Injectable contraception
Depot-Medroxyprogesterone Acetate
DMPA is formulated as microcrystals suspended in an aqueous solution. The approved dose for contraceptive purposes is 150 mg intramuscularly (gluteal or deltoid) every 3 months. A comparative trial established that the 100-mg IM dose is significantly less effective, but a reformulation, introduced in 2005, of 104 mg administered subcutaneously every 3 months is as effective as the 150 mg IM formulation. The contraceptive level is maintained for at least 14 weeks, providing a safety margin. It is one of the most effective contraceptives available, with about 1 pregnancy per 100 women after 5 years of consistent use.
DMPA is not a sustained-release system; it relies on high peaks of progestin to inhibit ovulation and thicken cervical mucus. The difference between low serum levels of progestins produced by sustained-release subdermal and intrauterine systems and a depot system like DMPA is as much as tenfold. Other widely used injectables are norethindrone enanthate, 200 mg every 2 months, and the monthly injectables, Lunelle (25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate) and Mesigyna (50 mg norethindrone enanthate and 5 mg estradiol valerate).
The indications and contraindications for the clinical use of DMPA are summarized in Table 1-8 .
TABLE 1-8 - INDICATIONS AND CONTRAINDICATIONS FOR USE OF DEPO-PROVERA
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Mechanism of Action
Accidental pregnancies occurring at the time of the initial injection of DMPA have been reported to be associated with higher neonatal and infant mortality rates, probably due to an increased risk of intrauterine growth restriction. The timing of the first injection is, therefore, very important. To ensure effective contraception, the first injection should be administered within the first 5 days of the menstrual cycle (before a dominant follicle emerges), or a backup method is necessary for 2 weeks. The duration of action can be shortened if attention is not paid to proper administration. The injection must be given deeply in muscle by the Z-track technique and not massaged. It is prudent to avoid locations at risk for massage by daily activities.
Efficacy
Advantages
Like sustained-release forms of contraception, DMPA does not require daily compliance and is not related to the coital event. Continuation rates are better and repeat pregnancy rates are reduced compared with oral contraceptive use in teenagers; however, continuation and repeat pregnancy rates are similar when adolescents begin these methods in the immediate postpartum period. DMPA is useful for women whose ability to remember contraceptive requirements is limited. It should be considered for women who lead disorganized lives or who are mentally retarded, but it can be difficult for some women to plan a clinician visit for injection every 3 months. Self-injection with subcutaneous DMPA can provide a more convenient alternative in these cases.
The freedom from the side effects of estrogen allows DMPA to be considered for patients with congenital heart disease, sickle cell anemia, or a previous history of thromboembolism and for women older than 30 years who smoke or have other risk factors such as hypertension or diabetes mellitus. The absolute safety with regard to thrombosis is mainly theoretical; it has not been proved in a controlled study. However, an increased risk of thrombosis has not been observed in epidemiologic evaluation of DMPA users, and a World Health Organiza-tion (WHO) case-control study could find no evidence for increased risks of stroke, myocardial infarction, or venous thromboembolism.
An important advantage exists for patients with sickle cell disease because evidence indicates an inhibition of in vivo sickling with hematologic improvement during treatment. The frequency and the intensity of painful sickle cell crises are reduced.
Another advantage is that DMPA increases the quantity of milk in nursing mothers, a direct contrast to the effect seen with combination contraception. The concentration of the drug in the breast milk is negligible, and no effects of the drug on infant growth and development have been observed. In a careful study of male infants being breastfed by women treated with DMPA, no metabolites of DMPA could be detected in the infant's urine and no alterations could be observed in the infant levels of FSH, LH, testosterone, and cortisol. Because of the slight positive impact on lactation, DMPA can be administered immediately after delivery. A study to investigate the impact of early initiation found no adverse effects on breastfeeding.
DMPA should be considered in patients with seizure disorders ; an improvement in seizure control can be achieved probably because of the sedative properties of progestins.
Other benefits associated with DMPA use include a decreased risk of endometrial cancer, comparable with that observed with oral contraceptives, and probably the same benefits found with the actions of the progestins in oral contraceptives: reduced menstrual flow and anemia, less pelvic inflammatory disease (PID), less endometriosis, fewer uterine fibroids, and fewer ectopic pregnancies. A failure to document a reduced risk of ovarian cancer by the World Health Organization probably reflects the study's low statistical power and the high parity in the DMPA users.
DMPA, like oral contraception, can reduce the risk of pelvic inflammatory disease; however, the only study was hampered by small numbers. Suppression of ovulation means that ectopic pregnancies are abolished and ovarian cysts are rare.
The greater the number of choices that women have, the more likely they are to find a contraceptive that works well for them. For some women, the primary advantages of DMPA are privacy and ease of use. No one but the user needs know about the injection, and the 3-month schedule can be easy to maintain for women who do not mind injections. In some societies, injections are respected as efficacious; in these situations, DMPA is the most popular contraceptive despite bleeding changes and other side effects. The advantages of the use of DMPA are summarized in Table 1-9 .
TABLE 1-9 - ADVANTAGES OF THE USE OF DEPO-PROVERA
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Problems
If necessary, breakthrough bleeding can be treated with exogenous estrogen, 1.25 mg conjugated estrogens, or 2 mg estradiol, given daily for 7 days. A nonsteroidal antiinflammatory drug (NSAID) given for a week is also effective; another option is to administer an oral contraceptive for 1 to 3 months. Giving the DMPA injection earlier than 3 months does not change the bleeding pattern. Most women can wait for amenorrhea without treatment if they know what to expect with time. Transdermal estrogen did not improve irregular bleeding enough to enhance continuation rates by young women who had had an abortion.
About one third of patients discontinue DMPA by the end of 1 year, 50% by the end of 2 years, and about 80% by the end of 3 years. The 1-year continuation rate in Texas public clinics was only 29%, much lower than reported elsewhere. It was equally low among young women who requested an injection immediately after elective abortion. In a large international study, the most common medical reasons for discontinuing DMPA during the first 2 years of use were headaches (2.3%), weight gain (2.1%), dizziness (1.2%), abdominal pain (1.1%), and anxiety (0.7%).
In Western societies, depression, fatigue, decreased libido, and hypertension are also encountered. Whether medroxyprogesterone acetate causes these side effects is difficult to know because they are very common complaints in nonusers as well. When DMPA users are studied closely, no increase in depressive symptoms can be observed, even in women with significant complaints of depression prior to treatment.
Attempts to document weight gain specifically associated with DMPA have had mixed results, some finding no increase and others a small increase (e.g., about 4 kg over 5 years in one and 11 kg over 10 years in another).In a placebo-controlled experiment, DMPA had no effects on food intake, energy expenditure, or body weight. As with oral contraception, the weight gain may not be hormone-induced but reflect lifestyle and aging. On the other hand, specific patients and certain ethnic groups may be more susceptible to weight gain; for example, significant weight gain was reported in Navajo women using DMPA and in already overweight African American teens. Those who were of normal weight at initiation of DMPA did not gain more than control subjects.
If symptoms are truly due to the progestin, unlike pills, implants, rings, and patches, DMPA takes 6 to 8 months after the last injection to disappear. Clearance is slower in heavier women. Approximately half of women who discontinue DMPA can expect normal menses to return in 6 months after the last injection, but 25% will wait a year before resumption of a normal pattern.
Cancer
Breast Cancer
Other Cancers
An increased risk of cervical dysplasia cannot be documented even with long-term use (4 or more years). No increase in adenocarcinoma or adenosquamous carcinoma could be detected in the WHO study. The WHO study has not detected an increased risk of invasive squamous cell cancer of the cervix in DMPA users; however, the risk of cervical carcinoma in situ was slightly elevated in the WHO case-control study. It is not certain whether this is a real finding or a consequence of unrecognized biases, especially detection bias.Metabolic Effects
There are no clinically significant changes in carbohydrate metabolism or in coagulation factors. There are no studies available assessing the impact of DMPA in women with diabetes mellitus or in women with previous gestational diabetes.
Effect on Bone Density
The degree of bone loss in these studies is not as severe as that observed in the early postmenopausal years. Furthermore, this amount of bone loss is not so great that at least a portion of it cannot be regained. Bone density measurements in women who stopped using DMPA indicated that the loss was largely regained in the lumbar spine but not in the femoral neck within 2 years even after long-term use, and in another cohort of past users, both spinal density and hip density were somewhat restored 30 months after discontinuation. Most importantly, cross-sectional studies of postmenopausal women in New Zealand and in a large multicenter worldwide population could not detect a difference in bone density comparing former users of DMPA with never users, indicating that any loss of bone during use is likely to be modest.
Bone density increases rapidly and significantly during adolescence. Almost all of the bone mass in the hip and the vertebral bodies is accumulated in girls by age 18, and the years immediately following menarche are especially important. For this reason any drug that prevents this increase in bone density can increase the risk of osteoporosis later in life. A prospective study in 47 adolescents documented that DMPA (15 users) was associated with a loss of lumbar bone density (approximately 1.5% in 1 year) compared with the normal increases observed in users of Norplant (7 users) and oral contraceptives (9 users).
The mixed results, the degree of bone loss, and evidence that some bone loss is regained all argue that the use of DMPA should not be limited by this concern and that supplemental estrogen treatment is not indicated (and would influence and complicate compliance). This concern will require ongoing surveillance of past users. However, at present, concern about bone loss should not be a reason to avoid this method of contraception. It is unlikely that bone loss occurs sufficiently to substantially raise the risk of osteoporosis later in life.
Effect on Future Fertility
Subcutaneous Administration of DMPA
All of these problems are addressed by subcutaneous injection of 104 mg, rather than 150 mg, of DMPA suspended in 0.65 mL of excipients that differ from those used in IM DMPA. The peak DMPA concentrations are lower, but efficacy remains high; there were no pregnancies in the initial clinical trial among 1783 women, 11% of whom were obese. Bone density did not change over a year of use, and return to ovulation was faster than with the traditional IM formulation. Bleeding patterns are like those of IM DMPA, except that women become amenorrheic more slowly; at one year about 45% of users are amenorrheic, compared with 54% using IM DMPA.
The needle packaged with subcutaneous DMPA is different from the one used for IM administration, making self-injection possible. A subset of women in the initial clinical trial were able to give their own injections without difficulty and had no pregnancies.
Short-Term Injectable Contraceptives
Monthly or every-other-month injectable combinations of estrogen and progestin are not new, having been developed over several decades. This method of contraception is popular in China, Latin America, and eastern Asia. A preparation widely used in China consists of 250 mg 17-hydroxyprogesterone caproate and 5 mg estradiol valerate, known as Chinese Injectable No. 1.Lunelle (Cyclofem)
One disadvantage is the need for a monthly injection; another disadvantage is the likelihood that the combination of estrogen and progestin will inhibit lactation. The requirement for a monthly injection can be made more convenient by the use of an automatic device for self-administration.Approximately 80% of women who are amenorrheic on Depo-Provera will develop vaginal bleeding if switched to Lunelle. The same contraindications, concerns, problems, and probably benefits reported with oral contraception should apply to Lunelle, which is no longer sold in the United States but is available in many other countries.
Norethindrone Enanthate
Dihydroxyprogesterone Acetophenide and Estradiol Enanthate
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