Adolescent Health Care: A Practical Guide

Chapter 47

Long-Acting Progestins

Anita L. Nelson

Long-acting progestin contraceptives have many features that make them particularly attractive to female adolescents. They are in the top tier of efficacy, are long lasting, safe, and convenient. Because they contain no estrogen, progestins may be used by women with contraindications to that hormone, including history of thrombosis. Long-acting progestin contraceptives are available in three different delivery systems—injections, implants, and intrauterine contraceptives. The levonorgestrel intrauterine system (LNG-IUS) is discussed in Chapter 44. The injections are currently available in two different formulations. The levonorgestrel-releasing (LNG) implants have not been available in the United States since 1998. However, the single-rod etonogestrel-releasing (ENG) implant was approved by the U.S. Food and Drug Administration (FDA) in July 2006 and is becoming increasingly available in the U.S.

Injectable Progestins

Today, there are two different formulations of depot medroxyprogesterone acetate (DMPA) available in the United States—the traditional 150 mg formulation (Depo-Provera, Pfizer Inc., Kalamazoo MI), which is injected intramuscularly every 11 to 13 weeks (DMPA-IM) and a newer formulation with different buffers (depo-subQ provera 104, Pfizer Inc., New York, NY), which is administered subcutaneously every 12 to 14 weeks (DMPA-SC). The two formulations have very similar labeling and side effect profiles.

Efficacy

The failure rate with correct and consistent use of the DMPA-IM is 0.3%. However, recalculation of typical-use failure rates to reflect potential late returns for reinjection yields a typical-use failure rate of 3% (Trussell, 2004). O'Dell et al. (1998) compared DMPA and oral contraceptives (OCs) in postpartum female adolescents and found that the DMPA users had median duration of use of 8.1 months compared to 5.4 months for OC users. More importantly, the repeat pregnancy rates by 15 months were lower in the DMPA users (15%) as compared to OC users (36%).

In clinical trials involving 16,023 women-cycles of DMPA-SC use, there were no pregnancies (Jain et al., 2004b). Importantly, patient weight did not influence efficacy. The clinical trials included women with body mass indices (BMIs) that ranged from 18.2 to 46.7 kg/m². Typical-use failure rates are not yet available.

Mechanisms of Action

DMPA is a contraceptive agent; that is, it prevents fertilization. DMPA has two primary contraceptive mechanisms of action. DMPA thickens cervical mucus to prevent sperm entry into the upper genital track and it suppresses gonadotropin levels, especially at midcycle, which blocks ovulation (Jain et al., 2004a). The progestin also alters the endometrial lining, which has profound impacts on bleeding patterns, but has not been demonstrated to affect efficacy. Similarly, progestin may also affect tubal motility, but the clinical relevance of that observation is not known. There were no ectopic pregnancies in recent clinical trials with DMPA-SC (Jain et al., 2004b).

Drug Interactions

Aminoglutethimide increases hepatic clearance of DMPA and, if administered concomitantly with DMPA, may significantly depress serum concentrations of medroxyprogesterone acetate. Some antiretroviral medications impact cytochrome P-450 activity, but have not been reported to affect DMPA efficacy. Anticonvulsants do not detract from the contraceptive protection afforded by DMPA.

Contraindications

The list of medical contraindications is limited. From labeling, the following conditions are listed as contraindications:

Contraindications Comments Known or suspected pregnancy No clinical benefit offered Undiagnosed vaginal bleeding May delay diagnosis of pathology Known or suspected malignancy of breast Receptor positive cancers can respond to progestin

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Contraindications Comments Active thrombophlebitis, or current or past history of thromboembolic disorders or cerebral vascular disease No evidence progestin impacts coagulation factors Significant liver disease Hepatic clearance needed Allergy to medroxyprogesterone acetate (MPA) or its ingredients Rare

World Health Organization (WHO) has even fewer medical contraindications for DMPA use. The only condition that is rated by WHO as category 4 (should not use) is current breast cancer. Conditions with WHO categories 3 or 4 ratings are listed in Table 47.1.

Administration

Labeling for both DMPA products advises that injections in women with regular cycles should be administered in the first 5 days of a normal menstrual cycle. It also states that women who are switching from other contraceptive methods should be given the first dose in a manner that ensures continuous contraceptive coverage. According to labeling, breast-feeding women wait 6 weeks after delivery for their first injection. Reinjections for DMPA-IM are to be scheduled in 11 to 13 weeks; reinjections for DMPA-SC are to be in 12 to 14 weeks. Avoid massaging the injection site after injection because early massage increases the surface area of the drug, allows faster absorption, and results in shorter effective life.

For female adolescents, these recommendations for injection can be too restrictive. Often teens are in immediate need of contraception. Female adolescents often follow a “start–stop” pattern of DMPA use (Polaneczky and Liblanc, 1998). After one or two injections, teens may discontinue DMPA use or switch to another method such as patches, OCs, or condoms, although quite frequently they return later for at least another injection of DMPA. In part, this intermittent pattern of use reflects the dynamics of adolescent sexual activity and relationships. However, in part it reflects the young woman's coping with side effects (see subsequent text).

Whatever the pattern of use is over time, it is important to be ready to administer the injections in response to the young woman's needs. Because of these needs, the WHO advises that women can have their first DMPA injection within the first 7 days of menses without the need for back-up contraceptives (World Health Organization, 2005). WHO guidelines also state that a woman can have a DMPA injection at any other time in the cycle if it is reasonably certain that she is not pregnant. If she is beyond the first 7 days of her cycle, she should abstain from intercourse or use an additional contraceptive method for 7 days after her off-label injection time. Petta et al. (1998) demonstrated that cervical mucus becomes impenetrable within 7 days of injection at any time in the cycle. If there has been recent unprotected intercourse, WHO also suggests that emergency contraception be offered. Reassuringly, Borgatta et al. (2002) found no fetal anomalies with intrauterine exposure to DMPA.

One algorithm used to expedite DMPA start/restart (Quick Start or Same-day Start) is outlined in Figure 47.1. The Quick Start or Same-day Start DMPA injection has been shown to save 46% of women a return visit for injection (Balkus and Miller, 2005). The pregnancy rate among the same-day starters was <1% (1 of 104); there is no known harm done by early intrauterine exposure to DMPA.

In a second study, researchers offered Quick Start OCs as a bridge to DMPA injection, which was done at the time of the OC-withdrawal bleeding. They reported that 86% of the women were satisfied with this bridge (Morroni et al., 2004). This underscores the need for immediate effective contraception.

Advantages

1. Extremely effective: Pregnancy protection is excellent, although that feature is not highly prized by teens themselves. Only 15% of those interviewed cited that as a reason for selecting DMPA (Harel et al., 1995).
2. Private: With DMPA there is no external evidence of contraceptive use (no pill packs or condoms to hide), but itemized insurance bills or changes in needs for sanitary protection may raise adult suspicions.
3. Convenient and low maintenance: Many studies have found that this feature is “most important” or “likely important” to 89.3% of teens surveyed (Harel et al., 1995). This same survey found that the most important reason teens continued to use DMPA was that “they didn't have to take the pill every day” (54%), and the second reason was that it was “easier to take” than their previous method (16%). Most teens were not concerned about the need for return to health care providers for reinjection.
4. Cost-effective without high initial cost: Because payment for DMPA is almost “pay as you use it,” DMPA can initially be more affordable than implants or intrauterine contraceptives.
5. Intermediate-term method with built-in grace period.
6. No estrogen contraindications or side effects.
7. Frequent amenorrhea with long-term use: This is helpful for busy women, athletes, patients with anemia, those with human immunodeficiency virus (HIV) infection, those with coagulopathies or renal failure, those taking anticoagulants, and mentally challenged women.
8. Reduced incidence of painful sickle cell crises (de Abood et al., 1997).
9. Decreased risk of endometrial and, perhaps, epithelial ovarian cancer.
10. May be used off label by breast-feeding women after delivery (Halderman and Nelson, 2002). Providing convenient and reliable contraception to teen mothers can make a significant contribution in reducing the rate of repeat pregnancies.
11. Thick cervical mucus and amenorrhea: This limits the incidence of pelvic inflammatory disease in patients with cervicitis.
12. DMPA-SC is also used to treat symptomatic endometriosis (Crosignani et al., 2005).

Metabolic Impacts

Because there is no estrogen component, DMPA causes no alterations in coagulation factors, angiotensinogen, or hepatic globulin production. Blood pressure (BP)

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measurements are unchanged with DMPA (World Health Organization Expanded Programme of Research, Development and Research Training in Human Reproduction Task Force on Long-Acting Systemic Agents for Regulation of Fertility, 1983). However, the serum levels of progestin with the injections are higher than is seen with the implants or intrauterine contraceptives. DMPA has greater impact on glucose tolerance, insulin levels, and lipid profiles. For healthy subjects, the changes in glucose tolerance are not clinically significant (Liew et al., 1985). Teens with glucose intolerance or overt diabetes must be monitored closely when using the DMPA injections. However, because glucose and insulin levels are increased during DMPA use. DMPA can lower total cholesterol (TC) and triglycerides; it has a negligible impact on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) (Deslypere et al., 1985).

TABLE 47.1 World Health Organization 2004 Medical Eligibility Criteria for Contraceptive Use

I, initiation; C, continuation; POCs, progestogen-only contraceptives; DMPA, depot medroxyprogesterone acetate; LNG, levonorgestrel-releasing; ENG, etonogestrel-releasing. WHO Categories: 1. A condition for which there is no restriction for the use of the contraceptive method 2. A condition where the advantages of using the method generally outweigh the theoretical or proven risks 3. A condition where the theoretical or proven risks usually outweigh the advantages of using the method 4. A condition which represents an unacceptable health risk if the contraceptive method is used Category Conditions with Category 3 and/or Category 4 DMPA LNG/ENG Implant Clarifications/Evidence Breast-feeding <6 wk postpartum 3 3 Clarification: There is concern that the neonate may be at risk of exposure to steroid hormones during the first 6 wk postpartum. However, in many settings pregnancy morbidity and mortality risks are high, and access to services is limited. In such settings, POCs may be one of the few types of methods widely available and accessible to breast-feeding women immediately postpartum. Evidence: Studies have shown that among breast-feeding women <6 wk postpartum, progestogen-only contraceptives did not affect breast-feeding performance, and infant health and growth. However, there are no data evaluating the effects of progestogen exposure through breast milk on brain and liver development. Multiple risk factors for arterial cardiovascular disease (such as older age, smoking, diabetes, and hypertension) 3 2 Clarification: When multiple major risk factors exist, risk of cardiovascular disease may increase substantially. The effects of DMPA may persist for some time after discontinuation. Hypertension · Elevated blood pressure levels (properly taken measurements) systolic >160 mm Hg or diastolic > 100 mm Hg · Vascular disease 3 2 Evidence: Limited evidence suggests that among women with hypertension, those who used progestogen-only injectables had a small increased risk of cardiovascular events compared with women who did not use these methods. Deep venous thrombosis (DVT)/Pulmonary embolism (PE) Current DVT/PE 3 3 Current and history of ischemic heart disease 3 I C 2 3 Stroke (history of cerebrovascular accident) 3 I C 2 3 Headaches I C I C Migraine with aura, at any age 2 3 2 3 Unexplained vaginal bleeding(suspicious for serious underlying condition) Before evaluation 3 3 Clarification: If pregnancy or an underlying pathological condition (such as pelvic malignancy) is suspected, it must be evaluated and the category adjusted after evaluation. Breast disease 4 4 Breast cancer · Current · Past and no evidence of current disease for 5 years 3 3 Diabetes · Nephropathy/retinopathy/neuropathy · Other vascular disease or diabetes of >20 years' duration 3 2 Viral hepatitis Active 3 3 Cirrhosis Severe (decompensated) 3 3 Liver tumors 3 3 Drugs which affect liver enzymes · Rifampicin · Certain anticonvulsants (phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine) 2 3 Clarification: Although the interaction of rifampicin or certain anticonvulsants with LNG/ENG implants is not harmful to women, it is likely to reduce the effectiveness of LNG/ENG implants. Use of other contraceptives should be encouraged for women who are long-term users of any of these drugs. Evidence: Use of certain anticonvulsants decreased the contraceptive effectiveness of POCs.

Disadvantages

1. Side effects (see later discussion).
2. Must continue to remind patients of the need for safer sex practices and provide a method to reduce the risks of sexually transmitted infections (STDs).
3. Requires medical intervention (unless self injection of subcutaneous DMPA becomes available). A hotline is available 24 hours a day, 7 days a week in English and Spanish to answer patient's questions and to remind patients about appointments for reinjection (1-866-554 DEPO (3376)).

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4. Delays return to fertility: Average delay is 10 months after last injection but there is considerable variation in that estimate. Higher BMIs are associated with slower return to fertility.
5. Immediate anaphylactic reactions (extremely rare).

FIGURE 47.1 Quick Start DMPA. Initial injection or late reinjection (>13 weeks since last injection) of DMPA. DMPA, depot medroxyprogesterone acetate; EC, emergency contraception; UCG, urinary chorionic gonadotropin. (From Nelson AL, Haatcher RA, Zieman M, et al. A pocket guide to managing contraception, 3rd ed. Tiger, GA: Bridging the Gap Foundation, 2002:117.)

Side Effects

1. Menstrual changes: Missed menstrual periods and amenorrhea become more common over time with DMPA. After the first year of use, approximately 50% of DMPA users are amenorrheic, and after 2 years that number rises to 75%. With the initial 1 to 3 injections, many women experience significant unscheduled menstrual spotting, and bleeding. Early reinjection (at 6 weeks) did not alter the bleeding episodes, onset of bleeding, or total days of bleeding after the second injection, compared with standard timing of reinjection (Harel et al., 1995). Similarly, the practice of giving a 300-mg dose initially is notrecommended, because the risk of developing other side effects is proportionately increased. Although there are no studies of effective interventions, clinicians often advise short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen 800 mg orally 3 times a day for 3 days) or low-dose estrogen supplementation to reduce immediate bleeding irregularities. Research is now underway to understand the impacts progestin-only methods have on the endometrium and its underlying vascular supply in order to develop more targeted therapies to deal with the unscheduled spotting and bleeding.
2. Bone mineral density (BMD) changes: Controlled cross-sectional studies of older, long-term DMPA users found that, although the BMD of DMPA users was statistically significantly lower than that of controls, BMD measurements normalized after women stopped using DMPA. Former users of DMPA have BMD measurements identical to that of never users (Orr-Walker et al., 1998; Petitti et al., 2000). For women who have completed bone

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formulation, DMPA may create temporary, probably reversible decreases in bone mineralization, akin to the changes seen during pregnancy and lactation.

The impact that DMPA may have on decreasing BMD through suppression of estrogen is a critical issue for teens, because most lifetime bone mineralization occurs during adolescence. Several studies have demonstrated that many female adolescents using DMPA not only fail to increase their BMD as expected but they may also experience bone loss, such that their BMD measurements on DMPA are lower than they were at baseline. One recent study has demonstrated that adolescent DMPA users had 4% to 7% decrease in BMD compared to unprotected controls. Partial recovery of BMD was seen in many women in short-term follow-up after DMPA discontinuation.

The FDA issued a black box warning for both formulations of DMPA advising “Women who use Depo-Provera Contraceptive Injection may lose significant BMD. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fractures in later life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (e.g., >2 years) only if other birth control methods are inadequate.” The labeling also advises that if prolonged use is contemplated, the patient's BMD should be evaluated.

Unfortunately, this recommendation has led to some confusion in female adolescents. Using the T-score, which compares the teen's BMD to the peak BMD of a healthy 20- to 30-year-old woman, will predictably demonstrate “osteopenia” or “osteoporosis.” Younger women have not yet reached their peak bone mass. The California Office of Family Planning sent clinicians' recommendations that “Bone mineral density screening should not be recommended to a client for the sole purpose of evaluating appropriateness of DMPA usage” (Office of Family Planning, 2005). If there is to be a dual-energy x-ray absorptiometry (DXA) evaluation, it is important to focus on the Z-score, which compares the patient's BMD to that of age-matched controls to see if the patient has any bone-related concerns that should be considered when deciding to continue DMPA use beyond 2 years.

An alternative approach to use when evaluating female adolescents for prolonged DMPA use is to determine if the young woman has other underlying risks for low BMD, such as family history of osteoporosis, heavy cigarette smoking, corticosteroid use, eating disorders, or excessive exercise patterns. For women without additional risk factors for low BMD, many experts believe that the 2-year restriction appears unwarranted (Dialogues in Contraception Editorial Board, 2005). All adolescents, whether they use DMPA or not, should be advised to consume at least 1,300 mg calcium and adequate vitamin D (minimum of 200–400 IU) to ensure maximal bone accretion. O'Brien et al. (2003) have demonstrated that higher calcium intake by adolescent women, even in pregnancy, protects against trabecular bone loss. For women with additional risk factors for low BMD, possible health risks associated with prolonged DMPA use should be balanced against the patient's ability and likelihood of effectively using alternative effective means of contraception. Some experts have recommended measuring a woman's follicle-stimulating hormone (FSH) or estradiol level just before reinjection to determine if DMPA use has induced hypoestrogenemia. If not, her risks of BMD loss is likely minimal (Beksinska et al., 2005). The addition of estrogen supplements is protective of bone in adolescent girls who receive DMPA for contraception (Cromer et al., 2005) and may be a prudent option for women who do not have contraindications to that hormone. In 20 women with endometriosis, the use of DMPA-SC was shown to have significantly less impact on BMD than leuprolide (Crosignani et al., 2005).

3. Hypoestrogenic symptoms: Most users of DMPA maintain adequate estradiol levels in the follicular range. However, in a small percentage of users, ovarian hormonal production is more profoundly suppressed and estradiol levels can fall into the postmenopausal range. These patients may complain of dry vagina, dyspareunia (Miller et al., 2000), and even hot flashes. Once other causes have been excluded, these symptoms respond well to physiological estrogen supplementation or to a change in method (e.g., vaginal contraceptive ring).
4. Weight changes: Despite widespread belief that DMPA use increases weight, clinical trials do not consistently support any attributable risk for weight gain. Complicating the analysis is the fact that U.S. women gain an average of >2 lb/year regardless of the contraceptive method used. Female adolescents gain even more weight. Furthermore, individual weight changes vary considerably.

Uncontrolled studies conducted in the late 1960s and in the 1970s showed that women who used DMPA had a mean weight increase of 5 lb during the first year, 1 lb by 2 years, and 13.8 lb by 4 years (Schwallie and Assenzo, 1974). Moore et al. (1995) monitored women who used OCs, DMPA, or implants for 1 year and found no significant weight gain in any group; the average weight gain with DMPA use was +0.1 lb. Cromer et al. (1994) did not note weight gain in teens with DMPA use, but Harel et al. (1996) found DMPA-associated weight gain, which persisted for 6 months after discontinuance. Risser et al. (1999) reported weight gains of 3 to 4.5 lb while using DMPA; heavier teens had greater gains. The only double blind, placebo-controlled study of this issue was for a short term, but found no weight changes in DMPA users compared to either baseline weight or to placebo control (Pelkman et al., 2001). Importantly, DMPA users had no change in their appetite or basal metabolic rates. There may be subgroups of women who are more susceptible to weight gain with DMPA use; Templeman et al. (2000) reported a 9.8 lb (±10.5 lb) weight gain. Given that obesity is a growing major public health problem in the United States, ongoing evaluation of and education about weight is a part of quality health care. However, theoretical concerns about potential adverse impacts that DMPA could have on her weight in the absence of a patient's personal experience should not preclude the use of injectable contraception.

5. Breast tenderness: Mastalgia is reported in 15% to 20% of women starting DMPA, but this side effect usually decreases rapidly.
6. Mood disturbances: Although there is no consistent evidence that DMPA use causes psychological side

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effects, such as nervousness, insomnia, somnolence, fatigue, dizziness, and depression, labeling mentions these as possible side effects. Many patients with chronic depression tolerate DMPA, but use in those cases must be individualized (Kaunitz, 1999). Westhoff (1996) reported that community epidemiological survey depression scores after DMPA did not change compared with baseline scores, but Civic et al. (2000) reported an increased likelihood that DMPA users would report depressive symptoms, compared with nonusers.

7. Headaches: Progestin may increase headaches by increasing fluid retention, but no placebo-controlled study results are available.
8. Other changes: Acne, alopecia, hirsutism, fluid retention, changes in libido, changes in cervical secretions, nausea, cholestatic jaundice, and local skin reaction to injection have been reported but have seldom been serious enough to warrant a change in method.

Summary

DMPA-IM and DMPA-SC are attractive contraceptive options for female adolescents. They provide top-tier efficacy, are low in maintenance, and are safe. The side effect profile and the need for periodic reinjection pose challenges for long-term continuation. Adolescents at risk for STDs need to use dual methods (male condoms) to meet all their reproductive needs.

Etonogestrel-Releasing Implant

Subdermal implants provide long-acting, extremely effective, rapidly reversible contraception that requires little user effort. Progestin-only implants avoid estrogen side effects and can be used by virtually every woman. There are only a few medical conditions that were rated 3 (risks usually outweigh advantages) or 4 (unacceptable health risk) for implant use in the WHO 2004 medical eligibility criteria for contraceptive use; they are listed in Table 47.1.

Clinical experience with the LNG implant (Norplant 6 Contraceptive System, Wyeth, Philadelphia, PA) suggested new properties and features that would be important for the next generation of implants. These features included a single-rod system (to simplify insertion and removal), release of hormones sufficient to inhibit ovulation (to increase acceptance of the method), a duration of action of at least 2 to 3 years (for effective birth spacing), and a smaller diameter implant (to allow for use of an injection system for insertion). These features have been incorporated into the ENG implant.

The ENG implant (Implanon, NV Organon, Oss, the Netherlands) is available in more than 30 countries, including the United Kingdom, Chile, Australia, Indonesia, and 10 European countries. It has been used by more than 2 million women worldwide since 1999.

Description of System

The ENG implant is a single-rod contraceptive implant made of a core and a membrane. The core consists of steroid microcrystals containing 68 mg etonogestrel (3-ketodesogestrel) imbedded in a rod of ethylene vinyl acetate (EVA) copolymer. This core is covered by a thin EVA copolymer membrane measuring 0.06 mm. The implant is 40 mm long and has an external diameter of 2 mm. ENG (the biologically active metabolite of desogestrel) has no demonstrated estrogenic, anti-inflammatory, or mineralo-corticoid activity, but it does have weak androgenic and anabolic activity and strong antiestrogenic activity. The relative binding affinity of ENG to progesterone receptors in rat uterine activity is 10 times greater than that of progesterone (Jordan, 2002). The implant provides contraceptive protection at least for 3 years. The ENG implant comes individually packaged in the needle of a sterile, disposable, specifically designed inserter for subdermal placement.

Mechanisms of Action

The ENG-implant was developed specifically to inhibit ovulation. It acts as a contraceptive to prevent fertilization by providing sustained release of a relatively low dose of contraceptive hormone. Dose finding studies concluded that a release rate of 25 to 30 µg ENG per day, resulting in serum levels of 90 pg/mL, would be needed to inhibit ovulation (Wenzel et al., 1998). No ovulation was found in any test cycle during the first 2 years of ENG implant use. Ovulation was first seen at 30 months; two women (3.1% of subjects) ovulated at least once from 30 to 36 months of use (Makarainen et al., 1998; Davies et al., 1993). With those exceptions, gonadotropin studies showed a consistent prevention of luteinizing hormone (LH) surges. The progestins also make the cervical mucus viscous and impenetrable by sperm, so fertilization does not take place (Meirik et al., 2003; Croxatto, 2002).

However, in contrast to DMPA, ENG implant use does not cause hypoestrogenemia. There was interindividual variability, but no consistently high or low estradiol (E₂) levels were seen; 95% of the measures were more than 110 pmol/L. Although ovulation is inhibited effectively, by year 1, FSH and estradiol serum levels were consistent with follicular development in most subjects (Makarainen et al., 1998).

ENG impacts on the endometrium are measurable. The mean value of the endometrial stripe determined by transvaginal ultrasound was 4 mm. Endometrial biopsies did not show atrophy but showed inactive or weakly proliferative endometrium (Jordan, 2002). Sperm transport in the uterus and fallopian tubes also was slowed. However, because both ovulation suppression and cervical mucus viscosity prevented the union of gametes, these impacts on the endometrium and the tube may be superfluous (Glasier, 2002).

There is no accumulation of ENG over time. The average half-life (t_1/2) elimination of ENG is approximately 25 hours, which is much lower than the 42 hours found with the LNG implant system. However, ENG is lipophilic, so women with higher BMIs are expected to have greater volumes of distribution and longer t_1/2 elimination (40 hours in heavier women versus 20 hours in lighter women) (Wenzl et al., 1998). The variation in half-lives of elimination and the variation in serum concentrations of hormones are much smaller with ENG implant than with the LNG implants (Makarainen et al., 1998). Etonogestrel is bound mainly to albumin, in contrast to levonorgestrel binding to sex hormone binding globulin, which is more sensitive to circulating estradiol levels (Wenzl et al., 1998).

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Contraceptive Efficacy

The core data set includes 1,716 women from more than a dozen representative countries, who were treated for 53,530 cycles. No pregnancies were seen in ENG-implant users, resulting in a Pearl index of 0.0 (0.00–0.09). Additional studies in the United States and China raised the total number of woman-cycles, all without any pregnancies. Efficacy in heavier women was not so well studied. Only 365 women who weighed ≥70 kg were reported in the literature. However, none of these women experienced any pregnancies (Newton and Newton, 2003).

After more than 200,000 ENG implant devices had been placed in Australia, Harrison-Woolrych et al. (2005) analyzed the 218 pregnancies reported with ENG-implant use. Researchers could not determine cause in 45 cases, but of the remaining 173 women the greatest single reason for “failure” of the device (84 women; 48.6%) was that the clinician had never actually inserted the rod. The second most frequent cause of implant “failure” (46 women; 26.6%) was that the patient was already pregnant before insertion. Only 13 pregnancies were attributed to product failure. Therefore, the failure rate was <1/1,000. Many of these problems have been corrected in Australia (Wenck and Johnston, 2004). The lessons learned from these postmarketing experiences in Australia have been incorporated into the training. U.S. clinicians are being given information about patient selection and thorough training in insertion and removal techniques.

Drug Interactions

Serum ENG levels are quite low. Concomitant use with other drugs that enhance cytochrome P-450 activity reduces implant efficacy. WHO lists anticonvulsants and other drugs as a category 3 for this reason (World Health Organization, 2004) (Table 47.1).

Return to Fertility

In four studies involving 32 women, return to ovulation after implant removal was studied by ultrasound or serum progesterone concentrations for up to 3 months; 30 of 32 (94%) women demonstrated return to fertility, usually within 3 weeks of removal (Davies et al., 1993). Because return to ovulation is rapid after implant removal, women desiring continued pregnancy prevention should begin another method immediately or have a new rod inserted through the incision made for removal (Cherry, 2002).

Continuation Rates

Continuation rates in the clinical trials varied considerably by country. Overall 81.8% of women continued to use the ENG implant for up to 24 months (Edwards and Moore, 1999). In Europe and Canada, continuation rates were 70% during the study. In Southeast Asia, continuation rates were 99%.

Since its introduction into mainstream use in Britain, Smith and Reuter (2002) have reported that in three clinical services in that country, the 6-month continuation rates ranged between 84% and 88%, and the 12-month continuation rates were 67% to 78%. Smith and Reuter (2002) found that intolerance of side effects and a change of mind about wanting contraception were leading reasons for requesting removal. Recent U.S. continuation rates were similar to the British experience; 67% continued for 1 to 2 years.

Breast-feeding Women

In an open, comparative, nonrandomized trial of breast-feeding women 6 weeks postpartum, the effects of the ENG implant on 42 women were contrasted with those seen in 38 women using a nonmedicated intrauterine device (IUD). The volume of breast milk production and the quality of milk content (total fat, total protein, and lactose) were not affected by the use of the ENG implant. The timing and quantity of supplementary feedings did not differ between the groups. There were no statistically significant differences in the growth parameters in the infants (Reinprayoon et al., 2000). However, the authors agreed with the WHO recommendation that insertion of ENG implant be delayed until the infant is 6 weeks old, because the risk of pregnancy is low during the first 3 weeks postpartum and because of the absence of knowledge about the impact on the newborn's central nervous system during its rapid early extrauterine development period (World Health Organization, 2004; Reinprayoon et al., 2000; Diaz, 2002).

Insertion

The ENG implant comes packaged in a preloaded, sterile, disposable inserter. Clinicians must be trained and maintain their competency in the appropriate insertion and removal techniques. Insertion of ENG implant is fundamentally different from the techniques used for LNG implant. ENG implant should be inserted during the first 5 days of a woman's menstrual cycle. An area is identified on the medial aspect of the nondominant upper arm, 6 to 8 cm above the elbow, in the sulcus between the biceps and the triceps. The skin is cleansed with an antiseptic agent. A small amount (<0.5 cc) of local anesthetic with lidocaine is infused. The needle of the syringe with the implant loaded in is introduced directly under the skin and advanced in the subdermal layer while tenting the skin until the needle hub is at the level of the skin. The obturator is rotated 90 degrees, moving the plunger into position. Stabilizing the base, the needle is smoothly retracted, leaving the implant behind. The implant remains invisible for most women, but it is easy to palpate. It is important to palpate the area immediately after the removal of the insertion needle to confirm implant placement. Pressure is applied to the skin incision site for hemostasis. A steristrip is placed to close the incision. Routine precautions should be provided for postinsertion care.

In clinical trials, the time for insertion from the skin entry to complete insertion was 1 minute. It should be noted that this does not include the time for preparation or anesthetic injection and onset of action.

There was a low complication rate with insertion in the clinical studies; only 10 out of 1,710 (0.6%) women reported complications. The most common were bleeding at insertion site or failure of the insertion device. No expulsions occurred, but 1% of women complained of pain at the insertion site at some time during the trial (Edwards and Moore, 1999).

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Removal

Removal of ENG implants is distinctly more straightforward than the removal of the LNG capsules for several reasons. First, the single-rod system requires the removal of only one implant, not six. Secondly, the ENG rod is stiffer than the LNG capsules and is easier to palpate for localization at the time of removal. With LNG capsules insertion, the position of previous capsules could be disturbed by the placement of later ones—the so-called “U-ing” of capsules where the advancing trocar could catch the edge of a previously inserted implant and displace it upward in the arm. The single-rod system does not have the potential for those complications. And finally, the EVA capsule of the ENG rod induces less fibrous formation around the rod than did the silastic LNG capsules.

The digital extrusion or “pop out” technique is encouraged for removal. In the “pop out” technique, the rod is first palpated, and the area is cleansed. Approximately 0.5 to 1.0 cc of local anesthetic is infused beneath the distal tip of the rod. A 2 mm incision parallel to the rod is made at the distal tip of the implant. Then pressure is applied at the proximal end, pushing the rod toward the incision until it pops out, at which time it can be grasped with fingers or forceps (Darney et al., 1992). Instrument removal with noncrushing clamps also may be utilized. In clinical studies, the ENG implant was removed in less than 5 minutes in most women.

It should be noted that because there is no free drug inside the capsule, a broken capsule is not associated with spillage of medication as it might have been with the LNG capsules. Although the ENG rod is firmer and stiffer than the LNG capsules, it is possible that the rod may be placed so deeply that it is not palpable. ENG is not easily visualized with plain film x-rays. Lantz et al. (1997) have demonstrated that nonpalpable ENG rod implants can be best visualized under ultrasound guidance, indirectly by identifying the posterior acoustic shadow cast by the implant.

Capsule Fracture

The ENG rod is very robust. There are only two case reports of fractures of the capsule in situ. In one case, the fracture occurred after a “rough and tumble” with the subject's 7-year-old son (Pickard and Bacon, 2002). In the second case, no cause for the broken capsule was identified (Agrawal and Robinson, 2003).

Advantages

1. Extremely effective: No pregnancies were reported in clinical trials. Rates in clinical practice are only 1 in 1,000 users.
2. Private: Implants are not generally visible, but the same factors that compromise DMPA privacy occur with implants.
3. Convenient and low maintenance: One office insertion procedure provides up to 3 years of contraceptive protection.
4. Cost-effective.
5. No estrogen contraindications or side effects.

Metabolic Impacts

Bone Mineral Density

There has been concern that ovarian suppression with DMPA may be associated with bone loss secondary to estrogen deficiency. However, Makarainen et al. found that no woman using ENG implant had consistently low estradiol concentrations (Makarienen et al., 1998). In an open, prospective, comparative 2-year study of 44 ENG implant users and 29 nonmedicated IUD users, Beerthuizen et al. (2000) found that estradiol levels were not significantly suppressed at any point. Importantly, the changes from baseline BMD measurements in implant users were not different from those in the IUD group. Even the ENG implant users with amenorrhea had no deleterious impact on their BMD. Although the authors did not analyze their findings by age, they concluded that their study demonstrated that ENG implant use would be safe in young women who had not achieved maximum bone density.

Carbohydrate Metabolism

Comparative trials of ENG implant versus LNG implant by Biswas et al. (2001) in 80 healthy volunteers, aged 18 to 40, for 24 months revealed a slight increase in insulin resistance with use of both implants. Fasting glucose levels with ENG implant remained stable throughout the study period. Fasting insulin levels had large interindividual variations at all times; however, at 24 months, a statistically significant increase was seen with ENG implant. The 2-hour oral glucose tolerance test demonstrated small increases over baseline glucose levels only after 24 months of use (12%), but 2-hour insulin levels were elevated consistently. Area under-the-curve analysis revealed statistically significant increases in glucose (30%–60%) and insulin levels (50%) by 6 months. Fasting Hb A_Ic levels were also increased throughout the study period. Although each of these changes was statistically significant, it should be noted that virtually all the values remained in the normal range. No glucose intolerance or diabetes was induced.

Lipid Impacts

Biswas et al. (2003) followed up 80 healthy volunteers randomized to use ENG implant or LNG implant for 2 years. At the end of the study, ENG implant users had slight decreases in TC (8.9%), HDL-C (5.8%), and LDL-C (5.9%), but there were no significant differences in their HDL/TC ratios or HDL/LDL ratios, indicating that the ENG implant implants are unlikely to contribute directly to any increased cardiovascular risk. However, the atherogenic risk ratio of apolipoprotein A-I (Apo A-I) to Apo B worsened, both because Apo A-I initially dropped (0.3%) and because Apo B increased by 25%.

Coagulation Factors and Other Hepatic Effects

Because initial international studies indicated that levonorgestrel-containing OCs were associated with less thrombosis than desogestrel-containing pills, Egberg et al. (1998)conducted a randomized comparative trial of LNG and ENG implants in 56 women. They measured the impact each implant system had on hemostasis (coagulation times and factors for coagulation, anticoagulants, and fibrinosis). In general, statistically significant changes to antithrombotic tendencies were seen in activated partial thromboplastin time (APTT), antithrombin III (AT-III) activity, protein C activity, and protein S free antigen, as well as plasminogen. They also monitored potential prothrombotic changes seen in factor VII activity, D-dimer antigen, and α₂-antiplasmin activity. However, in a parallel study, the use of two baseline measurements for each subject showed that the change seen in the different parameters with the

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implants generally were not greater than the differences between the two baseline values. Both implants had similar small effects on the hemostatic system; the authors concluded that they were not suggestive of a tendency toward thrombosis. The same investigators studied liver function with the two implant systems and found that total bilirubin and γ-glutamyl transferase increased, whereas alanine aminotransferase and aspartate aminotransferase levels decreased. Total bilirubin increased with ENG implant. The clinical implications of this mild increase in healthy subjects are probably not significant, but the implications of such a rise for women with hepatic compromise are not known (Dorflinger, 2002).

Disadvantages

1. Side effects (see subsequent text).
2. Provides no protection against STDs. Dual methods are needed for at-risk couples.
3. Requires medical intervention, including insertion and removal procedures performed by trained clinicians.
4. Expensive, with large up-front costs.

Side Effects

Changes in Bleeding Patterns

Menstrual bleeding changes are to be expected with progestin-only methods. There was no consistency or predictable trends in the bleeding patterns seen in individual women using ENG implants. Amenorrhea rates start low (<20%) at 3 months, but by 6 months approximately 20% of users had no menses, and, for the rest of the study, approximately 30% to 40% of women were amenorrheic. Amenorrhea occurred at any constant estradiol level, either early or late follicular levels (Makarainen et al., 1998). The incidence of infrequent bleeding (<3 bleeding episodes/90 days) decreased in the first 3 months. Frequent bleeding (>5 bleeding/spotting episodes in the 90-day period) was relatively unchanged in early use and decreased for the remainder of the study. Prolonged bleeding (at least one episode lasting at least 14 days) was relatively common in the first 3 months but decreased over time. Hemoglobin levels of women studied were relatively unchanged. Importantly, the bleeding patterns were unpredictable. A woman who initially experienced amenorrhea could later report frequent or prolonged bleeding. Normal menses returns within 3 months of removal of capsules in almost all subjects (Zheng et al., 1999).

Weight Changes

Weight increase was reported as an adverse event by 6.4% of all ENG implant users in the clinical trial. In the clinical trials, weight gain was the reason for discontinuation in 1.5% of users. It is also the side effect that is most difficult to interpret. What proportion of the observed gains were attributed to ENG implant, and which resulted from natural gains? The observations reported included the following:

• Within 3 months of insertion, 36.4% of women gained at least 1 kg, and approximately 10% had gained at least 3 kg.
• At the end of a year, more than half of women (53.5%) gained at least 1 kg, and 21.9% were at least 3 kg heavier than baseline.
• At the end of 2 years, 64.4% of study completers had documented gains of at least 1 kg, and 36.9% had at least 3 kg weight increase.
• Lighter women (<50 kg) were more likely to gain weight than those whose baseline weight was >50 kg (Edwards and Moore, 1999).

Headaches

Although headache has been the most frequent complaint of users of implantable contraception (Brache et al., 2002), in the clinical trials with ENG implant, the frequency of women complaining of headache was generally not excessive. In the comparative trial, 21% of the ENG implant users complained of headaches, but only 4.7% of women discontinued the method for this reason (Edwards and Moore, 1999). It should also be remembered that in the randomized, double-blinded, 6-month trial of low-dose OCs for acne therapy, 20.5% of placebo users reported headaches compared to 18.4% of OC users (Redmond et al., 1997).

Acne

Acne was the most frequently reported drug-related adverse event in the ENG implant clinical trials. Slightly more than 15% of the women reported acne as an adverse event, but only 1% of users had the implants removed because of this problem.

Mood Changes, Nervousness, and Depression

There are no estimates of risks attributable for these mood problems. In the clinical trials, ENG implant users reported rates of nervousness that varied between 1% and 1.2% in all study sites except Chile, where 30% of women complained of this problem. Requests for removal for each of these complaints ranged from 0% to 2% (Brache et al., 2002).

Blood Pressure

Significant BP increases were defined as BP_S >140 mm Hg or increased by 20 mm Hg over baseline or last visit reading or BP_D >90 mm Hg or increased by 10 mm Hg over baseline or last visit reading. Such increases were observed in 0.7% of women (10/1,640) at any time during the 24 months of the studies. In comparative studies, 0.6% of ENG implant users and 0.7% of LNG implant users had significant increases.

Ovarian Cysts

Progestins are known to slow atresia of ovarian cysts. In the large clinical trials, ovarian cysts were found on physical examination in 2% to 3% of implant users. In Chile, 9% of ENG implant users were found at some time to have such cysts (Brache et al., 2002). In asymptomatic women, no action was needed.

Summary

Clinical experience has demonstrated that the ENG contraceptive implant provides unsurpassed contraceptive efficacy, working primarily by ovulation suppression and thickened cervical mucus to prevent fertilization. This is achieved with very low levels of progestin and has very little metabolic impact in part because ovarian production of estradiol continues in the follicular range. Overall

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continuation rates with this method have been encouraging. Return to fertility is very rapid. Medical contraindications are rare, so virtually any woman can be offered this implant. The bleeding patterns with ENG implant are generally better than with previous generations of implants, but they are still unpredictable. Unscheduled bleeding can be disruptive for a woman. Therefore, careful patient counseling is imperative and may help reduce discontinuations for menstrual changes. Weight changes may be less well tolerated, but other side effects, such as headaches and acne, rarely cause patient discontinuation. Both the insertion and removal procedures have been greatly simplified and are more easily accomplished in a busy office practice. However, specific training is required.

Web Sites

For Teenagers and Parents

http://kidshealth.org/teen/sexual_health/contraception/contraception depo.html. Teen site with information about DMPA-IM.

http://www.depoprovera.com/. Pfizer site on DMPA-IM.

http://www.depo-subqprovera104.com/. Pfizer site on DMPA-SC.

http://www.plannedparenthood.org/pp2/portal/files/portal/medicalinfo/birthcontrol/pub-depo-provera.xml. Planned Parenthood information about DMPA-IM.

http://familydoctor.org/016.xml. AAFP information about DMPA-IM.

http://www.youngwomenshealth.org/femalehormone1.html. Children's Hospital Boston Web site on contraception including DMPA-IM.

http://www.cfoc.org/411AboutSex/birthcontrol/. Campaign For Our Children teen site with information about many contraceptives including DMPA-IM.

For Health Professionals

http://www.depoprovera.com/. Pfizer site on DMPA-IM.

http://www.depo-subqprovera104.com/. Pfizer site on DMPA-SC.

http://www.organon.com/products/gynecology/contraception/implanon.asp. Organon site for ENG implant (not yet approved in the United States).

Telephone Hotlines for Health Providers

DMPA hotline: 1-866-554-DEPO (3376)

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