cause or exacerbate depressive symptoms in certain subpopulations of women, including some patients with a history of premenstrual syndrome or mood disorders.23, 24 Accordingly, clinicians should not consider a history of depression to contraindicate DMPA use but should follow-up such women closely when they initiate any progestin-based therapy, including DMPA.

Few controlled studies conducted in developed counties have evaluated weight changes associated with use of DMPA. A small, short-term United States study, however, failed to confirm that DMPA causes weight gain.25 In observational studies in adolescents and older women, DMPA has had variable effects on weight. Three studies reported nonsignificant changes in weight among women who used DMPA for up to one year.26, 27, 28 Three other studies found gains ranging from 3–6 kg.29, 30, 31 However, these three trials were conducted in postpartum adolescents, Navajo Indians, and blacks, all groups who may intrinsically be at increased risk for weight gain. In contrast, the only randomized, controlled trial found no evidence that DMPA increases appetite or weight in women of normal weight observed during the two menstrual cycles before and first menstrual cycle after the initial injection of DMPA.32 Because this study included only 20 volunteers and the subjects received only one injection of DMPA, additional randomized, clinical trials to assess the impact of DMPA (if any) on appetite and weight would be welcome.

With regard to the risk of transmission of sexually transmitted diseases, it has been suggested that long-acting progestins may promote HIV transmission based on two studies in Rhesus monkeys showing vaginal mucosal thinning.33 However, studies in women using DMPA have found minimal or no effect on the vaginal epithelium.34, 35

Preliminary experience with the use of DMPA at one United States family planning clinic found that among women receiving an initial injection, only 57% returned for a second injection. Of those who returned for a second injection, 63% went on to receive a third.36 Another preliminary United States study found a 12-month continuation rate of 42%.37 These observations underscore the importance of candid counseling regarding DMPA side effects and the desirability of identifying ways to facilitate access to repeat contraceptive injections.10 In this regard, recent studies in China, Bolivia, and Mexico have shown that women initiating use of DMPA who receive intensive, structured counseling regarding possible hormonal changes and side effects are three to four times more likely to continue use than those who receive routine counseling.10, 11, 12

 

Noncontraceptive Benefits and Therapeutic Uses

The broad array of noncontraceptive benefits (Table 2)38, 39, 40, 41, 42 and therapeutic uses (Table 3)38, 43, 44, 45, 46, 47, 48, 49 of DMPA suggest that this injectable progestin can be used for a diverse group of women, including contraceptive candidates and women with a variety of gynecologic and nongynecologic disorders.

 

Table 2. Noncontraceptive benefits of depot medroxyprogesterone acetate


Noncontraceptive Benefits Reference
Prevention of:  
 Iron deficiency anemia 38
 Pelvic inflammatory disease 38
 Ectopic pregnancy 39
 Endometrial cancer 40, 42
 Hysterectomy in women with uterine leiomyomas 41

 

 

Table 3. Therapeutic uses* of depot medroxyprogesterone acetate (DMPA)


Therapeutic Use Reference
Consider DMPA treatment  
For:  
Menorrhagia/dysmenorrhea (including when associated with uterine leiomyoma) 43
Premenstrual syndrome syndrome 44
Pain in women with endometriosis 4
Hemoglobinopathy 46
Seizures refractory to conventional anticonvulsants 47
Menstrual hygiene problems in handicapped women 48
Endometrial hyperplasia 38
Vasomotor symptoms in menopausal women 38
Pelvic pain/dyspareunia of ovarian origin after hysterectomy
Ovulatory pain 49
Metastatic breast cancer 38
Metastatic endometrial cancer 38

*Use of DMPA for indications other than contraception or endometrial cancer constitutes off-label use not approved by the FDA.
†This therapeutic use of DMPA is supported by author's clinical experience.
‡Approved indication for Depo-Provera® injectable suspension containing 400 mg/mL MPA.

 

The risk for endometrial cancer is decreased 80% in users of DMPA, and protection appears to persist after cessation of use.42 Likewise, DMPA users have a decreased risk for iron-deficiency anemia, pelvic inflammatory disease, and ectopic pregnancy.38, 39 An epidemiological study found that DMPA has a strong protective effect against menorrhagia associated with uterine leiomyomas and reduces the need for hysterectomy in women with these common benign tumors growths.41, 50 It is possible (but has not been documented) that the prolonged ovulation suppression associated with DMPA might provide protection against ovarian cancer.16, 38, 51, 52

Clinical experience suggests that for some women, particularly for those bothered by painful menstrual cramps, use of DMPA reduces premenstrual syndrome symptoms.44 The tendency of DMPA to cause amenorrhea can make it a particularly appropriate contraceptive choice for women with menorrhagia, dysmenorrhea, and iron-deficiency anemia.38 In many cases, the use of DMPA or other progestins effectively treats menorrhagia and dysmenorrhea associated with uterine fibroids.43 Clinicians have used progestins in the management of endometriosis for decades. A recently published clinical trial confirmed DMPA's effectiveness in treating pain associated with this disease.45

DMPA is also appropriate for mentally handicapped women with menstrual hygiene problems.48 The use of DMPA has also been associated with hematologic improvement in women with sickle cell disease.46 There also is evidence indicating that DMPA has intrinsic anticonvulsant activity.47, 50, 53, 54 Because the efficacy of DMPA's contraceptive protection does not appear attenuated by the use of enzyme-inducing anticonvulsants as well as this method's intrinsic anticonvulsant properties, DMPA would appear to represent the contraceptive of choice for many women with seizure disorders. DMPA has also been successfully used in the treatment of a variety of other gynecologic, menopausal, and oncologic conditions (see Table 3). Clinicians should recognize that the use of DMPA for indications other than contraception or metastatic endometrial cancer constitutes off-label use.

 

Impact on Reproductive Tract Cancer Risk

The WHO examined the risks of breast, endometrial, ovarian, and cervical carcinoma associated with DMPA.40, 42, 55, 56 Results from these large case-control studies reveal that DMPA does not increase the risk of these tumors. In fact, DMPA was found to have an even more profound protective effect against endometrial cancer than that attributed to oral contraceptives (OC). Data from New Zealand have also indicated that use of DMPA does not increase the risk of breast cancer.57

Use of DMPA appears to reduce plasma high-density lipoprotein levels, an observation of unknown clinical importance.20 With regard to the risk of cardiovascular events, published epidemiological studies have shown no adverse effect of DMPA use.58, 59 This is in contrast to combination OC, because the use of which increases the overall risk of venous thromboembolism and, in women who smoke, increases the risk of myocardial infarction and stroke.59 Unlike combination OC, use of progestin-only DMPA does not cause any apparent increase in hepatic production of coagulation factors and has no adverse effect on blood pressure. Based on the absence of such changes, the American College of Obstetricians and Gynecologists suggest that DMPA is an appropriate contraceptive option for women in whom use of combination OC is considered unsafe (Table 4).60, 61

 

Table 4. Clinical situations in which depot medroxyprogesterone acetate (DMPA) may be an appropriate contraceptive choice


Cerebrovascular disease*
Complicated migraine headaches
 Migraines with focal neurologic phenomenon
 Migraines that intensify during combination oral contraceptive (OC) use
Congestive heart failure
Coronary artery disease
Diabetes
Lipid disorder (including hypertriglyceridemia)
Liver disease*
Concomitant medications that reduce efficacy of implants or OC (e.g. cambamazepine, phenytoin, phenobarbital, primidone, felbamate, topiramate, rifampin, griseofulvin)
Peripheral vascular disease (e.g. diabetes, lupus)
Postpartum (partially or nonbreastfeeding)
 Begin within 3 weeks postpartum
Fully breastfeeding
 Begin within 6 weeks postpartum
Smokers age > 35 years
Systemic lupus erythematosus
Scheduled for surgical procedures associated with an increased risk of thromboembolism
Scheduled for tubal sterilization
Thromboembolism* (history of and/or high risk for)

*Clinicians should be aware that prescribing DMPA for women with these conditions constitutes off-label use not approved by the FDA.

 

Recently, Sørensen and colleagues suggested that DMPA might adversely affect cardiovascular health based on the finding of reduced peripheral arterial hyperemia-induced flow-mediated dilatation (FMD) in DMPA users compared with untreated ovulatory women.62 The clinical implications, if any, of reduced FMD in healthy young women are not known.58 Another recent study found an increase in FMD of the brachial artery in menopausal women receiving conjugated estrogen combined with MPA, leading to speculation that such improvements in arterial function meant that hormone replacement therapy would prevent coronary artery disease.63 However, the findings of the Women's Health Initiative refute this and remind us that when making clinical decisions, studies relying on direct outcomes (e.g. myocardial infarctions or strokes) are preferable to those that rely on indirect, surrogate markers such as vascular reactivity. In view of the reassuring epidemiological safety data surrounding DMPA use and the unknown clinical implications of FMD changes in healthy young women, there is no justification for the suggestion that this highly effective injectable contraceptive might adversely impact cardiovascular health.58

 

Bone Mineral Density Issues

Because use of DMPA reduces ovarian production of estradiol, its impact on bone mineral density (BMD) has been scrutinized. Clinicians should recognize that use of DMPA has not been linked with postmenopausal osteoporosis or fractures. Results of a meta-analysis of BMD among DMPA users and nonusers based on data from 10 cross-sectional and two longitudinal studies found that average BMD in current users was decreased but was within one standard deviation of the mean in nonusers.64 Reductions in BMD increased as the duration of DMPA use increased; however, no clinical evidence of osteoporosis, such as fractures, was noted.

Few studies have addressed the impact of DMPA use during adolescence, a period during which it is important to achieve optimal bone mineral density.65, 66, 67 Results of two United States studies suggest that users of DMPA achieve smaller gains in BMD than nonusers or adolescents using other forms of hormonal contraception.65, 66 Another United States study comparing DMPA and two types of OC in women aged 18–33 years found that there was a mean loss of lumbar spine BMD of approximately 3% in DMPA users over 12 months, whereas OC users experienced gains.67Thus, adolescent users of DMPA, like all teenagers, should be counseled regarding strategies to optimize bone mineralization, such as adequate intake of calcium, exercise, and avoidance of smoking and alcohol use.68

Reductions in BMD are reversible after discontinuation of DMPA use. A large cross-sectional study conducted in New Zealand, where DMPA has been routinely available as a contraceptive for several decades,69 found that BMD among postmenopausal women who had initiated DMPA use at a median age of 41 years and continued use for a median duration of 3 years was not significantly different from that in never-users at any site.70 A cross-sectional study in young adult women also found no evidence of reduced BMD in former DMPA users.71 More recently, a 3-year, longitudinal, prospective cohort study of 183 women who used DMPA at initiation and 274 nonusers found mean annualized BMD decreases among current users of .87% and 1.12% at the spine and hip, respectively.72 After cessation of DMPA use, mean annualized gains in BMD at the spine and hip were 1.41% and 1.03%, whereas nonusers had a gain of .4% at the spine and a loss of .05% at the hip.

These findings remind us that because the skeleton is a dynamic organ, long-term cross-sectional studies may not provide an accurate picture of long-term clinical effects of hormonal exposures. The effect of DMPA resembles the benign impact that lactation has on BMD, in that both lactation and DMPA reduce ovarian production of estradiol, leading to reversible declines in BMD.73, 74 A prospective multicenter study comparing BMD in DMPA users versus nonusers was initiated in 1994 and concluded in 2003. Results of this study should clarify the long-term impact of DMPA use, if any, on BMD.

An occasional DMPA user with multiple risk factors may present special concerns regarding BMD and future fracture risk. An example would be a 45-year-old, slender, white, cigarette-smoking DMPA user. Results of a recent randomized, double-blind controlled trial in 38 premenopausal women who had used DMPA for at least 2 years and had below-average baseline BMD at the lumbar spine (T score ≤0) confirm that low-dose estrogen supplementation (conjugated equine estrogen .625 mg) completely prevents any short-term loss of BMD associated with DMPA use.75 At all observations from 6–24 months, BMD at the lumbar spine was greater among DMPA users receiving estrogen supplementation compared with those receiving placebo, with statistically significant between-treatment differences at 18 and 24 months (Table 5). Therefore, in long-term, ongoing DMPA users with multiple additional risk factors for low BMD, it would be reasonable to supplement the injections with menopausal doses of estrogen.

 

Table 5. Greater lumbar spine bone mineral density in depot medroxyprogesterone acetate (DMPA) users receiving conjugated estrogens versus placebo75


Time on Therapy (mo) Between Group Difference (%) P-Value
12 1.9 .06
18 3.2 <.01
24 3.5 <.002

Based on data from Cundy T et al. J Clin Endocrinol Metab 88: 78, 2003.

 

 

Compliance, Adolescent Use, and Privacy Issues

Rates of OC failure and discontinuation can be exceedingly high among teenagers. In contrast, DMPA can provide highly effective and acceptable contraception in adolescent populations.17, 76, 77, 78, 79 A recent study of postpartum teenagers found that DMPA users were more likely to continue their contraceptive than OC users (55% vs. 27%) and had lower rates of repeat pregnancy (3% vs. 24%).80 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.77 Indeed, the growing prevalence of DMPA use among United States teenagers appears in part responsible for decreasing rates of adolescent pregnancy and abortion in this country.81, 82

Women with psychiatric illness or who are mentally handicapped may also benefit from the convenience of injectable contraceptives. Some women choose DMPA for privacy reasons. No one other than their health care providers need know it is being used.15

 

Use After Abortion and Delivery

Any method of hormonal contraception may be initiated immediately after induced or spontaneous termination of a first- or second-trimester pregnancy. Women remain at increased risk for thromboembolism for several weeks after childbirth. Ovulation does not occur in nonbreastfeeding women before 25 days postpartum.83 Based on these observations, some experts initiate combination OC for nonbreastfeeding women during the third postpartum week (i.e. days 15–21 postpartum), even though package labeling suggests that OC not be initiated before 4 weeks postpartum.84 Because progestin-only OC and DMPA do not contain estrogen, they may be initiated immediately postpartum (see Table 1).60, 61

Use of combination OC can reduce the quantity and duration of lactation, although such use by well-nourished breastfeeding women does not appear to result in infant development problems. Progestin-only contraceptives do not impair lactation and, in fact, may increase the quality and duration of lactation. Thus, DMPA represents an appropriate choice for lactating women. When initiated immediately or at 6 weeks postpartum, DMPA has not been shown to decrease duration of lactation or infant weight gain.85, 86 Because the manufacturers of DMPA did not submit data to the FDA regarding immediate postpartum use in lactating women, however, package labeling advises initiating DMPA in lactating women at 6 weeks postpartum (see Table 1). Clinical experience at the University of Florida Health Science Center–Jacksonville with immediate postpartum initiation of DMPA in lactating women is extensive and reassuring with respect to infant and maternal outcomes. An American College of Obstetricians and Gynecologists Practice Bulletin likewise supports the maternal and neonatal safety of immediate postpartum administration of DMPA, whether or not the mother is lactating.61

 

Use When Estrogen Is Contraindicated

Use of long-acting progestin contraceptives may be appropriate when contraceptive doses of estrogen are contraindicated. Both pregnancy and combination OC use confer an increased risk for morbidity and mortality in women with the following conditions: (1) age older than 35 who smoke, have hypertension, or have diabetes; (2) coronary artery or other vascular disease; (3) increased risk for thromboembolism; (4) systemic lupus erythematosus (SLE);87 (5) overt hypertriglyceridemia; and (6) active liver disease.

Although combination OC use is contraindicated in patients with overt hypertriglyceridemia, progestin-only methods have not been shown to aggravate the condition. Further, although active liver disease is a contraindication for combination OC use, a small clinical trial of oral MPA in adults with chronic liver disease suggested that DMPA may be a safe contraceptive choice for women with liver ailments.88 My clinical experience has also been reassuring in this context.

Package labeling lists some of the aforementioned conditions as contraindications to the use of injectable contraception. Although clinicians should familiarize themselves with the contraindications listed on package labeling for all medications they prescribe, progestin-only hormonal methods are appropriate contraceptive choices for many women with the aforementioned conditions.53 Selected conditions for which DMPA use may be appropriate are listed in Table 4.

A history of breast cancer is listed on package labeling as a contraindication to use of all hormonal birth control methods. Intrauterine devices represent an appropriate reversible contraceptive choice for breast cancer survivors.

 

Concomitant Medications

Anticonvulsants and antibiotics that induce hepatic enzymes (see Table 3) can reduce the contraceptive efficacy of OC and levonorgestrel implants.89, 90 The contraceptive efficacy of DMPA in women using hepatic enzyme inducers has not been explicitly studied; however, physicians with substantial experience prescribing DMPA (150 mg every 3 months) for women using anticonvulsants have not reported contraceptive failure among such patients.6

 

Cost Issues

In addition to enhancing quality of life by allowing couples to choose whether and when they wish to bear children, effective contraception saves health care costs. An analysis of 15 contraceptive methods found that over a 5-year period, DMPA and the copper-T IUD were the two most cost-effective reversible contraceptives.91 Ironically, traditional and managed-care health insurance plans are far more likely to pay for tubal sterilization (considerably less cost-effective than the two reversible methods mentioned) than for injectable, intrauterine, or OC.92 The following cases detail a variety of DMPA management issues and illustrate a variety of challenging contraceptive candidates for whom DMPA may represent a prudent choice.

 

CASE A: ANTICONVULSANT DRUG USE

After having a seizure disorder diagnosed, a 20-year-old woman recently began therapy with carbamazepine. Two years previously, she had started use of combination OC and had been experiencing regular well-scheduled withdrawal bleeding. After beginning the anticonvulsant, however, breakthrough bleeding occurred. Recent cervical cytology was normal. Likewise, speculum examination revealed no evidence of vaginal or cervical pathology.

Appropriate Contraception

Drugs that induce the hepatic P450 enzyme system (see Table 3) increase the metabolism of sex steroids, thus potentially reducing the effectiveness of OC. Because no reduction in the contraceptive efficacy of 150 mg of DMPA has been reported in women receiving concomitant drugs that induce hepatic enzymes, injectable contraceptives would be an appropriate choice in this case. DMPA also appears to have intrinsic anticonvulsant activity. Similar considerations apply to women using the enzyme-inducing antibiotic rifampin.

CASE B: POSTPARTUM LACTATING MOTHER

A 27-year-old has just delivered a healthy infant and will be discharged from the hospital the next day. She plans to breastfeed her infant.

Appropriate Contraception

Because combination OC can reduce breast milk volume, they are not an optimal method for lactating women. In addition, combination OC should not be initiated before 2–3 weeks postpartum because of their thrombogenic potential. DMPA, as well as progestin-only (mini) pills, can be initiated immediately postpartum and do not suppress lactation. Although package labeling indicates that clinicians should wait until 6 weeks postpartum before initiating progestin-only methods in breastfeeding women, published data indicate that immediate postpartum initiation of long-acting progestin contraceptives and minipills does not compromise lactation or neonatal health.

 

CASE C: CONTRACEPTIVE NEEDS AND PERIMENOPAUSAL SYMPTOMS IN A CIGARETTE SMOKER

A 39-year-old woman recently became divorced from her husband, who underwent vasectomy. She smokes one pack of cigarettes daily and notes that her menses have become less predictable. At night she is sometimes kept awake by hot flashes. She has started to date a new partner.

Appropriate Contraception and Management

Perimenopausal symptoms and menopause occur on average 1 or more years earlier in women who smoke cigarettes. Although combination OC would restore predictable menses and offer effective contraception for this woman, their use is contraindicated in women older than 35 years who smoke. DMPA would safely provide effective contraception for this woman. Concomitant estrogen supplementation (e.g. conjugated equine estrogen .625 mg or its equivalent)74 would also be appropriate because the cigarette smoking and vasomotor symptoms suggest the presence of hypoestrogenism, and estrogen supplementation prevents loss of BMD in women using DMPA contraception. Finally, safe sex including condoms use should be reviewed with any woman embarking on a relationship with a new partner.

 

CASE D: PERIMENOPAUSAL WOMAN REQUESTING SYMPTOMATIC RELIEF AND BIRTH CONTROL

A 46-year-old woman widowed for 2 years recently began a new relationship. Her partner has been using condoms, but she is concerned about their effectiveness in preventing pregnancy. She has also noticed that her menstrual periods, which used to be “like clockwork”, are less predictable. Sometimes she skips a period for several months at a time. Some months she has been having hot flushes that are uncomfortable during the daytime and also interfere with her sleep. She is a healthy, nonsmoking woman who enjoys bicycling and tennis. Because she works shifts as an emergency department physician, she is skeptical regarding her ability to consistently use an oral medication.

Appropriate Contraception and Management

This woman's clinician needs to address two issues: provision of effective contraception and management of perimenopausal symptoms. Use of DMPA will provide effective birth control and suppress her vasomotor symptoms.93

Because she may already be developing perimenopausal hypoestrogenemia, which could be exacerbated by use of DMPA, it is reasonable to add supplemental estrogen (e.g. conjugated equine estrogen 6.25 mg daily or its equivalent) during use of DMPA.74 With this regimen, she can anticipate having amenorrhea over time. Other contraceptive options that might be appropriate for this patient include intrauterine devices and the contraceptive patch or ring.

Should this patient choose DMPA (with or without estrogen supplementation), how long should she continue to use either of these contraceptive methods? When should she consider switching to hormonal replacement? Measuring gonadotropins is not useful in assessing when perimenopausal-aged women have become menopausal, particularly if such women are using hormonal contraceptives.94, 95, 96, 97 The median age of menopause (when contraception is no longer needed) is 51–52 years, meaning that 50% of women of this age are still ovulatory. By age 55, in contrast, at least 80% of women are menopausal.98, 99

If the perimenopausal woman described here chooses DMPA plus estrogen, she will be exposed to doses of estrogen considerably less procoagulant than those contained in combination OC, which are themselves known to be safe in healthy, nonsmoking, perimenopausal women. Therefore, it is reasonable to continue DMPA (with or without estrogen) without gonadotropin testing until the patient is in her mid 50s. At that time, contraception can be arbitrarily discontinued and the patient seamlessly transitioned to menopausal hormonal therapy, if she wishes. This laboratory-free strategy is simple, inexpensive, and allows women to minimize or entirely avoid unpleasant perimenopausal and postmenopausal symptoms.

 

MEDROXYPROGESTERONE ACETATE/ESTRADIOL CYPIONATE

The monthly injectable combination of 25 mg of medroxyprogesterone acetate and 5 mg of estradiol cypionate (MPA/E2C; Lunelle; Pfizer) was approved by the United States FDA in October 2000 but has not been available in the United States since February 2003 as the result of manufacturing concerns. It remains available in some countries abroad where it is known as Cyclo-Provera or Cyclofem. Studied extensively by the WHO in the 1980s and 1990s, trials in approximately 12,500 women (approximately 10,400 woman-years) established the contraceptive efficacy and side effect and safety profile of MPA/E2C.100,101,102,103,104,105,106 Based on extensive clinical and introductory trial experience in the United States and abroad, the failure rate of MPA/E2C can be estimated at .1 failures per 100 women-years.107,108 No pregnancies were reported in the pivotal United States clinical trial (N = 775), which included women as heavy as 309 pounds.107 In contrast to DMPA, return to fertility occurs rapidly (within 60 days) after MPA/E2C discontinuation.109 No congenital anomalies were reported among 55 subsequent live births.

In contrast to DMPA, most long-term users of MPA/E2C report regular menses after the first cycle of use (average cycle length: 28 days).107 In the United States-based multicenter trial, MPA/E2C users experienced more bleeding/spotting days compared with OC users, but the overall number was similar to or less than that observed in healthy, nonpregnant, nonlactating women not using hormonal contraception.107,110,111 Only 2.5% (19/775) of MPA/E2C users in the United States trial discontinued treatment because of irregular bleeding.107

Other side effects reported by MPA/E2C users include headache, breast tenderness, weight gain, dysmenorrhea, and acne, which are all consistent with those expected among users of combined hormonal contraceptives.107 The frequency of these side effects was greatest during the first 3 months of use, decreasing with ongoing use. There were no reports of depression. No clinical significant changes in blood pressure, blood glucose, or liver and kidney function tests were noted.107 MPA/E2C does not appear to cause clinically important changes in lipid metabolism. After 1 year of use, an overall decrease in lipid values, including a significant decrease in HDL cholesterol, was seen in users of MPA/E2C.112 However, the total cholesterol-to-HDL cholesterol ratio was maintained.112

In contrast to low-dose combination OC and similar to DMPA, MPA/E2C does not appear to cause procoagulant changes.100 In WHO clinical trials to date in more than 15,000 users of MPA/E2C and in the United States clinical trial in 775 users, no cases of thromboembolic disease, myocardial infarction, or cerebral vascular events have been reported.50 Nevertheless, contraindications for MPA/E2C listed on package labeling parallel those listed for combination OC.

CONCLUSION

DMPA and MPA/E2C contraception offer women safe, effective, convenient, and reversible birth control choices. Long-term use of DMPA, a 3-month injectable, is characteristically associated with amenorrhea. Many United States teenagers and other contraceptive candidates who prefer highly effective, long-acting birth control have achieved contraceptive success with DMPA. Lactating women and others in whom contraceptive doses of estrogen are contraindicated can also use this progestin-only birth control method. 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.

A monthly estrogen–progestin injectable contraceptive, MPA/E2C should appeal to women who are concerned about daily pill administration, who prefer regular cycles to amenorrhea, and who find monthly injections acceptable and accessible. MPA/E2C, like OC, also represents an appropriate choice for women who prefer a short-acting contraceptive. Currently, estrogen-related contraindications listed on the package labeling parallel those for combined OC. Should MPA/E2C again become available in the United States, we will learn how to facilitate initiation and continuation of this safe, highly effective, monthly contraceptive. By individualizing contraceptive selection, counseling, and management approaches based on relevant behavioral and medical considerations reviewed in this chapter, we can maximize our patients' success with injectable contraceptives.

REFERENCES

1

Klitsch M: Injectable hormones and regulatory controversy: An end to the long-running story? Fam Plann Perspect 25:37, 1993

 

2

Kaunitz AM: Long-acting injectable contraception with depot medroxyprogesterone acetate. Am J Obstet Gynecol 170:1543, 1994

 

3

Westhoff C: Depot-medroxyprogesterone acetate injection (Depo-Provera®): A highly effective contraceptive option with proven long-term safety. Contraception. 68:75, 2003

 

4

Mishell DR Jr: Pharmacokinetics of depot medroxyprogesterone acetate contraception. J Reprod Med 41:381, 1996

 

5

Trussell J, Kost K: Contraceptive failure in the United States: A critical review of the literature. Stud Fam Plann 18:237, 1987

 

6

Sapire KE: Letter to the Editor: Depo-Provera and carbamazepine. Br J Fam Plann 15:130, 1990

 

7

American College of Obstetricians and Gynecologists: Contraceptives and congenital anomalies. ACOG Committee Opinion 124. Washington, DC, ACOG, 1993

 

8

Borgatta L, Murthy A, Chuang C et al: Pregnancies diagnosed during Depo-Provera use. Contraception 66:169, 2002

 

9

Schwallie PC, Assenzo JR: The effect of depot medroxyprogesterone acetate on pituitary and ovarian function, and the return of fertility following its discontinuation: A review. Contraception 10:181, 1971

 

10

Lei ZW, Wu SC, Garceau RJ et al: Effect of pretreatment counseling on discontinuation rates in Chinese women given depot medroxyprogesterone acetate for contraception. Contraception 53:357, 1996

 

11

Hubacher D, Goco N, Gonzalez B et al: Factors affecting continuation rates of DMPA. Contraception 60:345, 2000

 

12

Canto De Cetina TE, Canto P, Luna MO: Effect of counseling to improve compliance in Mexican women receiving depot-medroxyprogesterone acetate. Contraception 63:143, 2001

 

13

Alvarez-Sanchez F: The clinical performance of Norplant implants over time: A comparison of two cohorts. Stud Fam Plann 19:118, 1988

 

14

Belsey EM: Vaginal bleeding patterns among women using one natural and eight hormonal methods of contraception. Contraception 38:181, 1988

 

15

Nelson AL: Counseling issues and management of side effects for women using depot medroxyprogesterone contraception. J Reprod Med 41:S5:391, 1996

 

16

Kaunitz AM: Menstruation: Choosing whether…and when. Contraception 62:277, 2000

 

17

Smith RD, Cromer BA, Hayes MA et al: Medroxyprogesterone acetate (Depo-Provera) use in adolescents: Uterine bleeding and blood pressure patterns, patient satisfaction, and continuation rates. Adolesc Pediatr Gynecol 8:24, 1993

 

18

Glasier AF, Smith AB, van der Spuy ZM et al: Amenorrhea associated with contraception—an international study on acceptance. Contraception 67:1, 2003

 

19

Civic D, Scholes D, Ichikawa L et al: Depressive symptoms in users and non-users of depot medroxyprogesterone acetate. Contraception 61:385, 2000

 

20

Westhoff C: Depot medroxyprogesterone acetate contraception: Metabolic parameters and mood changes. J Reprod Med 41:S5:401, 1996

 

21

Westhoff C, Truman C, Kalmuss D et al: Depressive symptoms and Depo-Provera. Contraception 57:237, 1998

 

22

Gupta N, O'Brien R, Jacobsen LJ et al: Mood changes in adolescents using depot-medroxyprogesterone acetate for contraception: A prospective study. J Pediatr Adolesc Gynecol 14:71, 2001

 

23

Bjorn I, Bixo M, Mjod KS et al: Negative mood changes during hormone replacement therapy: A comparison between two progestins. Am J Obstet Gynecol 183:1419, 2000

 

24

North American Menopause Society. Role of progestogen hormone therapy for postmenopausal women: Position statement of The North American Menopause Society Menopause 10:113, 2003

 

25

Moore L, Valuck R, McDougall C et al: A comparative study of one year weight gain among users of medroxyprogesterone acetate, levonorgestrel implants, and oral contraceptives. Contraception 52:215, 1995

 

26

Mainwaring R, Hales HA, Stevenson K et al Metabolic parameter, bleeding, and weight changes in U.S. women using progestin only contraceptives Contraception 51:149, 1995

 

27

Risser WI, Gefter LR, Barratt MS et al: Weight change in adolescents who used hormonal contraception. J Adolesc Health 24:433, 1999

 

28

Danli S, Qingxiang S, Guowei S: A multicentered clinical trial of the long-acting injectable contraceptive Depo Provera in Chinese women. Contraception 62:15, 2000

 

29

Matson SC, Henderson KA, Mcgrath GJ: Physical findings and symptoms of depot medroxyprogesterone acetate use in adolescent females. J Pediatr Adolesc Gynecol 10:18, 1997

 

30

Espey E, Steinhatt J, Ogburn T et al: Depo-Provera associated weight gain in Navajo women. Contraception 62:55, 2000

 

31

Templeman C, Boyd H, Hertweck SP: Depomedroxyprogesterone acetate use and weight gain among adolescents. J Pediatr Adolesc Gynecol 13:45, 2000

 

32

Pelkman CL, Chow M, Heinbach RA et al: Short-term effects of a progestational contraceptive drug on food intake, resting energy expenditure, and body weight in young women. Am J Clin Nutr 73:19, 2001

 

33

Mauck CK, Callahan MM, Baker J et al: The effect of one injection of Depo-Provera® on the human vaginal epithelium and cervical ectopy. Contraception 60:15, 1999

 

34

Kuhn L, Denny L, Pollack AE et al: Prevalence of visible disruption of cervical epithelium and cervical ectopy in African women using Depo-Provera®. Contraception 59:363, 1999

 

35

Miller L, Patton DL, Meier A et al.Depomedroxuprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet Gynecol 96:431, 2000

 

36

Westfall JM, Main DS, Barnard L: Continuation rates among injectable contraceptive users. Fam Plann Perspect 28:275, 1996

 

37

Polaneczky M, Guarnaccia M, Alon J et al: Early experience with the contraceptive use of depot medroxyprogesterone acetate in an inner-city clinic population. Fam Plann Perspect 28:174, 1996

 

38

Cullins VE: Noncontraceptive benefits and therapeutic uses of depot medroxyprogesterone acetate. J Reprod Med 41:S5:428, 1996

 

39

Pardthaisong T, Gray R: In utero exposure to steroid contraceptives and outcome of pregnancy. Am J Epidemiol 134:795, 1991

 

40

Kaunitz AM: Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer. J Reprod Med 41:S5:419, 1996

 

41

Lumbiganon, Rugpao S, Prandha-Fung S: Protective effect of depot-medroxyprogesterone acetate on surgically-treated uterine leiomyomas: A multinational case-control study. Br J Obstet Gynaecol 103:909, 1995

 

42

Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives Int J Cancer 49:186, 1991

 

43

American College of Obstetricians and Gynecologists: Uterine leiomyomata. ACOG Technical Bulletin 192. Washington, DC, ACOG, 1994

 

44

Muse K: Hormonal manipulation in the treatment of premenstrual syndrome. Clin Obstet Gynecol 35:658, 1992

 

45

Vercellini P, De Giorgi O, Oldahi S et al: Depot medroxyprogesterone acetate versus an oral contraceptive combined with very-low-dose danazol for long-term treatment of pelvic pain associated with endometriosis. Am J Obstet Gynecol 175:396, 1996

 

46

De Ceulaer K, Hayes R, Gruber C et al: Medroxyprogesterone acetate and homozygous sickle-cell disease. Lancet 2:229, 1982

 

47

Mattson RH, Cramer TA, Caldwell BV et al: Treatment of seizures with medroxyprogesterone acetate: Preliminary report. Neurology 34:1255, 1984

 

48

Elkins TE, Gafford LS, Wilks CS et al: A model clinic approach to the reproductive health concerns of the mentally handicapped. Obstet Gynecol 68:185, 1986

 

49

Fraser IS, Dennerstein GJ: Depo-Provera use in an Australian metropolitan practice. Med J Aust 160:553, 1994

 

50

Kaunitz AM: Injectable contraception. New and existing options Obstet Gynecol Clin North Am 27:741, 2000

 

51

Eaton SB, Wood JW, Pike MC et al: Women's reproductive cancers in evolutionary context. Quart Rev Biol 69:353, 1994

 

52

Liang AP, Levenson AG, Layde PM et al: Risk of breast, uterine corpus, and ovarian cancer in women receiving medroxyprogesterone injections. JAMA 249:2909, 1983

 

53

Fredericksen MC: Depot medroxyprogesterone acetate contraception in women with medical problems. J Reprod Med 41:S5:414, 1996

 

54

Nelson AS, Zieman M: DMPA: Has it been a decade already? The Female Patient 27:57, 2002

 

55

The World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives: Breast cancer and depot medroxyprogesterone acetate: A multinational study. Lancet 338:833, 1991

 

56

Depot-medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives Int J Cancer 49:191, 1991

 

57

Skegg DC, Noonan EA, Paul C et al: Depot medroxyprogesterone acetate and breast cancer. JAMA 273:779, 1994

 

58

Kaunitz AM: Long-term use of contraceptive depot medroxyprogesterone acetate in young women impairs arterial endothelial function assessed by cardiovascular magnetic resonance [letter]. Circulation 107:67, 2003

 

59

World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Report of a WHO Scientific Group World Health Organ Tech Rep Ser 877:i–vii, 1–89, 1998

 

60

American College of Obstetricians and Gynecologists: Hormonal contraception. ACOG Technical Bulletin 198. Washington, DC, ACOG, 1994

 

61

American College of Obstetricians and Gynecologists: The use of hormonal contraception in women with coexisting medical conditions. ACOG Practice Bulletin 18. Washington, DC, ACOG, 2000

 

62

Sørensen MB, Collins P, Ong PJL et al: Long-term use of contraceptive depot medroxyprogesterone acetate in young women impairs arterial endothelial function assessed by cardiovascular magnetic resonance. Circulation 106:1546, 2002

 

63

Hashimoto M, Miyao M, Akishita M et al: Effects of long-term and reduced-dose hormone replacement therapy on endothelial function and intima-media thickness in postmenopausal women. Menopause 9:58, 2002

 

64

Banks E, Berrington A, Casabonne D: Overview of the relationship between use of progestogen-only contraceptives and bone mineral density. Br J Obstet Gynaecol 108:1214, 2001

 

65

Cromer BA, Blair JM, Mahan JD et al: A prospective comparison of bone density in adolescent girls receiving depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives. J Pediatr 129:671, 1996

 

66

Scholes D, Lacroix AZ, Ott SM et al: Bone mineral density in women using depot medroxyprogesterone acetate for contraception. Obstet Gynecol 93:233, 1999

 

67

Berenson AB, Radecki CM, Grady JJ et al: A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol 98:576, 2001

 

68

Kass-Wolff JH: Bone loss in adolescents using Depo-Provera. J Soc Pediatr Nurs 6:21, 2001

 

69

Paul C, Skegg DCG, Williams S: Depot medroxyprogesterone acetate: Patterns of use and reasons for discontinuation. Contraception 56:209, 1997

 

70

Orr-Walker BJ, Evans MC, Ames RW et al: The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women. Clin Endocrinol 49:615, 1998

 

71

Petitti DB, Piaggio G, Mehta S et al: Steroid hormone contraception and bone mineral density: A cross-sectional study in an international population. Obstet Gynecol 95:736, 2000

 

72

Scholes D, LaCroix AZ, Ichikawa LE et al: Injectable hormone contraception and bone density: results from a prospective study. Epidemiology 13:581, 2002

 

73

Kalkwarf HJ, Specker BL: Bone mineral loss during lactation and recovery after weaning. Obstet Gynecol 86:26, 1995

 

74

Sowers M, Corton G, Shapiro B et al: Changes in bone density in women with lactation. JAMA 269:3130, 1993

 

75

Cundy T, Ames R, Horne A et al: Randomized controlled trial of estrogen replacement therapy in long-term users of depot medroxyprogesterone acetate. J Clin Endocrinol Metab 88:78, 2003

 

76

Cromer BA, Smith RD, Blair JM et al: A prospective study of adolescents who choose among levonorgestrel implants (Norplant), medroxyprogesterone acetate (Depo-Provera), or the combined oral contraceptive pill as contraception. Pediatrics 94:687, 1994

 

77

Davis AJ: Use of depot medroxyprogesterone acetate contraception in adolescents. J Reprod Med 41:S5:407, 1996

 

78

O'Dell C, Forke C, Polaneczky M et al: Depo-Provera vs. oral contraceptive use by postpartum adolescents (abstract) J Adolesc Health 20:127, 1997

 

79

Chotnopparatpattara P, Taneepanichskul S: Use of depot medroxyprogesterone acetate in Thai adolescents. Contraception 62:137, 2000

 

80

Templeman CL, Cook V, Goldsmith LJ et al: Postpartum contraceptive use among adolescent mothers. Obstet Gynecol 95:770, 2000

 

81

Henshaw SK: Unintended pregnancy in the United States. Fam Plann Perspect 309:24, 1998

 

82

Achievements in public health, 1900–1999. MMWR Morb Mortal Wkly Rep 48:1073, 2002

 

83

Gray RH, Campbell OM, Zacur HA et al: Postpartum return of ovarian activity in nonbreastfeeding women monitored by urinary assays. J Clin Endocrinol Metab 64:645, 1987

 

84

Speroff L, Darney P: A Clinical Guide for Contraception, p 322 3rd ed. Baltimore, Williams and Wilkins, 2001

 

85

Guiloff E, Ibarra-Polo A, Zanartu J et al: Effect of contraception on lactation. Am J Obstet Gynecol 118:42, 1974

 

86

Karim M, Ammar R, El Mahgoub S et al: Injected progestogen and lactation. Br Med J 1:200, 1971

 

87

Jungers P, Dougados M, Pelissier C et al: Influence of oral contraceptive therapy on the activity of systemic lupus erythematosus. Arthritis Rheum 25:618, 1982

 

88

Sotaniemi EA, Hynnynen T, Ahlqvist J et al: Effects of medroxyprogesterone on the liver function and drug metabolism of patients with primary biliary cirrhosis and chronic active hepatitis. J Med 9:117, 1978

 

89

Back DJ, Orme ML: Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 18:472, 1990

 

90

Haukkamaa M: Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment. Contraception 33:559, 1986

 

91

Trussell J, Leveque JA, Koenig JD et al: The economic value of contraception: A comparison of 15 methods. Am J Public Health 85:494, 1995

 

92

Gold RB, Richards CL: Improving The Fit: Reproductive Health Services in Managed Care Settings. New York, Alan Guttmacher Institute, 1996

 

93

Morrison JC, Martin DC, Blair RA: The use of medroxyprogesterone acetate for relief of climacteric symptoms. Am J Obstet Gynecoil 138:99, 198

 

94

Burger HG: Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition3/4an analysis of FSH, oestradiol and inhibin. Eur J Endocrinol 130:38, 1994

 

95

Castracane VD, Gimpel T, Goldzieher JW: When is it safe to switch from oral contraceptives to hormonal replacement therapy? Contraception 52:371, 1995

 

96

Creinin MD: Laboratory criteria for menopause in women using oral contraceptives. Fertil Steril 66:101, 1996

 

97

Gebbie AE, Glasier A, Sweeing V: Incidence of ovulation in perimenopausal women before and during the menopausal transition. Contraception 52:221, 1995

 

98

McKinlay SM, Bifano NL, McKinlay JB: Smoking and age at menopause in women. Ann Intern Med 103:350, 1985

 

99

Stanford JL, Hartge P, Brinton LA et al Factors influencing the age at natural menopause. J Chronic Dis 40:995, 1987

 

100

Newton JR, d'Arcangues C, Hall PE: Once-a-month combined injectable contraceptives. J Obstet Gynaecol 14:S1:S1, 1994

 

101

World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-Acting Systemic Agents for Fertility Regulation: A multicentered Phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection: II. The comparison of bleeding patterns Contraception 40:531, 1989

 

102

World Health Organization special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Long-Acting Systemic Agents for Fertility Regulation: A multicentered Phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection: I. Contraceptive efficacy and side effects Contraception 37:1, 1988

 

103

Hall PE and the Task Force on Research on Introduction and Transfer of Technologies for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization: The introduction of Cyclofem into family planning programmes: Experiences from studies in Indonesia, Jamaica, Mexico, Thailand and Tunisia. Contraception 49:489, 1994

 

104

Sang GW, Shao QX, Ge RS et al: A multicentered phase II comparative clinical trial of Mesigyna, Cyclofem and injectable No. 1 given by intramuscular injection to Chinese women: I. Contraceptive efficacy and side effects Contraception 51:167, 1995

 

105

Sang GW, Shao QX, Ge RS et al: A multicentered phase III comparative clinical trial of Mesigyna, Cyclofem and injectable No. 1 given by intramuscular injection to Chinese women: II. The comparison of bleeding patterns Contraception 51:185, 1995

 

106

Cuong DT, My Huong NT: Comparative phase III clinical trial of two injectable contraceptive preparations, depot-medroxyprogesterone acetate and Cyclofem, in Vietnamese women. Contraception 54:169, 1996

 

107

Kaunitz AM, Garceau RJ, Cromie MA: and the Lunelle Study Group: Comparative safety, efficacy, and cycle control of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum® 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic). Contraception 60:179, 1999

 

108

Kaunitz AM: Injectable long-acting contraceptives. Clin Obstet Gynecol 44:73, 2001

 

109

Bahamondes L, Lavin P, Ojeda G et al: Return of fertility after discontinuation of once-a-month injectable contraceptive Cyclofem®. Contraception 55:307, 1997

 

110

Garceau RJ, Wajszczuk CJ, Kaunitz AM: Lunelle Study Group: Bleeding patterns of women using Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) compared with those of women using Ortho-Novum® 7/7/7 (norethindrone/ethinyl estradiol triphasic) or other oral contraceptives. Contraception 62:289, 2000

 

111

Belsey EM, Pinol APY: and Task Force on Long-Acting Systemic Agents for Fertility Regulation: Menstrual bleeding patterns in untreated women. Contraception 55:57, 1997

 

112

Cromie MA, Maile MH, Wajszczuk: and Investigators from the Lunelle Study Group: Comparative effects of Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension) and Ortho-Novum® 7/7/7 oral contraceptive (norethindrone/ethinyl estradiol triphasic) on lipid profiles. Contraception 61:51, 2000