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THE USE OF LONG-ACTING CONTRACEPTIVES IN ADOLESCENTS
ADOLESCENT GYNECOLOGY, PART I1 THE! SEXUALLY ACTIVE ADOLESCENT
0031-3955/99 $8.00
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THE USE OF LONG-ACTING CONTRACEPTIVES IN ADOLESCENTS Zeev Harel, MD, and Barbara Cromer, MD
Levonorgestrelimplants (Norplant) and depot medroxyprogesterone acetate (DMPA) injections (Depo-Provera), long-acting contraceptives approved by the US Food and Drug Administration, are effective, convenient, coitus independent, 29 These factors make them important and and require no daily compliance.“ desirable options for preventing teenage pregnancies. l5rz5,
PHARMACOLOGIC ACTIONS
The implants, which consist of six small, flexible, Silastic rods containing levonorgestrel (a second-generation progestin) placed subdermally, provide immediate contraception effective for at least 5 years. Each capsular implant contains 36 mg levonorgestrel. The capsules are sealed with a Silastic adhesive and sterilized. Each capsule is 2.4 mm in diameter and 34 mm in length.15 The implants release approximately 80 pg/d levonorgestrel in the first 6 months, giving a blood level of 0.3 to 0.5 ng/mL. This release rate decreases gradually to 30 to 35 pg/d for the remainder of implant with blood levels of 0.29 to 0.35 ng/mL.l0 DMPA is a microcrystalline suspension of medroxyprogesterone acetate (a first-generation progestin). After intramuscular injection of 150 mg of DMPA, serum concentrations of medroxyprogesterone acetate range from 1.5 to 3.0 ng/ mL for a few days. Serum concentrations gradually decrease and remain relatively constant at approximately 1 ng/mL for 2 or 3 months. Although variable from person to person, serum concentrations decrease gradually thereafter to From the Division of Adolescent Medicine, Hasbro Children’s Hospital; the Department of Pediatrics, Brown University, Providence, Rhode Island (ZH); the Division of Adolescent Medicine, Children’s Hospital; and the Department of Pediatrics, Ohio State University, Columbus, Ohio (BC)
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less than 0.2 ng/mL during the sixth month and become undetectable (< 0.02 ng/mL) at about 7.5 to 9.0 months following administration.& The implants and DMPA are progestins with similar antiestrogen activity but that differ in their binding to glucocorticoid receptors, androgen receptors, and sex hormone-binding globulin (SHBG, Table 1).Levonorgestrel has a greater progestogenic potency, allowing a smaller dose of progestin to be used to inhibit ovulation; however, the greater binding of levonorgestrel to androgen receptors and to SHBGS0may lead to androgenic side effects, such as acne and hirsutism. DMPA strongly binds to glucocorticoid receptors,50which may lead to steroidlike effects, such as an increase in appetite and weight gain. MECHANISM OF ACTION
Long-acting, progestin-only contraceptives affect both the hypothalamicpituitary-ovarian axis and the genital tract. At the level of the hypothalamus, gonadotropin-releasing hormone (GnRH) pulse frequency increases, with no change in pulse amplitude.49At the pituitary level, luteinizing hormone (LH) pulsatility remains intact; however, LH pulse frequency increases, whereas LH pulse amplitude decreases, and the midcycle LH surge is s ~ p p r e s s e d Mean .~~ follicle-stimulatinghormone (FSH) secretion increases, and FSH responsiveness to gonadotropin-releasing hormone is augmented.49At the ovary, estradiol secretion is decreased and remains within the early follicular phase range.15,u, Follicular development and maturation are inhibited. As a result of a lack of estrogen and lack of the positive-feedback midcycle LH surge, ovulation is inhibited for as many as 7 to 9 months after a single DMPA injection%and does not occur in more than 50% of the cycles in Norplant users.- The low blood levels of levonorgestrel provided by Norplant are sometimes not enough to completely suppress gonadotropins. Consequently, FSH and LH may be released, resulting in follicular development and periodic increases in estradiol. Stimulation by gonadotropins may result in excessive follicular enlargement63 and in transient functional ovarian cysts that have been reported in as many as 10% of Norplant users.2O A subsequent decrease in estradiol levels may lead to irregular bleeding in women using this method. Despite the occasional occurrence of ovulatory cycles in Norplant users, this method remains effective mainly
Table 1. CHARACTERISTICSOF MEDROXYPROGESTERONE ACETATE AND LEVONORGESTREL Characteristic
Progestational Antiestrogen Relative binding affinity to glucocorticoid receptors Relative binding affinity to androgen receptors Relative binding affinity to SHBG
Medroxy progesterone Acetate (Depo-Provera)
Levonorgestrel (Norplant)
++ ++
++ ++
f
t
-
(about 50 times more) -
-
tt 7t
(about 9 times more) (about 500 times more)
SHBG, Sex hormone-binding globulin. Adaptedfrom Pollow K,Juchem M, Grill HJ,et a1 Gestodene: A novel synthetic progestin: Characterization of binding to receptor and serum proteins. Contraception 40325341,1969;with permission.
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because of other long-acting, progestin-only contraceptive-induced changes at the level of the uterus, cervix, and vagina. At the level of the uterus, the endometrium remains thin and nonproliferative, and implantation (if ovulation does occur) is inhibited.15,25 In the cervix and vagina, long-acting, progestin-only contraceptives reduce secretions and thicken the cervical mucus to inhibit sperm penetration." INDICATIONS AND CONTRAINDICATIONS FOR USE
Long-term contraception is an attractive choice for adolescents who have had problems of compliance with other contraceptive methods and for adolescents who are at risk for complications from combined estrogen-and-progestin oral contraceptive pills (OCPs). Preliminary reports also suggest that DMPA has a beneficial effect on seizure activity in patients with seizure disordersP as well as a potential for reducing painful crises in patients with sickle cell disease.18 The long-acting contraceptives are contraindicated in pregnancy and in patients with sex hormone-dependent tumors or active liver disease. Although the package labeling lists a personal history of thromboembolism as a contraindication, the long-acting, progestin-only contraceptives have not been associated with clinically signihcant changes in coagulation parametersz4,55 or with an increased rate of stroke among users.n CLINICAL ADVANTAGES AND DISADVANTAGES AND POTENTIAL MEDICAL CONCERNS
The obvious advantage to patients of both implants and DMPA is that their use obviates the need for daily or event-specific compliance. Because the rate of compliance with OCPs is generally low in female adole~cents,2~ pregnancy rates are discouragingly high in this population. Therefore, the advent of a device (implants), which, after the initial procedure, provides high contraceptive efficacy without any involvement of these patients for 5 years, is very appealing. Teenagers desiring a long-acting contraceptive who have difficulty accurately predicting their life circumstances over the next 5 years may prefer a shorter period of protection, such as the 3-month period provided by DMPA injection. The implants are a cost-effective contraceptive method when used for the full 5-year lifespan; however, if an adolescent discontinues the implant before she has used it for at least 4 years, the injectable DMPA becomes the less costly option.70 Two areas of concern regarding clinical complications of DMPA deserve further investigation and elucidation. First, after the finding of breast tumors in dogs given huge doses of DMPA, two large epidemiologic studies were conducted to explore the risks in h~ma11~.4~, 74 Women who had used DMPA for a long period of time and who initiated use many years previously were not at increased risk for breast cancer, but the relative risk was increased twofold in women fewer than 35 years of age within 5 years of initial use.41,47,74 "his lack of overall increase in risk, and the fact that the increase in risk was confined to young-adult recent users, suggest that DMPA may accelerate the growth of already existing tumors rather than promote the formation of new ones.4l The other area of concern relates to potential progressive loss of bone density with prolonged use of DMPA, the putative mechanism being through suppression of ovarian production of estrogen via central suppression of gonadotropins. In a
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cross-sectional design, Cundy et all3 found lower bone density in older women who had used DMPA for more than 5 years compared with that of nonhormonal contr01s.’~In a follow-up study of a similar group of women, partial recovery was found after discontinuation of the method.14 In a prospective study in adolescents, Cromer et a1 found a significant decrease in bone density after 2 years of treatment compared with an increase among girls using implants or no hormonal therapy7 This increase in bone density in adolescents using Norplant may be attributed to periodic increases in estrogen levels in these patients. Given that adolescence is a crucial time for bone growth and consolidation,4 further investigation is needed to define the losses, the mechanisms, and the potential for recovery when treatment is discontinued. Two different issues of clinical concern relate to the implants. First, although the procedure for insertion is simple and ideally suited for primary care providers, removal of the rods is more difficult, occasionally requiring multiple visits; radiograph procedures; and, in rare cases, general anesthesia. Recent articles have been published with maneuvers designed to facilitate the removal procedure.58,69 The second issue is that implants have been linked, apparently because of the tiny amounts of Silastic material in the walls of the rods, with the same clinical syndromes associated with breast implants. Several class-action suits have been brought against the distributor based on complaints such as arthritis and chronic fatigue syndrome. A review of the literature reveals not even a case report documenting these symptom constellations; however, possibly because of such publicity, a dramatic decrease in the popularity of this contraceptive method has occurred. Progestins, depending on their dosage and androgenicity, can increase lowdensity lipoprotein (LDL) cholesterol plasma levels and decrease high-density lipoprotein (HDL) cholesterol plasma levels, changes that may predispose to the development of atherosclerosis.36Although initial studies in adult women suggested unfavorable lipid changes (11-24% increase in LDL cholesterol, 1015% decrease in HDL cholesterol, 3-39% decrease in apolipoprotein AI/B ratio) with DMPA” and with implants (increase in total cholesterol, increase in LDL cholesterol’), a study among US women found no statistically significant differences among pre-use and during-use lipid profiles of users of these meth0ds.3~ Delayed return to fertility, often mentioned as a disadvantage associated with DMPA use in adults, may be viewed as an advantage by parents of adolescents seeking contraception. Studies of adults suggest that delayed return to fertility after DMPA, although typically months after the last injection, may be as long as a year, whereas the return to fertility is immediate upon removal of implants.48In a study of adolescents, a high pregnancy rate was observed after discontinuation of implants and DMPA,30emphasizing the need to expedite the transition to a new contraceptive method upon discontinuation of these methods in adolescents. EXPERIENCE WITH LONG-TERM PROGESTINS IN ADOLESCENTS
Over the past 5 years, several surveys of clinical issues related to long-term progestins, most focusing on implants? 3, 12, 7.z 26, 33,51, 56, 65 have been published. Some have compared clinical aspects of implants with those of OCPs and other method^.^,^," Fewer surveys have included the examination of similar issues in DMPA 30, 38, 45, Adolescent contraceptive candidates choosing implants or DMPA tend to be older; to have had previous pregnancies and sexually
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transmitted diseases (STDs); and to have used, unsuccessfully, OCPs.6,22* 29, 51, 56, ffi The most frequently cited reasons for selecting a long-acting contraceptive were reliability, convenience, and prior problems with OCPs.2, Although DMPA is less visible than the implants, only 17% of adolescents cited the confidential nature of DMPA as a reason for selecting this rneth0d.2~ Several studies have examined adolescents’ attitudes toward initial choice and later satisfaction with the long-acting contraceptives. In a survey of 328 young women, Gold and CoupeyZ7found that DMPA had a higher acceptability rate (62%) than did implants (24%). In a study using structured interviews of 151 postpartum adolescents, those who had already had two live births were more likely to choose implants than ”other methods.” Other determinants of implant selection included involvement of a parent in the selection, peers who used implants, and Medicaid coverage.4o Using a qualitative methodology, Kuiper et al” examined 41 adolescents girls’ attitudes toward the implants. Their sample included girls using either Norplant or another form of contraception. The specific decision making seemed to cluster into three distinct areas: (1) social conditions, such as peer attitudes (including sex partners’ attitudes), and prospective stigma with use of the method; (2) informational sources, of which person-to-person transmission was the most important; and (3) personal attributes, such as personal goals and sense of control. Adolescents who chose a long-acting contraceptive seemed to be satisfied with the method; 74%51to 86%’ were satisfied with Norplant, and 84YP to 87%% were satisfied with DepoProvera. The majority (78%) of adolescents who had used Depo-Provera indicated that they would recommend the method to a friend.29 A potential concern with implants was that adolescents might not return for routine reproductive care and thus might miss early identification and management of STDs; however, Rainey et a1%found that compliance with return appointments for reproductive health care among adolescent implants users, although poor, was not significantly worse than the appointment compliance of adolescents who did not use implants. Although Cromer et a18 found a lower return rate after 6 months of initiation among adolescent implant users (48%) compared with DMPA users (70%) and OCP users (56%), two thirds of the noncompliant patients on implants returned with one prompting phone call? With DMPA injections, the concern was that adolescents would find the required frequent clinic visits (every 3 months) difficult to comply with. An initial report, however, found that most (80%) adolescents who used DMPA were not concerned about the %month return visits to the clinic and viewed it as a positive attribute of this meth0d.2~ Another important concern is that the use of long-term contraception would lead to a decrease in condom use and thus to an increase in the incidence of STDs. In general, condom use by adolescents on any type of hormonal contraceptive is poor. Only 21% of OCP users, 18% of DMPA users, and 9% of implant users reported consistent use of condoms,3. with 20% of condom users reporting a decrease in condom use within the first year after initiation of any hormonal contraceptive m e t h ~ dFurthermore, .~ the reported rate of condom use at last intercourse among sexually active adolescents on some form of hormonal contraception was less (52%) than that reported by adolescents not using hormonal methods (69Y0)~;however, other studies of adolescents found that the incidence of STDs did not significantly differ among implant users and users of OCPs or condoms” 51 and that condom use did not change significantly from baseline to follow-up among patients using DMPAZ9or implants.” Efforts should be made to increase the use of a barrier method among adolescents using hormonal contraception.
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Consistent findings have been recorded among the various surveys examining the continuation rates and pregnancy rates for the long-term progestins in adolescents. Continuation rates for implants are generally high, approximating 90% over 6 to 15 months compared with much lower rates (< 60%) observed concurrently in OCP users.3*12, 22, 26* 51 Findings related to continuation rates for adolescent DMPA users are rather variable; they are consistently lower than those reported for implant users. Whereas continuation rates exceeding 75% at 9 monthsz9and 1 yeaP have been reported in select populations using DMPA, more recent studies have reported 1-year continuation rates closer to 40Y0.5~. 76 One consistent finding, however, is that about approximately one third of DMPA discontinuers restart this method within a few Unsurprisingly, pregnancy rates are much higher in OCP users (20-38%) over 6 to 15 months compared with 2% among implant users.=, 51 In a case study and review of the literature, Dias and 0Maral9 found that implant users with overweight and regular menstrual cycles were at greater risk for failure of this method. No pregnancies were reported in studies evaluating DMPA in adolescent^.^^, 38, 64 The long-acting contraceptives have played an important role in the attempt to prevent repeat pregnancies in adolescents. Postpartum levonorgestrel implant insertion has been associated with a siguficant decrease in the repeat pregnancy rate among adolescents in the United States.5l The probability of repeat pregnancy at 12 months postpartum among subjects choosing DMPA was also lower (11%)than the probability of repeat pregnancy (28%) among postpartum OCP users, but the 1-year continuation rate was only 34% among DMPA postpartum users.* To prevent subsequent pregnancy, many centers in the United States insert the implants or administer the first injection of DMPA in nonlactating mothers immediately postpartum, before discharge from the h0spital.4~. 51 Detectable amounts of levonorgestrel and DMPA have been identified in the milk of mothers who received these long-acting contraceptives postpartum. Some initial studies have shown that the use of progestins in lactating women may decrease breast milk protein contenP and have raised the possibility that this may negatively affect infant growth and development, as well as increase the potential for infections caused by reduced immunoglobulins in the breast milk. More recent studies, however, showed that administration of a long-acting, progestinonly contraceptive at 6 weeks postpartum did not adversely affect infant growth 54 Only a few studies have examined the effects of longand de~elopment?~, acting contraceptives administered before the sixth postpartum week in breastfeeding women?* Until more studies are available, the manufacturers of DepoProvera or Norplant recommend to initiate use only after the sixth postpartum week if exclusively breast-feeding. BEGINNING ADOLESCENTS ON LONG-ACTING, PROGESTIN-ONLY CONTRACEPTIVES
Adolescents considering long-acting contraceptives should be counseled about the benefits and the side effects of DMPA and implants before the beginning of either of these methods (Fig. 1). Because prior use of a combined OCP reduced the duration of menstrual bleeding during the first 6 months of use of a long-term, progestin-only contraceptive in one study,29the continued use of OCPs until initiation of implants or DMPA is recommended. The optimal time to initiate a long-acting contraceptive is within 5 days of the onset of menses. This practice ensures that these patients are not already pregnant and that bleeding (shedding of a proliferative endometrium) will not occur during the
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Profiles of good candidates for a long-term contraceptive method Poor pill compliance Previous pregnancy Selected medical conditions: Pregnancy contraindicated, seizure disorder, sickle cell disease
Review for contraindication Sex hormone - dependent tumor Active liver disease
Presentation of contraceptive menu Counsel about benefits and risks Encourage continuation with oral contraceptive pills until insertion or injection Return during menses
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Insertion or injection Figure 1. Beginning a teen on a long-term, progestin-only contraceptive.
immediate period following initiation. With Depo-Provera, subsequent injections should be scheduled at 12-week intervals. To enhance compliance with return appointments, clinics should establish a system of mailing reminder cards or reminding patients by phone, but only after confidentiality issues have been discussed and documented in the chart. The administration of repeat injections by visiting home health nurses may be considered in some settings. If these patients return for injections at between 12 and 14 weeks, the injection should be administered only after a negative urine pregnancy test. Beyond 14 weeks, a urine pregnancy test should be obtained, and these adolescents should be instructed to abstain from sex or to use a barrier method for 2 weeks. A negative pregnancy test at the end of these 2 weeks allows for a restart of DMPA. Perhaps most importantly, adolescents' health care providers should continue to provide counseling about these methods during use and should immediately address any concern or problem associated with DMPA or implants. An open-door, open-telephone policy may allay fears and address side effects as they arise and
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is important in the attempt to further increase continuation rate of these methods in adolescents. OCCURRENCE AND TREATMENT OF SIDE EFFECTS
Disrupted Menstrual Cycle
Menstrual abnormality is the major side effect and reason for discontinuation of long-term, progestin-only contraceptives.mBoth prolonged spotting or bleeding episodes and amenorrhea have been reported in adolescents using implants" 3, 6* 12, 22, 26, 33* 51* and DMPA.6,29, 38* 64 Although the continued use of DMPA has been associated with an increased Occurrence of amenorrhea: the continued use of levonorgestrel has been associated with resumption of regular menstrual cycles in approximately one third of adolescents using this method.5I Although the reason for the disrupted cycles is not yet completely understood, it has been attributed to the relative deficiency of estrogen in adolescents using DMPA and to fluctuations in estrogen levels during Norplant use. Indeed, estrogen has been found effective in the treatment of patients with bleeding episodes associated with use of long-term, progestin-only In the event of persistent bleeding while patients are using long-term, progestinonly contraceptives, physicians are recommended to proceed as follows: 1. Rule out STDs, such as gonorrhea or chlamydia. 2. Obtain hemoglobin and hematocrit counts. 3. Offer reassurance (if hemoglobin and hematocrit count is normal). 4. Prescribe a short course of conjugated estrogen (Premarin), 1.25 mg/d, or estradiol (Estrace), 2 mg/d for 7 to 21 days, or prescribe one or two cycles of OCPs. A short course of a nonsteroidal anti-inflammatory medication (ibuprofen, 800 mg three times a day for 5 d) has also been shown to reduce bleeding in users of long-acting contraceptives.21
Weight Gain
Weight gain has been noted with both DMPA and levonorgestrel use in adolescents and is the second most common side effect and reason for discontinuation of long-term, progestin-only contraceptives.mAn average weight gain of 3.9 kg has been reported after 1 year of levonorgestrel use in adolescent^.^ With DMPA, average weight gains of 6.0 +- 6.0 kg after 11 months and 9.0 ? 5.4 kg after 17 months have been reported among teenagers.%When changes in body mass index were reported, mean increases of 0.4 f 0.14 kg/m2 after 3 months, 1.08 ? 0.29 kg/m2 after 6 months,Z9and 1.1 -+ 0.3 kg/m2 after 9 monthsmhad been associated with DMPA use in adolescents. A mean increase of 1.3 ? 0.6 kg/mz in body mass index was reported after almost 22 months of levonorgestrel use in adolescents.30Because preoptic and hypothalamic neurons have been shown to accumulate 3H progestogen, long-term, progestin-only contraceptives may directly stimulate central hunger centers.57Glucocorticoid agonist activity7O interference with insulin action, and interference with serotonin metabolism35 might also lead to weight gain. At present, the approach to weight gain involves the recommendation for a healthy diet and an exercise plan. In future. studies with long-term, progestin-only contraceptives, efforts should be made to block
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the glucocorticoid agonist activity, improve peripheral insulin action, and increase serotonin buildup in the brain. Decreased Libido
A decrease in libido has been reported with the use of DMPA in adolescent^.^^^ 38 The decrease in estrogen levels observed with DMPA can lead to insufficient estrogenic effects at the levels of the sex organs and the CNS. Whether a decrease in the level of testosterone, caused by reduced ovarian androgen production, may lead to less libido in these patients, remains to be proven. DMPA has been shown to decrease the sex drive of male sex offenders,3l and preliminary results from animal research attributed this effect to direct action at the level of the brain." Whether long-term, progestin-only contraceptives affect CNS mechanisms controlling sexual behavior in female patients, particularly in adolescents, remains to be determined. Headaches
The increased occurrence of headaches has been reported as the third most common reason for discontinuing Depo-Provera and Norplant in adolescentsm; however, compared with baseline information, no significant change occurred in the frequency or type of headaches.during the first 6 months of use of DepoProvera or Norplant in adolescents.6Most of the reported headaches are mild and easily treated with nonsteroidal anti-inflammatory drugs. In patients with severe headaches, pseudotumor cerebri (increased intracranial pressure), which had been reported in women using implants, should be ruled out by funduscopic examination, in particular in obese adolescents or adolescents who had experienced excessive weight gainn Skin Changes
A loss of scalp hair was reported by 20% of patients who discontinued DMPA and by 10% of patients who discontinued implants to be the reason for discontinuation.30Acne was reported by 9% of adolescents who discontinued Depo-Provera and by 10% of those who discontinued Norplant.mWorsening of acne was reported by 24% of adolescents using implants*and by 15% of adolescents using DMPA," but, when assessed quantitatively, no significant changes occurred in numbers of acneiform lesions during the use of DMPA or implants by adolescents.6Excessive body hair growth was reported by 5% of adolescents who used implants.* These skin changes may be attributed in part to the antiestrogenic activity and androgenic potential of these progestins. Mood Changes
Because progestins may affect serotonin metabolism> 35 some physicians have expressed concern that the long-acting contraceptives may lead to mood changes. The literature is conflicting regarding the effects of the long-acting progestins on mood; the balance of the findings, however, indicates that a significant clinical effect may not exist. Regarding implants, Wagner recorded
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five cases of major depression and anxiety disorders that cleared after removal of the implants in adult women67;however, the cases were self-selected, resulting from phone-ins after a news media presentation of the potential association between implants and psychiatric disorders. Two studies, one of adults73and one of adolescents,6showed no increase in the incidence or severity of depression among implant users. Likewise, prospective studies found no increase in mood disturbance among DMPA users compared with their baseline mental status:, Galactorrhea An interesting finding among 64 teenagers on DMPA (notably, 35% of the group had initiated DMPA after pregnancy or therapeutic abortion) was that six (9%)developed galactorrhea? The only previous report of a similar finding was in a study of adults published in 1971, with 3 of 1123 users reporting galactorrhea-a much lower prevalence (0.3%). The purported mechanism is direct stimulation of the progestin on the acini of the mammary gland, with consequent production of fluid in the acini. This side effect is thought to be benign and resolves over time, even with continuation of the contraceptive method?
FUTURE LONG-ACTING HORMONAL CONTRACEPTIVES Implantable Contraception
To facilitate insertion and removal of the implants, attempts are being made to reduce the number of rods and to provide a biodegradable delivery system.17 Two-rod implants, which provide contraception for at least 3 years, are longer and more rigid and are already approved for use in a few countries.66Biodegradable implants would eliminate the need for removal but should be built in a way that allows removal if a patient so desires. One initial study found high pregnancy rates and other problems, such as migration of the capsules, local itching, and skin rash, in women using the biodegradable implants.I6 Injectable Contraception
Once-a-month injectable contraceptives include a combination of progestin and estrogen." Although all monthly injectables provide a better cycle control than does DMPA, an abnormal bleeding pattern is still the main complaint and reason for discontinuation.32In addition, the need to comply with monthly visits may pose an obstacle to their use in adolescents. Finally, combinations of a longacting progestin and a long-acting androgen are being studied as a potential long-acting contraceptive for men.@ SUMMARY
DMPA and implants have played an important role in the attempt to prevent teenage pregnancies. Adolescent health care providers should provide continued counseling to girls using DMPA or implants and should promptly address any concern associated with these methods. Future studies are war-
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ranted to explore ways to prevent or reduce the side effects of DMPA and implants, as well as to develop new, optimal, long-acting contraceptives. Detailed baseline information should be obtained in every future study that explores the presence of side effects during the use of long-acting contraceptives. ACKNOWLEDGMENTS The authors thank Wendy Wood, Karen Autieri, and Harold E. Regan, Jr, MA, for their skillful preparation of the manuscript.
References 1. Affandi B, Suharti K, Prihartono DJ, et a1 Serum lipids in Norplant implant users: A cross-sectional study. Contraception 36429434,1987 2. Berenson AB, Wiemann CM Patient satisfaction and side effects with levonorgestrel implant (Norplant) use in adolescents 18 years of age or younger. Pediatrics 92257260, 1993 3. Berenson AB, Wiemann CM, Rickerr VI, et a1 Contraceptive outcomes among adolescents prescribed Norplant implants versus oral contraceptives after one year of use. Am J Obstet Gynecol 176:58&592, 1997 4. Bonjour JP, Theintz G, Buchs B, et a1 Critical years and stages of puberty for spinal and femoral mass accumulation during adolescence. J Clin Endocrinol Metab 73555563, 1991 5. Cromer BA Depo-Frovera: Wherefore art thou? Adolesc Pediatr Gynecol 5:155-162, 1992 6. Cromer BA, Smith RD, Blair JM, et a1 A prospective study of adolescents who choose among levonorgestrel implant (Norplant), medroxyprogesteroneacetate (DepoProvera), or the combined oral contraceptive pill as contraception. Pediatrics 94:687694, 1994 7. Cromer BA, Blair JM, Mahan JD, et a1 A prospective comparison of bone density in adolescent girls on depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives. J Pediatr 129671-676, 1996 8. Cromer B, Schoenbachler R, Vesha K, et a1 Compliance in adolescents using different forms of hormonal contraception. Sexological Review 5:129-142, 1996 9. Cromwell P, Anyan W Depot medroxyprogesterone acetate galactorrhea [letter]. J Adolesc Health 23:61, 1998 10. Croxatto HB, Diaz S, Muanda P: Plasma levels of levonorgestrel in women during long term use of Norplant. Contraception 23197-209, 1981 11. Croxatto HB, Diaz S, Salvatierra AM, et al: Treatment with Norplant subdermal implants inhibits sperm penetration through cervical mucus in vitro. Contraception 36193-201,1987 12. Cullins VE, Remsburg RE, Blumenthal PD, et al: Comparison of adolescent and adult experiences with Norplant levonorgestrel contraceptiveimplants. Obstet Gynecol 83102&1032, 1994 13. Cundy T, Evans M, Roberts H Bone density in women receiving depot medroxyprogesterone acetate for contraception. BMJ 30313-16, 1991 14. Cundy T, Cornish J,Evans MC, et a 1 Recovery of bone density in women who stop using medroxyprogesterone acetate. BMJ 308247-248, 1994 15. Darney PD, Klaisle CM, Tanner S, et al: Sustained release contraceptives. Curr Probl Obstet Gynecol Fertil 13:87-125,1990 16. Darney PD, Klaisle CM, Monroe SE, et a1 Evaluation of a 1-year levonorgestrelreleasing contraceptive implant: Side effects, release rates, and biodegradability.Fertil Steril58:137-143, 1994 17. Darney PD: Hormonal implants: Contraception for a new century. Am J Obstet Gynecol 170153&1543,1994
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18. De Abood M, De Castill Z, Guerrero F, et al: Effect of Depo-Provera or Microgynon on the painful crises of sickle cell anemia patients. Contraception 56:313-316,1997 19. Dias PJ, OMara N: Norplant failure: An adolescent case study and review of the literature. J Pediatr Adolesc Gynecol 11:33-37, 1998 20. Diaz S, Pavez M, Miranda P, et al: A five-year clinical trial of levonorgestrel Silastic implants (Norplant). Contraception 25447456, 1982 21. Diaz S, Croxatto HB, Pavez M, et al: Clinical assessment of treatment for prolonged bleeding in users of Norplant implants. Contraception 4297-109, 1990 22. Dinerman LM, Wilson MD, Duggan AK,et a1 Outcomes of adolescentsusing levonorgestrel implants vs. oral contraceptives or other contraceptive methods. Arch Pediatr Adolesc Med 149:967-972, 1995 23. Emans SJ, Grace E, Woods ER, et al: Adolescents’ compliance with the use of oral contraceptive. JAMA 2573377-3381,1987 24. Fahmy K, Khairy M, Allam G, et al: Effect of depo-medroxyprogesterone on coagulation factors and serum lipids in Egyptian women. Contraception 44431434, 1991 25. Fraser IS, Weisberg E: A comprehensive review of injectable contraception with special emphasis on depot medroxyprogesterone acetate. Med J Aust l(supp1):l-19, 1981 26. Glantz S, Schaff E, Campbell-Heider N, et a1 Contraceptive implant use among inner city teens. J Adolesc Health 16389-395, 1995 27. Gold MA, Coupey SM Young women’s attitudes toward injectable and implantable contraceptives. J Pediatr Adolesc Gynecol 11:17-24, 1998 28. Hannon PR, Duggan AK, Serwint JR, et al: The influence of medroxyprogesterone on the duration of breast-feeding in mothers in an urban community. Arch Pediatr Adolesc Med 151:490-496, 1997 29. Harel Z. Biro FM. Kollar LM Deuo-Provera in adolescents: Effects of earlv second injection or prior oral contraceptio;. J Adolesc Health 16:379-384, 1995 30. Harel Z , Biro €44, Kollar LM, et al: Adolescents’ reasons for and experience after discontinuation of the long-acting contraceptives Depo-Provera and Norplant. J Adolesc Health 19:118-123, 1996 31. Kiersch TA Treatment of sex offenders with Depo-Provera. Bull Am Acad Psychiatry Law 18179-187,1990 32. Koetsawang S: Once-a-month injectable contraceptives: Efficacy and reasons for discontinuation. Contraception 49:387-398, 1994 33. Kozlowski KJ, Rickert VI, Hendron A, et a1 Adolescents and Norplant: Preliminary findings of side effects. J Adolesc Health 16373-378, 1995 34. Kuiper H, Miller S, Martinez E, et al: Urban adolescent females’ views on the implant and contraceptive decision-making: A double paradox. Fam Plann Perspect 29:167172, 1997 35. Ladisch W: Influence of progesterone on serotonin metabolism: A possible causal factor for mood changes. Psychoneuroendocrinology2257-266,1977 36. La Rosa J C The varying effects of progestins on lipid levels and cardiovasculardisease. Am J Obstet Gynecol 158:1621-1629, 1988 37. Mainwaring R, Hales HA, Stevenson K, et al: Metabolic parameter, bleeding, and weight changes in US women using progestin only contraceptives. Contraception 51:149-153, 1995 38. Matson SC,Henderson KA, McGrath GJ: Physical findings and symptoms of depot medroxwrogesterone acetate use in adolescent females. 1 Pediatr Adolesc Gvnecol 1 018-25,- 199’7 39. Mattson RH. Cramer 1A. Caldwell BV. et al: Treatment of seizures with medroxvprogesterone acetate: Preiiminary repoi. Neurology 34:1255-1258, 1984 40. Mears CJ, Hediger ML, Martin SS, et al: Social factors predicting postpartum choice of Norplant among African-American and non-Hispanic white adolescents. J Adolesc Health 21:167-171, 1997 41. Meirik 0, Thomas DB: Depot medroxyprogesterone acetate and breast cancer: A pooled analysis of the World Health Organization and New Zealand studies. JAMA 273:799-804,1995 42. Michael RP, Zunre D Medroxyprogesterone acetate decreases the sexual activity of
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male cynomolgus monkeys (macaca fascicularis): An action on the brain? Physiol Behav 53:783-788,1993 43. Middleman AB, Robertson LM, DuRant RH, et a 1 Use of hormonal methods of birth control among sexually active adolescent girls. J Pediatr Adolesc Gynecol 10193-198, 1997 44. Newton J R A review of "once-a-month combined injectable contraceptives. J Obstet Gynecol 14(Suppl 1):l-34, 1994 45. ODell CM, Forke CM, Polaneczky MM, et al: Depot medroxyprogesterone acetate or oral contraception in postpartum adolescents. Obstet Gynecol 91:609414, 1998 46. Ortiz A, Hiroi M, Stanczyk FZ, et a1 Serum medroxyprogesterone acetate (MPA) concentrations and ovarian function following intramuscular injection of Depo-MPA. J Clin Endocrinol Metab 44:32-38, 1977 47. Paul C, Skegg DCG, Spears GFS Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer. BMJ 299:759-762, 1989 48. Phardthaisong T, Gray RH, McDaniel EB Return to fertility after discontinuation of depot medroxyprogesterone acetate and intrauterine devices in Northern Thailand. Lancet 1:509-512, 1980 49. Poindexter AN, Dildy GA, Brodyand SA, et a1 The effects of a long-acting progestin on the hypothalamic-pituitary-ovarian axis in women with normal menstrual cycles. Contraception 48:3745,1993 50. Pollow K, Juchem M, Grill HJ, et a 1 Gestodene: A novel synthetic progestin: Characterization of binding to receptor and serum proteins. Contraception 40325-341, 1989 51. Polaneczky M, Slap G, Fork C, et a1 The use of levonorgestrel implants (Norplant) for contraception in adolescent mothers. N Engl J Med 331:1201-1206,1994 52. Polanecsky M, Liblanc M . Long-term depot medroxyprogesterone acetate (Depo-ProVera) use in inner city adolescents. J Adolesc Health 2381-88, 1998 53. Progestogen-only contraceptives dufing lactation: I. Infant growth. World Health Organization Task Force for Epidemiological Research on Reproductive Health: Special program of research, development and research training in human reproduction. Contraception 50:35-53,1994 54. Progestogen-only contraceptives during lactation: I. Infant development. World Health Organization Task Force for Epidemiological Research on Reproductive Health: Special program of research, development, and research training in human reproduction. Contraception 50:55-68, 1994 55. Pryor JA, Cooper KR, Bass JD, et a1 The effect of levonorgestrel (Norplant) contraception on coagulation as measured by antithrombine-111levels. J Miss State Med Assoc 37777-779, 1996 56. Rainey DY, Parsons LH, Kenney PG, et a1 Compliance with return appointments for reproductive health care among adolescent Norplant users. J Adolesc Health 16:385-388, 1995 57. Rees HD, Bonsall RW, Michael RP: Pre-optic and hypothalamic neurons accumulate (3H) medroxyprogesterone acetate in male cynomolgus monkeys. Life Sci 39:13531359, 1986 58. Reynolds R D The "Modified U technique: A refined method of Norplant removal. J Fam Pract 40173-180, 1995 59. Robertson DN, Sivin I, Nash HA, et a1 Release rates of levonorgestrel from Silastic capsules, homogeneous rods and covered rods in human. Contraception 27483-495, 1983 60. Rosenthal SL, Biro FM, Kollar LM, et al: Experience with side effects and health risks associated with Norplant implant use in adolescents. Contraception 52:283-285, 1995 61. Sarnmour MB, Ramadan ME, Salah M: Effect of chlormadinone on the composition of human milk. Fertil Steril24301-304,1973 62. Sangi-Haghpeykar H, Poindexter AN, Bateman L: Consistency of condom use among users of injectable contraceptives. Fam I'lann Perspect 29:67-75, 1997 63. Shaaban MM, Segal S, Salem HT, et al: Sonographic assessment of ovarian and endometrial changes during long-term Norplant use and their correlation with hormonal levels. Fertil Steril 5998-1002, 1993 64. Smith RD, Cromer BA, Hayes JR, et al: Medroxyprogesterone acetate (Depo-Provera)
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use in adolescents: Uterine bleeding and blood pressure patterns, patient satisfaction, and continuation rates. Adolesc Pediatr Gynecol8:24-28, 1995 65. Stevens-Simon C, Wallis J, Allen-Davis J: Which teen mothers choose Norplant? J Adolesc Health 16350-353, 1995 66. Sujuan G, Mingkun D, Linde Z, et a1 A five-year evaluation of Norplant I1 implants in China. Contraception 50:27-34,1994 67. Wagner KD Major depression and anxiety disorders associated with Norplant. J Clin Psychiatry 57152-157, 1996 68. Waites GMH Male fertility regulation: The challenges for the year 2000. Br Med Bull 49210-221,1993 69. Ward CR, Peterson CM, Hatasaka HH: A hook-fraction technique for Norplant removal. Obstet Gynecol86:848-850,1995 70. Westfall JM, Main DS:The contraceptive implant and the injectable: A comparison of costs. Fam Plann Perspect 2734-36, 1995 71. Westhoff C, Wieland D Depression in users of depo-medroxyprogesteroneacetate. Contraception 51:351-354,1995 72. Westhoff C, Truman C, Kalmuss D, et al: Depressive symptoms and Depo-Provera. Contraception 57237-240,1998 73. Westhoff C, Truman C, Kalmuss D, et a1 Depressive symptoms and Norplant contraceptive implants. Contraception 57241-245, 1998 74. World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives: Breast cancer and depot-medroxyprogesteroneacetate: A multinational study. Lancet 338:833-838,1991 75. World Health Organization: A multicenter comparative study of serum lipids and apolipoproteins in long-term users of DMPA and a control group of IUD users. Contraception 47177-191,1993 76. Zibners A, Cromer B, Hayes J: Continuation rates for hormonal contraception in adolescents. J Pediatr Adolesc Gynecol, in press 77. Wysowski DK, Green L Serious adverse events in Norplant users reported to the Food and Drug Administration‘s Medwatch spontaneous reporting system. Obstet Gynecol85538-542, 1995 Address reprint requests to Zeev Harel, MD Division of Adolescent Medicine Hasbro Children’s Hospital 593 Eddy Street Providence, RI 02903
0031-3955/99 $8.00
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THE USE OF LONG-ACTING CONTRACEPTIVES IN ADOLESCENTS Zeev Harel, MD, and Barbara Cromer, MD
Levonorgestrelimplants (Norplant) and depot medroxyprogesterone acetate (DMPA) injections (Depo-Provera), long-acting contraceptives approved by the US Food and Drug Administration, are effective, convenient, coitus independent, 29 These factors make them important and and require no daily compliance.“ desirable options for preventing teenage pregnancies. l5rz5,
PHARMACOLOGIC ACTIONS
The implants, which consist of six small, flexible, Silastic rods containing levonorgestrel (a second-generation progestin) placed subdermally, provide immediate contraception effective for at least 5 years. Each capsular implant contains 36 mg levonorgestrel. The capsules are sealed with a Silastic adhesive and sterilized. Each capsule is 2.4 mm in diameter and 34 mm in length.15 The implants release approximately 80 pg/d levonorgestrel in the first 6 months, giving a blood level of 0.3 to 0.5 ng/mL. This release rate decreases gradually to 30 to 35 pg/d for the remainder of implant with blood levels of 0.29 to 0.35 ng/mL.l0 DMPA is a microcrystalline suspension of medroxyprogesterone acetate (a first-generation progestin). After intramuscular injection of 150 mg of DMPA, serum concentrations of medroxyprogesterone acetate range from 1.5 to 3.0 ng/ mL for a few days. Serum concentrations gradually decrease and remain relatively constant at approximately 1 ng/mL for 2 or 3 months. Although variable from person to person, serum concentrations decrease gradually thereafter to From the Division of Adolescent Medicine, Hasbro Children’s Hospital; the Department of Pediatrics, Brown University, Providence, Rhode Island (ZH); the Division of Adolescent Medicine, Children’s Hospital; and the Department of Pediatrics, Ohio State University, Columbus, Ohio (BC)
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less than 0.2 ng/mL during the sixth month and become undetectable (< 0.02 ng/mL) at about 7.5 to 9.0 months following administration.& The implants and DMPA are progestins with similar antiestrogen activity but that differ in their binding to glucocorticoid receptors, androgen receptors, and sex hormone-binding globulin (SHBG, Table 1).Levonorgestrel has a greater progestogenic potency, allowing a smaller dose of progestin to be used to inhibit ovulation; however, the greater binding of levonorgestrel to androgen receptors and to SHBGS0may lead to androgenic side effects, such as acne and hirsutism. DMPA strongly binds to glucocorticoid receptors,50which may lead to steroidlike effects, such as an increase in appetite and weight gain. MECHANISM OF ACTION
Long-acting, progestin-only contraceptives affect both the hypothalamicpituitary-ovarian axis and the genital tract. At the level of the hypothalamus, gonadotropin-releasing hormone (GnRH) pulse frequency increases, with no change in pulse amplitude.49At the pituitary level, luteinizing hormone (LH) pulsatility remains intact; however, LH pulse frequency increases, whereas LH pulse amplitude decreases, and the midcycle LH surge is s ~ p p r e s s e d Mean .~~ follicle-stimulatinghormone (FSH) secretion increases, and FSH responsiveness to gonadotropin-releasing hormone is augmented.49At the ovary, estradiol secretion is decreased and remains within the early follicular phase range.15,u, Follicular development and maturation are inhibited. As a result of a lack of estrogen and lack of the positive-feedback midcycle LH surge, ovulation is inhibited for as many as 7 to 9 months after a single DMPA injection%and does not occur in more than 50% of the cycles in Norplant users.- The low blood levels of levonorgestrel provided by Norplant are sometimes not enough to completely suppress gonadotropins. Consequently, FSH and LH may be released, resulting in follicular development and periodic increases in estradiol. Stimulation by gonadotropins may result in excessive follicular enlargement63 and in transient functional ovarian cysts that have been reported in as many as 10% of Norplant users.2O A subsequent decrease in estradiol levels may lead to irregular bleeding in women using this method. Despite the occasional occurrence of ovulatory cycles in Norplant users, this method remains effective mainly
Table 1. CHARACTERISTICSOF MEDROXYPROGESTERONE ACETATE AND LEVONORGESTREL Characteristic
Progestational Antiestrogen Relative binding affinity to glucocorticoid receptors Relative binding affinity to androgen receptors Relative binding affinity to SHBG
Medroxy progesterone Acetate (Depo-Provera)
Levonorgestrel (Norplant)
++ ++
++ ++
f
t
-
(about 50 times more) -
-
tt 7t
(about 9 times more) (about 500 times more)
SHBG, Sex hormone-binding globulin. Adaptedfrom Pollow K,Juchem M, Grill HJ,et a1 Gestodene: A novel synthetic progestin: Characterization of binding to receptor and serum proteins. Contraception 40325341,1969;with permission.
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because of other long-acting, progestin-only contraceptive-induced changes at the level of the uterus, cervix, and vagina. At the level of the uterus, the endometrium remains thin and nonproliferative, and implantation (if ovulation does occur) is inhibited.15,25 In the cervix and vagina, long-acting, progestin-only contraceptives reduce secretions and thicken the cervical mucus to inhibit sperm penetration." INDICATIONS AND CONTRAINDICATIONS FOR USE
Long-term contraception is an attractive choice for adolescents who have had problems of compliance with other contraceptive methods and for adolescents who are at risk for complications from combined estrogen-and-progestin oral contraceptive pills (OCPs). Preliminary reports also suggest that DMPA has a beneficial effect on seizure activity in patients with seizure disordersP as well as a potential for reducing painful crises in patients with sickle cell disease.18 The long-acting contraceptives are contraindicated in pregnancy and in patients with sex hormone-dependent tumors or active liver disease. Although the package labeling lists a personal history of thromboembolism as a contraindication, the long-acting, progestin-only contraceptives have not been associated with clinically signihcant changes in coagulation parametersz4,55 or with an increased rate of stroke among users.n CLINICAL ADVANTAGES AND DISADVANTAGES AND POTENTIAL MEDICAL CONCERNS
The obvious advantage to patients of both implants and DMPA is that their use obviates the need for daily or event-specific compliance. Because the rate of compliance with OCPs is generally low in female adole~cents,2~ pregnancy rates are discouragingly high in this population. Therefore, the advent of a device (implants), which, after the initial procedure, provides high contraceptive efficacy without any involvement of these patients for 5 years, is very appealing. Teenagers desiring a long-acting contraceptive who have difficulty accurately predicting their life circumstances over the next 5 years may prefer a shorter period of protection, such as the 3-month period provided by DMPA injection. The implants are a cost-effective contraceptive method when used for the full 5-year lifespan; however, if an adolescent discontinues the implant before she has used it for at least 4 years, the injectable DMPA becomes the less costly option.70 Two areas of concern regarding clinical complications of DMPA deserve further investigation and elucidation. First, after the finding of breast tumors in dogs given huge doses of DMPA, two large epidemiologic studies were conducted to explore the risks in h~ma11~.4~, 74 Women who had used DMPA for a long period of time and who initiated use many years previously were not at increased risk for breast cancer, but the relative risk was increased twofold in women fewer than 35 years of age within 5 years of initial use.41,47,74 "his lack of overall increase in risk, and the fact that the increase in risk was confined to young-adult recent users, suggest that DMPA may accelerate the growth of already existing tumors rather than promote the formation of new ones.4l The other area of concern relates to potential progressive loss of bone density with prolonged use of DMPA, the putative mechanism being through suppression of ovarian production of estrogen via central suppression of gonadotropins. In a
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cross-sectional design, Cundy et all3 found lower bone density in older women who had used DMPA for more than 5 years compared with that of nonhormonal contr01s.’~In a follow-up study of a similar group of women, partial recovery was found after discontinuation of the method.14 In a prospective study in adolescents, Cromer et a1 found a significant decrease in bone density after 2 years of treatment compared with an increase among girls using implants or no hormonal therapy7 This increase in bone density in adolescents using Norplant may be attributed to periodic increases in estrogen levels in these patients. Given that adolescence is a crucial time for bone growth and consolidation,4 further investigation is needed to define the losses, the mechanisms, and the potential for recovery when treatment is discontinued. Two different issues of clinical concern relate to the implants. First, although the procedure for insertion is simple and ideally suited for primary care providers, removal of the rods is more difficult, occasionally requiring multiple visits; radiograph procedures; and, in rare cases, general anesthesia. Recent articles have been published with maneuvers designed to facilitate the removal procedure.58,69 The second issue is that implants have been linked, apparently because of the tiny amounts of Silastic material in the walls of the rods, with the same clinical syndromes associated with breast implants. Several class-action suits have been brought against the distributor based on complaints such as arthritis and chronic fatigue syndrome. A review of the literature reveals not even a case report documenting these symptom constellations; however, possibly because of such publicity, a dramatic decrease in the popularity of this contraceptive method has occurred. Progestins, depending on their dosage and androgenicity, can increase lowdensity lipoprotein (LDL) cholesterol plasma levels and decrease high-density lipoprotein (HDL) cholesterol plasma levels, changes that may predispose to the development of atherosclerosis.36Although initial studies in adult women suggested unfavorable lipid changes (11-24% increase in LDL cholesterol, 1015% decrease in HDL cholesterol, 3-39% decrease in apolipoprotein AI/B ratio) with DMPA” and with implants (increase in total cholesterol, increase in LDL cholesterol’), a study among US women found no statistically significant differences among pre-use and during-use lipid profiles of users of these meth0ds.3~ Delayed return to fertility, often mentioned as a disadvantage associated with DMPA use in adults, may be viewed as an advantage by parents of adolescents seeking contraception. Studies of adults suggest that delayed return to fertility after DMPA, although typically months after the last injection, may be as long as a year, whereas the return to fertility is immediate upon removal of implants.48In a study of adolescents, a high pregnancy rate was observed after discontinuation of implants and DMPA,30emphasizing the need to expedite the transition to a new contraceptive method upon discontinuation of these methods in adolescents. EXPERIENCE WITH LONG-TERM PROGESTINS IN ADOLESCENTS
Over the past 5 years, several surveys of clinical issues related to long-term progestins, most focusing on implants? 3, 12, 7.z 26, 33,51, 56, 65 have been published. Some have compared clinical aspects of implants with those of OCPs and other method^.^,^," Fewer surveys have included the examination of similar issues in DMPA 30, 38, 45, Adolescent contraceptive candidates choosing implants or DMPA tend to be older; to have had previous pregnancies and sexually
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transmitted diseases (STDs); and to have used, unsuccessfully, OCPs.6,22* 29, 51, 56, ffi The most frequently cited reasons for selecting a long-acting contraceptive were reliability, convenience, and prior problems with OCPs.2, Although DMPA is less visible than the implants, only 17% of adolescents cited the confidential nature of DMPA as a reason for selecting this rneth0d.2~ Several studies have examined adolescents’ attitudes toward initial choice and later satisfaction with the long-acting contraceptives. In a survey of 328 young women, Gold and CoupeyZ7found that DMPA had a higher acceptability rate (62%) than did implants (24%). In a study using structured interviews of 151 postpartum adolescents, those who had already had two live births were more likely to choose implants than ”other methods.” Other determinants of implant selection included involvement of a parent in the selection, peers who used implants, and Medicaid coverage.4o Using a qualitative methodology, Kuiper et al” examined 41 adolescents girls’ attitudes toward the implants. Their sample included girls using either Norplant or another form of contraception. The specific decision making seemed to cluster into three distinct areas: (1) social conditions, such as peer attitudes (including sex partners’ attitudes), and prospective stigma with use of the method; (2) informational sources, of which person-to-person transmission was the most important; and (3) personal attributes, such as personal goals and sense of control. Adolescents who chose a long-acting contraceptive seemed to be satisfied with the method; 74%51to 86%’ were satisfied with Norplant, and 84YP to 87%% were satisfied with DepoProvera. The majority (78%) of adolescents who had used Depo-Provera indicated that they would recommend the method to a friend.29 A potential concern with implants was that adolescents might not return for routine reproductive care and thus might miss early identification and management of STDs; however, Rainey et a1%found that compliance with return appointments for reproductive health care among adolescent implants users, although poor, was not significantly worse than the appointment compliance of adolescents who did not use implants. Although Cromer et a18 found a lower return rate after 6 months of initiation among adolescent implant users (48%) compared with DMPA users (70%) and OCP users (56%), two thirds of the noncompliant patients on implants returned with one prompting phone call? With DMPA injections, the concern was that adolescents would find the required frequent clinic visits (every 3 months) difficult to comply with. An initial report, however, found that most (80%) adolescents who used DMPA were not concerned about the %month return visits to the clinic and viewed it as a positive attribute of this meth0d.2~ Another important concern is that the use of long-term contraception would lead to a decrease in condom use and thus to an increase in the incidence of STDs. In general, condom use by adolescents on any type of hormonal contraceptive is poor. Only 21% of OCP users, 18% of DMPA users, and 9% of implant users reported consistent use of condoms,3. with 20% of condom users reporting a decrease in condom use within the first year after initiation of any hormonal contraceptive m e t h ~ dFurthermore, .~ the reported rate of condom use at last intercourse among sexually active adolescents on some form of hormonal contraception was less (52%) than that reported by adolescents not using hormonal methods (69Y0)~;however, other studies of adolescents found that the incidence of STDs did not significantly differ among implant users and users of OCPs or condoms” 51 and that condom use did not change significantly from baseline to follow-up among patients using DMPAZ9or implants.” Efforts should be made to increase the use of a barrier method among adolescents using hormonal contraception.
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Consistent findings have been recorded among the various surveys examining the continuation rates and pregnancy rates for the long-term progestins in adolescents. Continuation rates for implants are generally high, approximating 90% over 6 to 15 months compared with much lower rates (< 60%) observed concurrently in OCP users.3*12, 22, 26* 51 Findings related to continuation rates for adolescent DMPA users are rather variable; they are consistently lower than those reported for implant users. Whereas continuation rates exceeding 75% at 9 monthsz9and 1 yeaP have been reported in select populations using DMPA, more recent studies have reported 1-year continuation rates closer to 40Y0.5~. 76 One consistent finding, however, is that about approximately one third of DMPA discontinuers restart this method within a few Unsurprisingly, pregnancy rates are much higher in OCP users (20-38%) over 6 to 15 months compared with 2% among implant users.=, 51 In a case study and review of the literature, Dias and 0Maral9 found that implant users with overweight and regular menstrual cycles were at greater risk for failure of this method. No pregnancies were reported in studies evaluating DMPA in adolescent^.^^, 38, 64 The long-acting contraceptives have played an important role in the attempt to prevent repeat pregnancies in adolescents. Postpartum levonorgestrel implant insertion has been associated with a siguficant decrease in the repeat pregnancy rate among adolescents in the United States.5l The probability of repeat pregnancy at 12 months postpartum among subjects choosing DMPA was also lower (11%)than the probability of repeat pregnancy (28%) among postpartum OCP users, but the 1-year continuation rate was only 34% among DMPA postpartum users.* To prevent subsequent pregnancy, many centers in the United States insert the implants or administer the first injection of DMPA in nonlactating mothers immediately postpartum, before discharge from the h0spital.4~. 51 Detectable amounts of levonorgestrel and DMPA have been identified in the milk of mothers who received these long-acting contraceptives postpartum. Some initial studies have shown that the use of progestins in lactating women may decrease breast milk protein contenP and have raised the possibility that this may negatively affect infant growth and development, as well as increase the potential for infections caused by reduced immunoglobulins in the breast milk. More recent studies, however, showed that administration of a long-acting, progestinonly contraceptive at 6 weeks postpartum did not adversely affect infant growth 54 Only a few studies have examined the effects of longand de~elopment?~, acting contraceptives administered before the sixth postpartum week in breastfeeding women?* Until more studies are available, the manufacturers of DepoProvera or Norplant recommend to initiate use only after the sixth postpartum week if exclusively breast-feeding. BEGINNING ADOLESCENTS ON LONG-ACTING, PROGESTIN-ONLY CONTRACEPTIVES
Adolescents considering long-acting contraceptives should be counseled about the benefits and the side effects of DMPA and implants before the beginning of either of these methods (Fig. 1). Because prior use of a combined OCP reduced the duration of menstrual bleeding during the first 6 months of use of a long-term, progestin-only contraceptive in one study,29the continued use of OCPs until initiation of implants or DMPA is recommended. The optimal time to initiate a long-acting contraceptive is within 5 days of the onset of menses. This practice ensures that these patients are not already pregnant and that bleeding (shedding of a proliferative endometrium) will not occur during the
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Profiles of good candidates for a long-term contraceptive method Poor pill compliance Previous pregnancy Selected medical conditions: Pregnancy contraindicated, seizure disorder, sickle cell disease
Review for contraindication Sex hormone - dependent tumor Active liver disease
Presentation of contraceptive menu Counsel about benefits and risks Encourage continuation with oral contraceptive pills until insertion or injection Return during menses
+
Insertion or injection Figure 1. Beginning a teen on a long-term, progestin-only contraceptive.
immediate period following initiation. With Depo-Provera, subsequent injections should be scheduled at 12-week intervals. To enhance compliance with return appointments, clinics should establish a system of mailing reminder cards or reminding patients by phone, but only after confidentiality issues have been discussed and documented in the chart. The administration of repeat injections by visiting home health nurses may be considered in some settings. If these patients return for injections at between 12 and 14 weeks, the injection should be administered only after a negative urine pregnancy test. Beyond 14 weeks, a urine pregnancy test should be obtained, and these adolescents should be instructed to abstain from sex or to use a barrier method for 2 weeks. A negative pregnancy test at the end of these 2 weeks allows for a restart of DMPA. Perhaps most importantly, adolescents' health care providers should continue to provide counseling about these methods during use and should immediately address any concern or problem associated with DMPA or implants. An open-door, open-telephone policy may allay fears and address side effects as they arise and
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is important in the attempt to further increase continuation rate of these methods in adolescents. OCCURRENCE AND TREATMENT OF SIDE EFFECTS
Disrupted Menstrual Cycle
Menstrual abnormality is the major side effect and reason for discontinuation of long-term, progestin-only contraceptives.mBoth prolonged spotting or bleeding episodes and amenorrhea have been reported in adolescents using implants" 3, 6* 12, 22, 26, 33* 51* and DMPA.6,29, 38* 64 Although the continued use of DMPA has been associated with an increased Occurrence of amenorrhea: the continued use of levonorgestrel has been associated with resumption of regular menstrual cycles in approximately one third of adolescents using this method.5I Although the reason for the disrupted cycles is not yet completely understood, it has been attributed to the relative deficiency of estrogen in adolescents using DMPA and to fluctuations in estrogen levels during Norplant use. Indeed, estrogen has been found effective in the treatment of patients with bleeding episodes associated with use of long-term, progestin-only In the event of persistent bleeding while patients are using long-term, progestinonly contraceptives, physicians are recommended to proceed as follows: 1. Rule out STDs, such as gonorrhea or chlamydia. 2. Obtain hemoglobin and hematocrit counts. 3. Offer reassurance (if hemoglobin and hematocrit count is normal). 4. Prescribe a short course of conjugated estrogen (Premarin), 1.25 mg/d, or estradiol (Estrace), 2 mg/d for 7 to 21 days, or prescribe one or two cycles of OCPs. A short course of a nonsteroidal anti-inflammatory medication (ibuprofen, 800 mg three times a day for 5 d) has also been shown to reduce bleeding in users of long-acting contraceptives.21
Weight Gain
Weight gain has been noted with both DMPA and levonorgestrel use in adolescents and is the second most common side effect and reason for discontinuation of long-term, progestin-only contraceptives.mAn average weight gain of 3.9 kg has been reported after 1 year of levonorgestrel use in adolescent^.^ With DMPA, average weight gains of 6.0 +- 6.0 kg after 11 months and 9.0 ? 5.4 kg after 17 months have been reported among teenagers.%When changes in body mass index were reported, mean increases of 0.4 f 0.14 kg/m2 after 3 months, 1.08 ? 0.29 kg/m2 after 6 months,Z9and 1.1 -+ 0.3 kg/m2 after 9 monthsmhad been associated with DMPA use in adolescents. A mean increase of 1.3 ? 0.6 kg/mz in body mass index was reported after almost 22 months of levonorgestrel use in adolescents.30Because preoptic and hypothalamic neurons have been shown to accumulate 3H progestogen, long-term, progestin-only contraceptives may directly stimulate central hunger centers.57Glucocorticoid agonist activity7O interference with insulin action, and interference with serotonin metabolism35 might also lead to weight gain. At present, the approach to weight gain involves the recommendation for a healthy diet and an exercise plan. In future. studies with long-term, progestin-only contraceptives, efforts should be made to block
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the glucocorticoid agonist activity, improve peripheral insulin action, and increase serotonin buildup in the brain. Decreased Libido
A decrease in libido has been reported with the use of DMPA in adolescent^.^^^ 38 The decrease in estrogen levels observed with DMPA can lead to insufficient estrogenic effects at the levels of the sex organs and the CNS. Whether a decrease in the level of testosterone, caused by reduced ovarian androgen production, may lead to less libido in these patients, remains to be proven. DMPA has been shown to decrease the sex drive of male sex offenders,3l and preliminary results from animal research attributed this effect to direct action at the level of the brain." Whether long-term, progestin-only contraceptives affect CNS mechanisms controlling sexual behavior in female patients, particularly in adolescents, remains to be determined. Headaches
The increased occurrence of headaches has been reported as the third most common reason for discontinuing Depo-Provera and Norplant in adolescentsm; however, compared with baseline information, no significant change occurred in the frequency or type of headaches.during the first 6 months of use of DepoProvera or Norplant in adolescents.6Most of the reported headaches are mild and easily treated with nonsteroidal anti-inflammatory drugs. In patients with severe headaches, pseudotumor cerebri (increased intracranial pressure), which had been reported in women using implants, should be ruled out by funduscopic examination, in particular in obese adolescents or adolescents who had experienced excessive weight gainn Skin Changes
A loss of scalp hair was reported by 20% of patients who discontinued DMPA and by 10% of patients who discontinued implants to be the reason for discontinuation.30Acne was reported by 9% of adolescents who discontinued Depo-Provera and by 10% of those who discontinued Norplant.mWorsening of acne was reported by 24% of adolescents using implants*and by 15% of adolescents using DMPA," but, when assessed quantitatively, no significant changes occurred in numbers of acneiform lesions during the use of DMPA or implants by adolescents.6Excessive body hair growth was reported by 5% of adolescents who used implants.* These skin changes may be attributed in part to the antiestrogenic activity and androgenic potential of these progestins. Mood Changes
Because progestins may affect serotonin metabolism> 35 some physicians have expressed concern that the long-acting contraceptives may lead to mood changes. The literature is conflicting regarding the effects of the long-acting progestins on mood; the balance of the findings, however, indicates that a significant clinical effect may not exist. Regarding implants, Wagner recorded
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five cases of major depression and anxiety disorders that cleared after removal of the implants in adult women67;however, the cases were self-selected, resulting from phone-ins after a news media presentation of the potential association between implants and psychiatric disorders. Two studies, one of adults73and one of adolescents,6showed no increase in the incidence or severity of depression among implant users. Likewise, prospective studies found no increase in mood disturbance among DMPA users compared with their baseline mental status:, Galactorrhea An interesting finding among 64 teenagers on DMPA (notably, 35% of the group had initiated DMPA after pregnancy or therapeutic abortion) was that six (9%)developed galactorrhea? The only previous report of a similar finding was in a study of adults published in 1971, with 3 of 1123 users reporting galactorrhea-a much lower prevalence (0.3%). The purported mechanism is direct stimulation of the progestin on the acini of the mammary gland, with consequent production of fluid in the acini. This side effect is thought to be benign and resolves over time, even with continuation of the contraceptive method?
FUTURE LONG-ACTING HORMONAL CONTRACEPTIVES Implantable Contraception
To facilitate insertion and removal of the implants, attempts are being made to reduce the number of rods and to provide a biodegradable delivery system.17 Two-rod implants, which provide contraception for at least 3 years, are longer and more rigid and are already approved for use in a few countries.66Biodegradable implants would eliminate the need for removal but should be built in a way that allows removal if a patient so desires. One initial study found high pregnancy rates and other problems, such as migration of the capsules, local itching, and skin rash, in women using the biodegradable implants.I6 Injectable Contraception
Once-a-month injectable contraceptives include a combination of progestin and estrogen." Although all monthly injectables provide a better cycle control than does DMPA, an abnormal bleeding pattern is still the main complaint and reason for discontinuation.32In addition, the need to comply with monthly visits may pose an obstacle to their use in adolescents. Finally, combinations of a longacting progestin and a long-acting androgen are being studied as a potential long-acting contraceptive for men.@ SUMMARY
DMPA and implants have played an important role in the attempt to prevent teenage pregnancies. Adolescent health care providers should provide continued counseling to girls using DMPA or implants and should promptly address any concern associated with these methods. Future studies are war-
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ranted to explore ways to prevent or reduce the side effects of DMPA and implants, as well as to develop new, optimal, long-acting contraceptives. Detailed baseline information should be obtained in every future study that explores the presence of side effects during the use of long-acting contraceptives. ACKNOWLEDGMENTS The authors thank Wendy Wood, Karen Autieri, and Harold E. Regan, Jr, MA, for their skillful preparation of the manuscript.
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