Implant contraception

  Implant contraception

  Subdermal contraceptive implants offer women long-acting controlled release of progestins. Since the 1980s, these implants have been approved in more than 60 countries and used by 11 million women worldwide. Their high efficacy, along with their ease of use, makes them a good contraceptive option for several groups of women: those who require progestin-only methods because they should not use estrogen, teens who find adherence to a contraceptive regimen difficult, and healthy adults who desire long-term protection. The levonorgestrel (LNG) implant, no longer marketed in the United States, garnered a million American users but was sometimes difficult to insert and remove. A highly effective and long-lasting single-rod etonogestrel (ENG) implant (Implanon) makes implant contraception available again in the United States.

Benefits of Implantable Contraception

 

  Implants offer a variety of benefits to women. They provide long-term, effective prevention of pregnancy without the need for daily or weekly action, as with pills, rings or patches, or for regular injections. Implant contraception is cost-effective compared with short-acting methods or an unplanned pregnancy.The sustained administration of a low dose of progestin and maintenance of stable serum levels provide high efficacy, a long duration of action, a short fertility recovery time, and no reported serious cardiovascular effects.
  Research and development of progestin-only subdermal implants began in the 1960s, but initial research with implants containing very low doses of progestins found that they were unsuccessful in preventing ectopic pregnancies. Development of the LNG implant, a 6-capsule implantable system using the potent progestin LNG, followed. In 1991 it became the first FDA-approved contraceptive implant. A million U.S. women chose the LNG implant as their contraceptive, and it proved highly effective: over a 7-year duration of use, only about 1% of users became pregnant. Despite low rates of pregnancy and few serious side effects, limited supplies of the Silastic components and negative media coverage led to the LNG implant's withdrawal from distribution in 2002, which left no implant alternative for American women.
  The 15-year experience with the LNG implant instigated further development and improvements in implant design. A 2-rod LNG system was FDA approved in 1998 but never marketed in the United States, although it has many users in Europe and Asia. The FDA has reviewed a contraceptive implant containing 68 mg of etonogestrel (ENG), the active metabolite of desogestrel, in a single rod made of ethylene vinyl acetate (EVA). This 1-implant contraceptive, the most effective hormonal method of birth control yet developed, is now used by more than 2 million women in Europe and Asia. In Australia, a quarter of all women practicing contraception in 2004 used this implant.

Progestin-Only Contraception

 

   Levonorgestrel binds with high affinity to the progesterone, androgen, mineralocorticoid, and glucocorticoid receptors, but not to estrogen receptors. Etonogestrel has shown no estrogenic, antiinflammatory, or mineralocorticoid activity, but it has shown weak androgenic and anabolic activity and strong antiestrogenic activity. Unlike LNG, which is bound mainly to sex hormone–binding globulin, ENG is bound mainly to albumin, which is not significantly affected by varying endogenous or exogenous estradiol concentrations. The overall safety of ENG has been demonstrated through studies of combined estrogen-progestin OCs, the combined vaginal ring, and progestin-only OCs, all of which use desogestrel, a close relative of etonorgestrel, as a component.

Mechanisms of Action

 

  Progestin-containing implants have two primary mechanisms of action: inhibition of ovulation and restriction of sperm penetration through cervical mucus. The LNG implant disrupts follicular growth and inhibits the ovulatory process by exerting negative feedback on the hypothalamic-pituitary axis, causing a variety of changes that range from anovulation to insufficient luteal function. A small number of women using LNG implants will have quiescent ovaries, but most will begin to ovulate as blood concentrations of LNG gradually fall. The ENG implant suppresses ovulation by altering the hypothalamic-pituitary-ovarian axis and down-regulating the luteinizing hormone surge, which is required to support the production, growth, and maturation of ovarian follicles. Some women , especially those with higher endogenous estrogen, form ovarian cysts while using implants. These are not pathologic, are rarely painful and do not require treatment.
  Even if follicles grow during use of progestin implants, oocytes are not fertilized. If the follicle ruptures, the abnormalities of the ovulatory process appear to prevent release of a viable egg. Antiestrogenic actions of the progestins affect the cervical mucus, making it viscous, scanty, and impenetrable by sperm. These ovarian and cervical mechanisms of action provide high contraceptive efficacy and occur prior to fertilization. No signs of embryonic development have been found among implant users, a finding that indicates that progestin implants have no abortifacient properties.


   The high efficacy of Single-Rod Etonogestrel Implant- new device results from the capacity of a low dose of ENG to suppress ovulation and from its long duration of action. After subdermal insertion, users need do nothing more to have nearly complete protection from pregnancy for up to 3 years. The one rod is a great improvement over the old six-capsule LNG implant system, both in time and in ease of insertion. In the U.S. and European trials of the ENG implant system, which began in 1995, average insertion time was 1 minute and removal time was 3 minutes—much faster than with the LNG implant system.
  Its convenience is enhanced by other design features as well. The inserter is preloaded and disposable, and because only one rod is implanted, there is no chance that insertion of additional capsules will move previously placed capsules out of position. In addition, EVA, the plastic from which it is fabricated, makes it is less likely than older Silastic implants to form a fibrous sheath that can make removal more difficult. These differences likely simplify insertion and removal, which for patients means little discomfort, an unobtrusive implant, and almost no scarring. For clinicians it means faster and simpler insertion and removal procedures.

Pharmacology

 

  The ENG implant (Implanon) consists of one nonbiodegradable rod of 40% EVA and 60% ENG (40 mm × 2 mm) covered with a rate-controlling EVA membrane 0.06 mm thick. The rod contains 68 mg ENG, initially absorbed by the body at a rate of 60 mg per day and slowly declining to 30 mg per day after 2 years of use. The high initial rate of absorption is probably due to a significant amount of ENG released from the uncovered ends of the implant. Peak serum concentrations (266 pg/mL) of ENG are achieved within 1 day after insertion, suppressing ovulation. Like other contraceptive steroids, serum levels of ENG are reduced in women taking liver enzyme-inducing drugs such as carbamazepine, griseofulvin, phenytoin, and rifampicin but are not affected by antibiotics.
   Steady release of ENG into the circulation avoids first-pass effects on the liver. Bioavailability of ENG remains nearly 100% throughout 2 years of use. The elimination half-life of ENG is 25 hours, compared with 42 hours for LNG. After implant removal, serum ENG concentrations become undetectable within 1 week. Return of ovulation occurs in 94% of women within 3 to 6 weeks after the method is discontinued.

Efficacy

 

   The efficacy of the single-rod ENG implant was established as greater than 99% in clinical trials of 1100 women for a total of 26,700 cycles of use. Of these, 835 women completed 2 to 3 years and an additional 526 used the ENG implant for 3 years or longer. Neither intrauterine nor ectopic pregnancies were observed during these trials. Among the subjects were 365 women whose body weight was 154 pounds (70 kg) or more, none of whom became pregnant.

Metabolic Effects

 

  Published studies regarding the ENG implant indicate that metabolic effects are minimal and unlikely to be clinically significant. The ENG implant does not appear to have any clinically meaningful effect on lipid metabolism, carbohydrate metabolism, liver function, hemostatic factors, blood pressure, thyroid, or adrenal function.

Safety

  Overall, implants, including the ENG implant, are regarded as safe, with rates of adverse events (including death, neoplastic disease, cardiovascular events, anemia, hypertension, bone density changes, diabetes, gall bladder disease, thrombocytopenia, and pelvic inflammatory disease) comparable with those in women not using implants. The ENG implant reduced or eliminated menstrual pain in 88% of women previously experiencing dysmenorrhea; pain increased in only 2% of the ENG implant users. In a study comparing 42 pairs of infants and lactating mothers using the ENG implant with 38 pairs using intrauterine devices, there were no significant differences between groups in milk volume, milk constituents, timing or amount of supplementary food, or infant growth rates.
   Low-dose progestin contraceptives have few contraindications. They may be less effective in obese women and in those using drugs that stimulate the liver's cytochrome metabolism of steroids, such as some antibiotics (e.g., rifampin) and some anticonvulsants (e.g., phenytoin).

Insertion and Removal

 

Although the ENG implant is designed to facilitate rapid and simple insertion and removal, clinicians should first be trained. Insertion is less complex than with the six-capsule LNG implant, and average insertion time for the ENG implant is 1 to 2 minutes. The disposable applicator comes preloaded. The tip of the needle has two cutting edges, each with a different slope . The extreme tip is more angulated than the remainder and is sharp to facilitate initial penetration of the skin. The upper portion is less angulated and unsharpened to reduce the risk of reperforating the skin during advancement of the implant after initial penetration.

  For easy removal, the implant should be placed subdermally on the inner aspect of the nondominant arm, 6 to 8 cm above the elbow. After disinfecting the insertion site, a small amount (0.1 mL) of local anesthetic can be injected with a tuberculin syringe at the site of skin penetration, but this is not usually necessary because the 19-gauge insertion trocar is very sharp. After insertion, the implant might not be visible but should be palpable.
  For women who either have not been using a contraceptive method or have been using a nonhormonal method, insertion should occur between days 1 and 5 of menses. For women changing from a combination or progestin-only OC or from intrauterine contraception, the ENG implant can be inserted during a hormone-free week. For women changing from injectable contraception, insertion should occur on the day the next injection is scheduled. No backup is necessary if timing of insertion occurs as detailed in the product information. If the ENG implant is the contraceptive method selected following an abortion or delivery, it can be inserted immediately; no additional contraceptive method is required. In all cases, pregnancy should be excluded before insertion, although there is no evidence that hormonal contraceptives cause birth defects.
   The ENG implant can be removed at any time at the woman's discretion, but if left in place it remains effective for 3 years. Removal requires making a 2- to 3-mm incision at the distal tip of the implant and pushing the other end of the rod until it pops out. Mean removal time is commonly less than 5 minutes (2.6 to 5.4 minutes). Pain, swelling, redness, and hematoma have been reported during insertion and removal. Because return to ovulation is rapid following removal, women still desiring contraception should begin another method immediately or have a new rod inserted through the removal incision.

Disadvantages

 

  Although progestin-only contraceptives offer a safe and effective method of preventing pregnancy, they have some drawbacks. Implants require a minor surgical procedure by a trained clinician for insertion and removal. Cost-effectiveness of the method depends upon long-term use; early discontinuation negates this benefit. Lack of protection against sexually transmitted infections (STIs) is a disadvantage of the ENG implants as well as of all hormonal contraceptive methods.
  Side effects associated with the ENG implant include menstrual irregularities (infrequent bleeding (26.9%), amenorrhea (18.6%), prolonged bleeding (15.1%), frequent bleeding (7.4%)), weight gain (20.7%), acne (15.3%), breast pain (9.1%), and headache (8.5%), but these symptoms rarely provoked discontinuation.  Women using any of the progestin-only methods notice changes in bleeding patterns.  A comparative study of bleeding patterns in single-capsule ENG implant users and six-capsule LNG implant users found a statistically significant decrease in mean number of bleeding or spotting days in the ENG users (15.9 to 19.3 days versus 19.4 to 21.6 days; P = .0169). Because total uterine blood loss is reduced, users of progestin-only contraceptives (as well as OCs) are less likely to be anemic. However, the study also found that users of ENG implants had more variable bleeding patterns than users of the LNG implants. Table 1 -10 shows the differences in bleeding between implants, but it is impossible to predict which of these patterns a woman is likely to experience. Despite side effects and dependence on clinicians to insert implants, most women using implantable contraception are satisfied with the method and cite its long duration of use, convenience, and high efficacy.  

TABLE 1-10 - COMPARISON OF VAGINAL BLEEDING PATTERNS IN ENG AND LNG USERS

Bleeding Pattern[*]	ENG Implant (%) (n = 169)	LNG Implant (%) (n = 163)	Statistically Significant
Amenorrhea	21	5	Yes
Infrequent bleeding	27	22	Yes
Frequent bleeding	6	4	No
Prolonged bleeding	12	9	No

ENG, etonogestrel; LNG, levonorgestrel.

*	90-day reference periods.

Discontinuation Rates

 

   Discontinuation rates for the ENG implant have varied by area of use, ranging from 30.2% in Europe and Canada to 0.9% in Southeast Asia.  Bleeding irregularities are cited as the most common reason for discontinuation of the ENG implant. A meta-analysis of 13 studies published between 1989 and 1992 found that among 1716 women using the ENG implant, 5.3% discontinued in months 1 through 6, 6.4% discontinued in months 7 through 12, 4.1% discontinued in months 13 through 18, and 2.8% discontinued in months 19 through 24. Overall, 82% of women continued to use the ENG implant for up to 24 months.

Counseling

  Counseling women to expect bleeding irregularities reduces discontinuation of this system. Prospective users should receive complete information about bleeding irregularities so they can make informed decisions regarding the side effects they are willing to accept in order to benefit from high contraceptive efficacy. Preinsertion counseling and postinsertion follow-up are essential for continued use of implants. Satisfaction with the method increases with proper counseling and minimizes costly removals.
  Sexually active women are exposed to the risk of pregnancy as well as to the risk of STIs, such as human immunodeficiency virus, hepatitis B, human papillomavirus, Chlamydia trachomatis, syphilis, and gonorrhea, whose sequelae may be life threatening. Implantable contraceptives neither increase the risk of nor offer protection against STIs. Women counseled about contraception should also be informed about the risks of STIs and advised that use of condoms concomitantly with an effective method of pregnancy prevention is the best means of protection against unintended pregnancy and STIs. It seems likely that the ENG implant, like OCs and DMPA, reduces the risk of pelvic upper tract infection.
   Clinical experience with the ENG implant has demonstrated that method effectiveness and satisfaction are closely associated with patient education and provider training. In the first 18 months after the ENG implant was introduced in Australia in May 2001, an unexpectedly high number of adverse incidents were reported, and 100 unintended pregnancies occurred. Almost all of these events were traced to improper insertion by untrained clinicians or to poor patient selection, timing, and counseling. Policies that adequately document the process, procedure, and patient consent were initiated by the Royal Australian College of General Practitioners and have corrected the problems.
Intrauterine Hormonal Contraception
  Both medicated and nonmedicated intrauterine devices have been used for contraception. Those containing copper or synthetic progestins are more effective and have fewer side effects than simple plastic or stainless steel devices, and they have largely replaced the earlier varieties. Much information about intrauterine contraception is outdated and irrelevant because it is based on studies of these old contraceptives.
   The LNG-20 (Mirena), manufactured by Leiras-Schering AG in Finland, releases in vitro 20 mg of levonorgestrel per day. The vertical arm of this T-shaped device has a collar that contains 52 mg levonorgestrel dispersed in polydimethylsiloxane. The LNG is released initially at a rate of 20 mg per day in vivo, progressively declining and reaching half of the initial rate after 5 years. The levonorgestrel intrauterine delivery system (IUS) is approved for 5 years, but it lasts up to 10 years, and reduces menstrual blood loss and pelvic infection rates.  Indeed, the levonorgestrel IUS is about as effective as endometrial ablation for the treatment of menorrhagia. The local progestin effect directed to the endometrium can be used in patients taking tamoxifen, patients with dysmenorrhea, and postmenopausal women receiving estrogen therapy.  Smaller devices releasing 5 mg or 10 mg levonorgestrel have been developed in Europe for use for at least 5 years in postmenopausal women.
   The progestin-releasing IUS adds the endometrial action of the progestin to the foreign body reaction. The endometrium becomes decidualized with atrophy of the glands. The progestin IUS probably has two mechanisms of action: inhibition of implantation and inhibition of sperm capacitation, penetration, and survival. The levonorgestrel IUS produces serum concentrations of the progestin about half those of Norplant so that ovarian follicular development and ovulation are also partially inhibited; after the first year, cycles are ovulatory in 50% to 75% of women, regardless of their bleeding patterns. Finally, the progestin IUS thickens the cervical mucus, creating a barrier to sperm penetration. The progestin IUS decreases menstrual blood loss (about 40% to 50%) and dysmenorrhea; with the levonorgestrel IUS, bleeding can be reduced by 90% 1 year after insertion. About 50% of women become amenorrheic 1 year after insertion of the levonorgestrel IUS.  Average hemoglobin and iron levels increase over time compared with preinsertion values.

Efficacy

  The copper-releasing intrauterine contraceptive (IUC) (TCu-380A or Paragard) is approved for use in the United States for 10 years. However, the TCu-380A has been demonstrated to maintain its efficacy over at least 12 years of use. The TCu-200 is approved for 4 years and the Nova T for 5 years. The levonorgestrel IUS can be used for at least 7 years and probably 10 years. The levonorgestrel device that releases 15 to 20 mg levonorgestrel per day is as effective as the new copper IUCs.
  The nonmedicated IUCs never have to be replaced. The deposition of calcium salts on the IUC can produce a structure that is irritating to the endometrium. If bleeding increases after a nonmedicated IUC has been in place for some time, it is worth replacing it. Some clinicians recommend replacing all older IUCs with the new, more effective copper IUCs. This makes sense because newer IUCs are more effective.
  The risk of ectopic pregnancy does not increase with increasing duration of use with the TCu-380A or the levonorgestrel IUS.  In a 7-year prospective study, not a single ectopic pregnancy was encountered with the levonorgestrel IUD, and in a 5-year study, only one.  In 8000 woman-years of experience in randomized multicenter trials, there has been only a single ectopic pregnancy reported with the TCu-380A (which is one-tenth the rate with the Lippes Loop or TCu-200). Therefore, the risk of ectopic pregnancy during the use of the copper IUS or the levonorgestrel IUC is much lower compared with rates in noncontraceptive users; however, if pregnancy occurs, the likelihood of an ectopic pregnancy is high.
  The protection against ectopic pregnancy provided by the TCu-380A and the levonorgestrel IUD makes these IUDs acceptable choices for contraception in women with previous ectopic pregnancies ( Table 1-11 ).

TABLE 1-11 - ECTOPIC PREGNANCY RATES PER 1000 WOMAN-YEARS

Method	Rate
No contraceptive, all ages	3.00-4.50
Levonorgestrel IUS	0.20
TCu-380A IUC	0.20

IUC, intrauterine contraceptive; IUS, intrauterine delivery system.

Side Effects

 

  With effective patient screening and good insertion technique, the copper and medicated IUCs are not associated with an increased risk of infertility after their removal. Even if IUCs are removed for problems, subsequent fertility rates are normal.
   The symptoms most often responsible for IUC discontinuation are increased uterine bleeding and increased menstrual pain. Within 1 year, 5% to 15% of women discontinue IUC use because of these problems. Smaller copper and progestin IUDs have reduced the incidence of pain and bleeding considerably, but a careful menstrual history is still important in helping a woman consider an IUC. Women with prolonged, heavy menstrual bleeding or significant dysmenorrhea might not be able to tolerate copper IUCs but might benefit from a progestin IUC. Because bleeding and cramping are most severe in the first few months after IUC insertion, treatment with an NSAID (which inhibits prostaglandin synthesis) during the first several menstrual periods can reduce bleeding and cramping and help a patient through this difficult time. Even persistent heavy menses can be effectively treated with NSAIDs. NSAID treatment should begin at the onset of menses and be maintained for 3 days. A copper IUC is available in China that also releases a small amount of indomethacin; this device is associated with markedly less bleeding.
It is not unusual to have a few days of intermenstrual spotting or light bleeding. Although aggravating, this does not cause significant blood loss. Such bleeding deserves the usual evaluation for cervical or endometrial pathology. These changes can be objectionable for women who are prevented from having intercourse while bleeding.
Following insertion of a modern copper IUC, menstrual blood loss increases by about 55%, and this level of bleeding continues for the duration of IUC use. This is associated with a slight (1 to 2 days) prolongation of menstruation. Over a year's time, this amount of blood loss does not result in changes indicative of iron deficiency (e.g., serum ferritin). With longer use, however, ferritin levels are lower, suggesting a depletion of iron stores. Assessment for iron depletion and anemia should be considered in long-term users and in women susceptible to iron deficiency anemia. In populations with a high prevalence of anemia, these changes occur more rapidly, and iron supplementation is recommended.
Because of a decidualizing, atrophic impact on the endometrium, amenorrhea can develop over time with the progestin-containing IUS. With the levonorgestrel IUS, 70% of patients are oligomenorrheic and 30% to 40% are amenorrheic within 2 years.  In a group of women who used the levonorgestrel IUS for more than 12 years, 60% were amenorrheic; 12% experienced infrequent, scanty bleeding; and 28% had regular but light bleeding. For some women, the lack of periods is so disconcerting that they request removal. On the other hand, this effect on menstruation is manifested by an increase in blood hemoglobin levels.
The levonorgestrel IUS is very effective when used to treat menorrhagia.  This noncontraceptive benefit is of such a magnitude that this method of treatment achieves comparable results when compared to surgical methods such as endometrial ablation or hysterectomy.  Bleeding is even reduced in the presence of leiomyomas, along with a reduction in myoma size. The levonorgestrel IUS has been used successfully to treat endometriosis, and especially dysmenorrhea associated with endometriosis.
Sufficient progestin reaches the systemic circulation from the levonorgestrel-containing IUD so that androgenic side effects, such as acne and hirsutism, might occur; however, in one study no change could be detected in the circulating levels of sex hormone–binding globulin, and, therefore, clinical effects are unlikely. More extensive clinical studies are needed to assess the impact of this IUS on the lipoprotein profile, but it is unlikely that the low dose of levonorgestrel has an important effect on cardiovascular risk.

Infections

IUC-related bacterial infection is now believed to be due to contamination of the endometrial cavity at the time of insertion. Mishell's classic study indicated that the uterus is routinely contaminated by bacteria at insertion. Infections that occur 3 to 4 months after insertion are believed to be due to acquired STIs, not the direct result of the IUC. The early, insertion-related infections, therefore, are polymicrobial and are derived from the endogenous cervicovaginal flora, with a predominance of anaerobes.
A review of the World Health Organization database derived from all of the WHO IUC clinical trials concluded that the risk of pelvic inflammatory disease was six times higher during the 20 days after the insertion compared with later times during follow-up, but, most importantly, PID was extremely rare beyond the first 20 days after insertion. In nearly 23,000 insertions, however, only 81 cases of PID were diagnosed, and a scarcity of PID was observed in those situations in which STIs are rare. There was no statistically significant difference comparing the copper IUC with the inert Lippes Loop or progestin-containing IUC. These data confirm earlier studies that the risk of infection is highest immediately after insertion and that PID risk does not increase with long-term use.  The problem of infection can be minimized with careful screening and the use of aseptic technique. Even women with type 1 diabetes mellitus do not have an increased risk of infection.
Doxycycline (200 mg) or azithromycin (500 mg) administered orally one hour prior to insertion can provide protection against insertion-associated pelvic infection, but prophylactic antibiotics are probably of little benefit for women at low risk for STIs.
Compared with oral contraception, barrier methods, and hormonal IUCs, there is no reason to think that nonmedicated or copper IUCs can confer protection against STIs, specifically PID. However, the levonorgestrel-releasing IUC has been reported to be associated with a protective effect against pelvic infection, and the copper IUC is associated with lower titers of antichlamydial antibody.  In vitro, copper inhibits chlamydial growth in endometrial cells. Thus, the perception that IUC use is associated with pelvic infection (and infertility) is outmoded. Women who use IUCs must be counseled to use condoms along with the IUC whenever they have intercourse with a partner who could be an STI carrier. Because sexual behavior is the most important modifier of the risk of infection, clinicians should ask prospective IUC users about numbers of partners, their partner's sexual practices, the frequency and age of onset of intercourse, and history of STIs. Women at low risk are unlikely to have pelvic infections while using IUCs.

Injectable contraception

Injectable contraception

Depot-Medroxyprogesterone Acetate

 

  Depot-medroxyprogesterone acetate (DMPA or Depo-Provera) is the most thoroughly studied progestin-only contraceptive. Although its approval for contraception in the United States is recent (1992), it has been available in some countries since the mid-1960s. Much of our knowledge of the safety, efficacy, and acceptability of long-acting hormonal contraception comes from Indonesia, Sri Lanka, Thailand, and Mexico, where DMPA has been used and studied for decades. The long-delayed approval as a contraceptive in the United States was based on political and economic considerations rather than scientific ones.
   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

INDICATIONS

At least 1 year of birth spacing desired    Highly effective long-acting contraception not linked to coitus    Private, coitally independent method desired    Estrogen-free contraception needed    Breastfeeding    Sickle cell disease    Seizure disorder

CONTRAINDICATIONS

Absolute    Pregnancy    Unexplained genital bleeding    Severe coagulation disorders    Previous sex steroid–induced liver adenoma    Relative    Liver disease    Severe cardiovascular disease    Rapid return to fertility desired    Difficulty with injections    Severe depression

Mechanism of Action

 

  The mechanisms of action of DMPA are like those of other progestin-only methods: thickening of the cervical mucus, alteration of the endometrium, and blocking the LH surge to prevent ovulation. Suppression of FSH is not as intense as with the combination oral contraceptive; therefore, follicular growth is maintained sufficiently to produce estrogen levels comparable to those in the early follicular phase of a normal menstrual cycle. Symptoms of estrogen deficiency, such as vaginal atrophy or a decrease in breast size, do not occur, but bone density can be lost.
  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

 

  The efficacy of this method is equal to that of sterilization and better than that of oral methods.  Because serum concentrations are relatively high, efficacy is not influenced by weight or by the use of medications that stimulate hepatic enzymes. On the contrary, DMPA is an excellent contraceptive choice for women taking antiepileptic drugs because the high progestin levels raise the seizure threshold.
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

Easy to use, no daily or coital action required    Safe, no serious health effects    Very effective, as effective as sterilization, intrauterine contraception, and implant contraception    Free from estrogen-related problems    Private, use not detectable    Lactation is enhanced    Noncontraceptive benefits

Problems

 

  Major problems with DMPA are irregular menstrual bleeding, breast tenderness, weight gain, and depression.  By far, the most common problem is the change in menstrual bleeding. Up to 25% of patients discontinue in the first year because of irregular bleeding. The bleeding is rarely heavy; in fact, hemoglobin values rise in DMPA users. The incidence of irregular bleeding is 70% in the first year and 10% thereafter. Bleeding and spotting decrease progressively with each reinjection, so that after 5 years, 80% of users are amenorrheic (compared with 10% of Norplant users). Irregular bleeding can be disturbing and annoying, and, for many patients, it inhibits sexual activity; therefore, most users prefer the amenorrhea that comes with prolonged use.
  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

 

  A very large hospital-based case-control WHO study conducted over 9 years in three developing countries indicated that exposure to DMPA is associated with a very slightly increased risk of breast cancer in the first 4 years of use, but there was no evidence for an increase in risk with increasing duration of use. The number of cases with recent use was not large, and the confidence intervals reflected this. A possible explanation for this finding is the combination of detection and surveillance bias and accelerated growth of an already present tumor, a situation similar to those described with oral contraceptives.

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

 

  The impact of DMPA on the lipoprotein profile is uncertain. Although some studies fail to detect an adverse impact and claim that this is due to the avoidance of a first-pass effect in the liver, others have demonstrated a decrease in HDL cholesterol and increases in total cholesterol and LDL cholesterol.In a multicenter clinical trial by the World Health Organization, a transient adverse impact was present only in the few weeks after injection when blood levels were high. The clinical impact of these changes, if any, has yet to be reported.
  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

 

  Clinicians are concerned that the contraceptive use of DMPA is associated with the loss of bone, and the package insert announces this risk. It is attributed to the fact that blood levels of estrogen with DMPA are relatively lower over a period of time compared with a normal menstrual cycle, an idea that is supported by the demonstration that estrogen treatment prevents bone loss. Lumbar and hip bone loss has been documented in cross-sectional studies. An American cross-sectional study indicated a greater bone loss with increasing duration of use, especially in younger women, 18 to 21 years old.
  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

 

  The delay in becoming pregnant after ceasing use of DMPA is a problem unique to injectable contraception; all the other temporary methods allow a more prompt return to fertility. However, medroxyprogesterone acetate does not permanently suppress ovarian function, and the concern that infertility with suppressed menstrual function may be caused by DMPA has not been supported by epidemiologic data. The pregnancy rate in women discontinuing the injections because of a desire to become pregnant is normal. By 18 months after the last injection, 90% of DMPA users have become pregnant, the same proportion as for other methods. The delay to conception is about 9 months after the last injection, and the delay does not increase with increasing duration of use. Because of this delay, women who want to conceive promptly after discontinuing their contraceptive should not use DMPA. Suppressed menstrual function persisting beyond 18 months after the last injection is not due to the drug and deserves evaluation.

Subcutaneous Administration of DMPA

 

  Intramuscular DMPA has several disadvantages. Peak serum concentrations are higher than required for ovulation suppression and lead to decreased production of endogenous estradiol, so that bone density is lost. Prolonged release from muscle can delay return to ovulation for several months after the last IM injection. DMPA users must see a clinician every 3 months for repeat IM administration.
  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)

 

  Lunelle consists of 25 mg DMPA and 5 mg estradiol cypionate and is administered every 28 to 30 days (not to exceed 33 days) as a deep intramuscular injection. This method is as effective as Depo-Provera, but it avoids the problems of menstrual irregularity and heavy bleeding, as well as amenorrhea.In addition, the method is rapidly reversible; fertility rates after discontinuation are similar to those with oral contraceptives.
  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

 

  Norethindrone enanthate is given in a dose of 200 mg intramuscularly every 2 months. This progestin acts in the same way as Depo-Provera and has the same problems.A combination (Mesigyna) of norethindrone enanthate (50 mg) with estradiol valerate (5 mg) given monthly provides effective contraception with good cycle control. Compared with Lunelle, use of Mesigyna is associated with fewer bleeding problems. Fertility returns rapidly (within 1 month) after discontinuation.

Dihydroxyprogesterone Acetophenide and Estradiol Enanthate

 

  The combination of 150 mg dihydroxyprogesterone acetophenide with 10 mg estradiol enanthate (produced under various brand names) is the most widely used injectable contraceptive in Latin America. As with Mesigyna and Lunelle, the monthly regimen allows regular, and even reduced, cyclic bleeding. A lower dose (90 mg dihydroxyprogesterone acetophenide and 6 mg estradiol enanthate) provides the same effective contraception as the higher dose with similar bleeding patterns.

Vaginal and transdermal steroid contraception

   Vaginal and transdermal steroid administration has the potential advantage of avoiding the first pass through the liver and the high initial serum concentrations that are associated with the oral intake of steroid hormones. For example, the impact on blood clotting may be reduced because acute stimulation of liver protein synthesis is avoided. Whether vaginal and transdermal administration of steroid hormones is safer than oral administration must await future epidemiologic assessment, but this remains a theoretical possibility. Another important possible advantage of vaginal and transdermal steroid contraception is an improvement in compliance achieved by the elimination of a daily regimen of treatment

Vaginal Steroid Contraception

  The vaginal mucosa offers an excellent delivery site for steroid contraception. Absorption from the GI tract can be unpredictable and may be compromised by vomiting, drug-drug interference, or decreased intestinal absorption capacity. Avoidance of the first pass effect is particularly advantageous for compounds that undergo a high degree of hepatic metabolism; orally administered natural estrogens for example, are 95% metabolized by the liver. Oral administration results in marked fluctuations of contraceptive steroid serum concentrations that can lead to side effects like irregular bleeding and nausea. These daily changes are lower with vaginal than with oral or transdermal administration and lowest with implant and intrauterine methods.
  Vaginal contraceptive rings have been studied for 30 years. Six progestin-only and seven different progestin-estrogen (combined) vaginal contraceptive rings have been designed to provide 1 week to 1 year of contraception. Short-acting rings (1 week) contain weaker progestins like progesterone and medroxyprogesterone, and long-acting rings (up to 1 year) contain the more potent levonorgestrel and nesterone.

Only the NuvaRing vaginal combined steroid contraceptive is approved and available in the United States . It is a flexible, soft, transparent ring made of ethylene vinyl acetate (EVA) copolymer (60%) in which are contained crystals of etonogestrel (the biologically active metabolite of desogestrel, previously known as 3-ketodesogestrel) and ethinyl estradiol. This ring is covered with a 2-mm thick membrane of EVA. The ring is available in only one size, 4 mm in thickness and 54 mm in diameter (smaller than a diaphragm). The NuvaRing releases 15 mg ethinyl estradiol and 120 mg etonogestrel per day. The circulating estrogen levels reach a maximum level after 2 or 3 days and etonogestrel reaches maximum level after 7 days, and these levels remain stable for 35 days . The ring is inserted by the patient and worn for 3 weeks. Routine use requires the insertion of a new ring every 4 weeks to allow withdrawal bleeding, but continuous use is an appropriate option.

   The ring produces circulating progestin and estrogen levels that are only 40% and 30%, respectively, of the peak levels associated with an oral contraceptive containing 150 mg desogestrel and 30 mg ethinyl estradiol. These levels effectively inhibit ovulation, providing pregnancy rates of less than 1% in clinical trials.  Indeed, the ring contains enough steroid hormone to inhibit ovulation for at least a total of 5 weeks. If the vaginal ring is removed and not replaced within 3 hours, the manufacturer recommends backup contraception until the ring has been in place for 7 days.
  Taking into account bioavailability as influenced by protein binding, systemic exposure to etonogestrel is similar, comparing the vaginal ring to an oral contraceptive containing 150 mg desogestrel; however, the systemic exposure to ethinyl estradiol is about 50% of that of an oral contraceptive containing 30 mg ethinyl estradiol. This might explain the low incidence of estrogen-related side effects such as nausea and breast tenderness.  Breakthrough bleeding and spotting rates are lower (around 6%) when compared with an oral contraceptive containing 30 mg of ethinyl estradiol and much lower than with 15- or 20-mg pills.  
  It is not necessary to place the vaginal ring in a specific position; it need only be in contact with vaginal mucosa and need not surround the cervix. The vaginal ring is intended to be placed in a normal vagina; infections and anatomic abnormalities are reasons for clinicians and patients to consider other methods. The most common reasons for discontinuation (about 2% to 4% in the clinical trials) have been vaginal discomfort, unwanted awareness of the ring's presence, coital problems, or expulsion (during a year of use about 2% to 3% of women experience spontaneous expulsion). Women report that the ring is easy to insert and remove, and, although about 15% of women and 30% of partners report feeling the ring during intercourse, this is not a common reason for discontinuation. Removal for sexual intercourse is not recommended, but efficacy is maintained if the ring is replaced within 3 hours. Cervical cytology and the vaginal flora are not affected by the presence of the ring.
  The spermicide, nonoxynol-9, has no effect on the release and absorption of the hormones in NuvaRing, as assessed by the measurement of serum levels of ethinyl estradiol and etonogestrel. Combining a barrier method that contains nonoxynol-9 (in the widely advocated double method for protection against sexually transmitted diseases) should not affect the contraceptive efficacy of the ring. Vaginally applied antifungal agents (miconazole) likewise have no effect on absorption of contraceptive steroids released by NuvaRing, nor does the use of tampons.

Transdermal Steroid Contraception

Method

   The transdermal contraceptive patch (Ortho Evra) has an area of 20 cm² (4.5 cm × 4.5 cm) and three layers in a matrix-type arrangement. The backing outer polyester layer provides support for the middle layer that contains the adhesive and the hormones, and the inner layer is a polyester liner that is removed from the adhesive layer just before application. The size is that required to deliver an effective dose of the steroid hormones. The patch contains 750 mg ethinyl estradiol and 6.0 mg of norelgestromin and delivers 20 mg ethinyl estradiol and 150 mg norelgestromin each day when applied to discrete locations on the lower abdomen, upper outer arm, the buttock, or the upper torso (excluding the breast). Norelgestromin is the primary active metabolite of orally administered norgestimate and was previously known as 17-deacetylnorgestimate. Norelgestromin still undergoes liver metabolism with transdermal application; however, the resulting metabolite, levonorgestrel, is highly bound to sex hormone–binding globulin, limiting its biologic impact. About 97% of norelgestromin is bound to albumin and 3% is unbound.
  The patch is applied on the same day, but not on the exact same site, once each week for 3 weeks, followed by a week without use of the patch. Timing on the day of application need not be precise; the patch maintains adequate serum levels for 9 days. Instructions for first-day starts or Sunday starts of oral contraception are also recommended for the patch (backup contraception for 7 days unless the starting day is also day 1 of the menstrual period). As with oral contraceptives, patient and clinician may choose to use the contraceptive patch continuously, eliminating withdrawal bleeding but, perhaps, promoting irregular spotting.
   Detachment occurs with about 5% of patches, and about half occur in cycle 1 with inexperienced patients.  In studies of at least a year's duration, about 2% to 5% of patches were replaced. If the patch has been detached for more than 24 hours, a new patch is applied, initiating a new cycle and new change day (backup contraception for 7 days is recommended). Delay of a new patch cycle requires a new start with the usual 7-day backup. A delay within the patch cycle of no more than 2 days has no risk and does not change the cycle, but a delay of more than 2 days also requires the initiation of a new cycle and change day with backup. However, in a study that compared three treatment-free days in oral contraceptive and patch users, ovulation occurred significantly less with the patch compared with oral contraception.

Effects

   Serum hormonal concentrations are achieved rapidly after application: an average of about 0.7 ng/mL, which is within the range 0.6 to 1.2 ng/mL for norelgestromin, and an average of about 50 pg/mL, within the range of 25 to 75 pg/mL for ethinyl estradiol. These are ranges that are maintained by an oral formulation containing 250 mg norelgestromin and 35 mg ethinyl estradiol .  
   However, the kinetics are not identical to orally administered hormones; daily fluctuations are avoided, but the area under the curve (AUC) over a week of use is greater with the patch than with daily oral administration of 35 mg of ethinyl estradiol. Whether this difference increases the risk of thrombosis in patch users has not been determined, with the only two studies in disagreement. Contraceptive blood levels are maintained even if patch replacement is delayed up to 2 days (9 days total). Gonadotropin levels return to baseline values by 6 weeks after discontinuation. Daily use has been well studied, and activities such as exercise, bathing, swimming, and the use of a sauna or hot tub do not cause detachment or changes in the blood levels of the hormones.
  Transdermal contraception produces the same spectrum of actions associated with oral contraceptives, achieving the same high level of efficacy in clinical trials. Therefore, the same considerations reviewed earlier about oral contraception apply to transdermal contraception, including the same contraindications and noncontraceptive benefits. The avoidance of the liver first-pass effect offers the potential for less interaction with other drugs, but this is not known, and patients taking medications that affect liver metabolism should choose an alternative contraceptive. Tetracycline administration does not affect the blood concentrations of the steroid hormones with transdermal contraception, a neutral impact just as seen with oral contraceptives.
   Transdermal administration has effects on clotting proteins and lipoproteins like those seen with low-dose oral contraceptives. There are no clinically significant changes in coagulation parameters, triglycerides increase modestly, and the ratio of low-density lipoproteins to high-density lipoproteins (LDL/HDL ratio) declines slightly. As with oral contraceptives, women who are at high risk for thrombosis due to genetic effects like factor V Leiden or protein C or S deficiencies or who have very high triglycerides should consider hormonal contraceptives that do not contain estrogen.

Clinical Responses

   Ovulation suppression is comparable to that achieved with oral contraception, and failure rates in clinical studies are less than 1.0%.  Breakthrough bleeding and spotting rates with the transdermal method in randomized trials were comparable to those with monophasic and two triphasic formulations, except for a slightly higher incidence of spotting in the first two cycles.
  It is now well demonstrated that modern steroid contraception does not cause weight gain. The transdermal method is not an exception; body weight changes were identical in a randomized trial comparing the contraceptive patch with an identical placebo patch. There were 15 pregnancies in the contraceptive patch clinical trials, and five of these were among women with body weights greater than 90 kg (198 pounds). This is consistent with the greater failure rate reported in obese women taking oral contraceptives. However, a high rate of overall contraceptive efficacy is still achieved in heavy women because only a 10% to 20% variability in hormone levels can be attributed to increased body weight.
  Poor compliance is a major contributor to the typical failure rate associated with oral contraception. The once-a-week schedule with transdermal contraception is simpler and less susceptible to delays and omissions. In randomized trials ranging from four cycles to 13 cycles, about 10% to 20% more of the participants demonstrated good compliance with the transdermal method compared with oral contraception.  In the clinical trials with transdermal contraception, lower overall pregnancy rates with the patch compared with oral contraception have been attributed to better compliance. Most importantly, young patients, especially those younger than 20 years, demonstrated greater compliance with transdermal contraception compared with oral contraceptives than did older patients.
  About 20% of patients experience some degree of skin reaction at the application site, and about 2% discontinue the method for this reason.  Breast discomfort is experienced during the first few months by 20% of users, more often with transdermal contraception compared with oral contraceptives, but it is usually not severe and resulted in discontinuation in only 1% of users.