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.