US Pharm. 2006;6:62-70.     

According to the United States Census Bureau, in July 2003, there were approximately 62 million women of childbearing age in the U.S.1 Forty-three million (69%) of these women were fertile, sexually active, and did not desire to become pregnant.2 These statistics help portray the high public demand for contraceptive agents.

Contraceptive products comprise oral, transdermal, intravaginal, intrauterine, intramuscular, and subcutaneous preparations available in a variety of doses and estrogen-progestin combinations. Due to the extent of products offered, it can be difficult for health care providers to stay up-to-date on and understand the advantages and disadvantages of different dosage forms. This article provides an overview of hormonal contraceptive products and briefly discusses the risks and benefits associated with specific dosage forms to assist providers in the selection of the most appropriate product.

Estrogens
There are two types of estrogen found in contraceptives. The more common type is ethinyl estradiol. A few oral contraceptive products contain mestranol, which is metabolized by the liver to ethinyl estradiol. Mestranol is estimated to have half the potency of ethinyl estradiol.3 Estrogens are an important component of contraceptive products and work by preventing the formation of a follicle. When given in amounts that exceed normal endogenous levels, a negative feedback loop is created between the hypothalamus and anterior pituitary. This negative feedback loop prevents the release of follicle-stimulating hormone (FSH) from the anterior pituitary. When FSH levels are kept low, a follicle is not able to form and ovulation is prevented.3-5

Progestins
Progestins are classified into first, second, third, and fourth (or spironolactone-derived) generations. Progestin generations can be quite confusing, as some studies classify them based on the date that the progestin was introduced to the market, while others classify them according to the progestin's carbon-ring structure. Therefore, the same progestin can be classified in different generations depending on the reference used.6 For this reason, as well as the wide variation of side effects seen with progestins within the same generation, this article discusses progestins according to their degree of estrogenic, androgenic, and progestational activity.

Progestins are effective contraceptive agents when used alone or in combination with an estrogen product. When used in combination with an estrogen, progestins inhibit the luteinizing hormone (LH) surge, which is required for ovulation. When progestins are used alone, they are not thought to consistently inhibit ovulation, possibly because of the significantly lower doses of progestin in progestin-only contraceptives as compared to combination products.4 Progestin-only contraceptives are thought to function primarily by creating a hostile cervical environment (thickening of the mucus) and causing endometrial atrophy. These changes inhibit egg implantation and decrease the penetration of sperm and ovum transport.3-8

Each progestin is associated with a slightly different affinity for estrogen, androgen, and progesterone receptors (table 1) , resulting in the various side effects seen with each progestin. Side effects for different progestins are discussed later in this article.




Preparations
Formulations of hormonal contraceptives vary from traditional oral tablets and once-weekly patches to intrauterine devices that are effective for up to five years after implantation. When selecting a contraceptive product, patient preference, patient tolerance, the various adverse effect profiles, and the formulations available should all be considered in order to maximize efficacy and patient adherence.

Oral Contraceptives: The efficacy of oral contraceptives with perfect use is above 99%.3,9 This can be misleading to patients because perfect use implies that no doses are missed, the pill is taken at the same time every day, and appropriate backup methods are used when indicated. Studies have found that the efficacy rate drops to approximately 95% for typical use, which accounts for patient noncompliance and inappropriate use (e.g., no backup method used when indicated).3,6,8-10

Of all hormonal contraceptive dosage forms, oral preparations are available in the largest variety of products. Oral formulations differ with regard to the dose, as well as combination, of progestin and estrogen they contain. Newer formulations of oral contraceptives contain approximately one fifth the amount of estrogen and one tenth the amount of progestin compared to older preparations.3,6,8 Currently, oral combination contraceptive products contain ethinyl estradiol in doses ranging from high-dose preparations with 50 mcg to ultra-low-dose formulations containing 20 mcg. Average ethinyl estradiol doses range from 30 to 35 mcg. Products that consist of mestranol have 50 mcg of the hormone, which has been found to be equivalent to approximately 35 mcg of ethinyl estradiol.11,12 Estrogen doses were initially lowered after reports of increased risk of ischemic stroke, myocardial infarction, and pulmonary embolism with high-dose estrogen preparations.9,12-14 Doses have continued to decrease because contraceptive efficacy has not diminished with lower-dose formulations. 7,9

Alterations have also been made to initial oral combination products in order to more closely mimic a woman's natural menstrual cycle. These formulations vary the dose of estrogen, progestin, or both throughout the cycle and are called biphasic and triphasic preparations ( table 2).3,9,15 Monophasic preparations (table 3) are still available and contain a consistent amount of estrogen and progestin in each active tablet.



Yasmin (ethinyl estradiol/drospirenone) is a combination, monophasic oral contraceptive that is unique in that its progestin is structurally similar to spironolactone.7,15 Each tablet contains 30 mcg of ethinyl estradiol and 3 mg of drospirenone, which is equivalent to 25 mg of spironolactone.15 Due to the weak potassium-sparing diuretic effect that drospirenone exhibits, this product may be preferred by women who experience water retention associated with their menstrual cycle. Patients should be monitored for hyperkalemia while on Yasmin because of the anti­ mineralocorticoid properties of drospirenone. 7,15



An alternative to combination formulations is the progestin-only pill (POP), or mini pill. Progestin-only pills provide an oral alternative for lactating women, as progestins, unlike combination products, have not been shown to decrease milk production.4,5,8 POPs are also good options for women with contraindications or intolerance to estrogen-containing contraceptives and for women who would like to become pregnant in the near future, as progestin-only pills do not stop ovulation. Strict adherence to timing of daily dosing is necessary with progestin-only pills due to the decreased effect of the progestin on the cervical mucosa 22 hours after the dose is taken. A dose that is three hours late is considered missed and should be taken as soon as it is remembered. Literature suggests using alternative means of contraception for two days following late or missed doses.3,5,6,8,9 POPs should be taken continuously with no pill-free interval.

Progestin-only pills are slightly less effective than combination oral contraceptives. With perfect use, POPs have an efficacy rate of 99.5% compared with 99.9% for combination products.3,9 POPs are also associated with a greater degree of irregular bleeding. Approximately 35% to 45% of women on POPs experience spotting and breakthrough bleeding throughout the first three months of use; in comparison, 5% to 20% of women using combination oral contraceptives experience these adverse effects. 3,9 Other common side effects of POPs include headache, breast tenderness, nausea, and dizziness.9

Transdermal Contraceptives: The delivery of hormones through transdermal means was traditionally used for the administration of estrogen and testosterone. It was not until 2002 that Ortho Evra (ethinyl estradiol/norgestimate), a combination estrogen and progestin transdermal patch, became available as a form of contraception in the U.S. The patch's mechanism of action is similar to that of oral contraceptive pills in that 20 mcg of ethinyl estradiol and 150 mcg of norelgestromin, a metabolite of norgestimate, are released daily.15,16

When compared with perfect use of daily oral contraceptives, the patch had similar contraceptive efficacy (approximately 99%) for most patient populations. Transdermal contraceptives have an advantage over oral preparations in that compliance is enhanced because of once-weekly administration.17 In 2005, FDA added a bolded warning to Ortho Evra's prescribing information stating that the pharmacokinetic profile of Ortho Evra differs from that of the oral contraceptive pill.16 Specifically, compared to the pill, Ortho Evra exposes patients to higher steady state concentrations and lower peak concentrations of ethinyl estradiol. While increased estrogen exposure may increase the risk of serious adverse events, it is not known whether Ortho Evra is associated with a higher risk of adverse events compared to the oral contraceptive pill. Furthermore, Ortho Evra has been associated with higher rates of unintended pregnancies in patients weighing over 198 pounds (98 kg) and should therefore be used with caution in this population.6,15,16 Studies have reported increases in incidence of breast tenderness, poor cycle control, and application-site reactions with Ortho Evra when compared with oral preparations.15,16 Ovulation rapidly returns for a majority of patients after discontinuation of Ortho Evra, with most able to become pregnant within three months. For women with irregular periods prior to therapy, pregnancy may be delayed.15

The Ortho Evra patch is applied to the buttock, abdomen, upper outer arm, or upper torso on the first day of the patient's menstrual period. A new patch is applied every week for three weeks, followed by one patch-free week. Location of the patch should be rotated each week to help reduce the incidence of skin irritation. If the patch becomes partially or completely detached for less than one day, a new patch should be applied or the same patch can be used if it still contains its adhesive, and no backup method would be necessary. If the patch has been off for longer than a day, a new patch should be placed immediately and the new "patch change day" should be based on the day the new patch was applied. When the patch has been off for more than 24 hours, a backup means of contraception is recommended until the new patch has been on for seven consecutive days. A patch should not be reapplied if it has stuck to itself or to another surface.15,16

Intrauterine Device: There are two types of intrauterine devices (IUDs) approved in the U.S. The more commonly used IUD is a copper-containing system. Copper-containing IUDs are hypothesized to function by decreasing sperm's ability to reach the uterine cavity and fallopian tubes for fertilization, as well as by creating cellular changes to sperm that cause it to be nonviable.3-5 Efficacy rates for copper IUDs are over 99%. IUDs are associated with increased incidence of endometritis, pelvic infections, allergic skin reactions, tubal damage, and uterine perforation. One advantage of copper-containing IUDs is that the side effects associated with estrogen and progestins are avoided because it is a nonhormonal contraceptive product.

Other IUDs release hormones; these are Progestasert (progesterone) and Mirena (levo­ norgestrel). Progestasert was the first hormonal IUD, and it functions as a contraceptive by releasing progesterone and therefore altering the cervical environment. The Progestasert system is inserted by a physician and left in place for 12 months. The system must be replaced every 12 months to ensure contraceptive effectiveness. 5,18 Progestasert is associated with a higher risk of unexpected pregnancy when compared with other IUD systems and has an efficacy rate of 98%. Because of decreased efficacy and the need for yearly replacement, Progestasert is not widely used.19 Common adverse effects of Progestasert include intermenstrual spotting, and severe but rare effects include pelvic inflammatory disease (PID), fragmentation of device, and cervical perforation.4

The newest IUD available in the U.S., Mirena exerts its contraceptive effects by releasing 20 mcg of levonorgestrel daily. 5,15,20 Ovulation has been shown to be prevented in some cycles, but this system primarily functions secondary to progestin activity in the cervix. 19 Mirena has been proven over 99% effective for the five years following insertion. This system is associated with increased risks of PID and irregular bleeding but has been found to be associated with fewer complications when compared to copper-containing devices.5,15,19,20

Return to ovulation is immediate upon removal of IUDs, and approximately 80% of women are able to become pregnant within one year.4,19 IUDs may be appealing options for women who desire contraception over a long period of time.

Vaginal Contraceptive Ring: The vaginal contraceptive ring, NuvaRing (ethinyl estradiol/etonogestrel), works by delivering ethinyl estradiol at a rate of 15 mcg per day and etonogestrel, the active metabolite of deso­ norgestrel, at a rate of 120 mcg per day.15,20,21 Studies have shown that the Nuva­ Ring is 98% to 99% effective in preventing pregnancy and is generally well tolerated. 11,15,19,21 The NuvaRing is associated with a higher incidence of vaginitis, vaginal discomfort, and vaginal infections when compared to other forms of hormonal contraception and is not recommended for patients with cystocele, rectocele, or uterine prolapse.15,21

 

NuvaRing is a flexible ring that is inserted into the vagina by the fifth day of the menstrual cycle and is left in place for three weeks. After three weeks, the ring is removed for one week and a new ring is inserted at approximately the same time of day that the old ring was removed.15,21 If the NuvaRing is out of the vagina for less than three hours at any time during active therapy, the ring should be rinsed and reinserted and no backup method is necessary. If the ring is out of the vagina for more than three hours, a backup method should be initiated for the next seven days, as contraceptive efficacy may be diminished. Return to ovulation with the Nuva­ Ring is immediate, with ovulation commonly occurring within one month following discontinuation of the product.21

Intramuscular (IM) Injections: Depo-Provera (medroxyprogesterone acetate) was the first non­ oral hormonal contraceptive agent available in the U.S.11 Medroxyprogesterone 150 mg is injected into the deltoid or gluteal muscle every three months and functions by suppressing ovulation and altering the cervical environment. 5,22 The first injection must be given within the first five days of menstruation to ensure the patient is not pregnant. Efficacy rates are comparable to those with perfect use of oral contraceptive agents, and the drug is effective 24 hours after the injection is given, provided it is given within the first week of menses.21 Because injections are given once every three months, compliance issues seen with other contraceptive formulations are avoided, therefore yielding greater efficacy when comparing typical use of hormonal contraceptive products.22

Common adverse effects of Depo-Provera include irregular bleeding, weight gain, delays in return of ovulation, and possible reductions in bone mineral density, especially in smokers.22 Studies have shown that ovulation most often recurs six to 12 months after product discontinuation, with a median time of approximately seven months. Duration of use does not seem to be related to length of time to recurrence of ovulation.5,22

Subcutaneous Injections: In December 2004, Depo-SubQ Provera 104 received FDA approval for use as a contraceptive agent. By slightly altering the formulation of Depo-Provera, the first subcutaneous hormonal contraceptive product was created. Depo-SubQ Provera 104 is a suspension that contains 104 mg of medroxy­ progesterone acetate and comes packaged in a prefilled syringe. A subcutaneous injection is administered into the anterior thigh or the abdomen every three months and functions as a means of contraception by preventing ovulation and causing thinning of the endometrium. Results of three studies, which included more than 2,000 women collectively, reported no unintended pregnancies throughout the one-year follow-up period.23

Common adverse effects of Depo-SubQ Provera 104 are similar to those of Depo-Provera and include weight gain, injection site reactions, irregular bleeding, loss of bone mineral density, and delays of return to fertility. The median time to return of ovulation after product discontinuation is approximately 10 months.23 One advantage of the subcutaneous formulation when compared with the IM injection is ease of administration, and home administration may be appropriate and would save the patient from quarterly physician visits.

Risks of Hormonal Contraceptive Use
Common Adverse Effects: Adverse effects are a common reason for discontinuation of hormonal contraceptive agents and often produce confusion for health care providers who need to determine the cause and find an appropriate therapeutic alternative. One reason side effects vary between products is the diversity of estrogen and progestin doses used. For example, women experiencing nausea, vomiting, bloating, decreased libido, and breast tenderness may be receiving too much estrogen and may benefit from a contraceptive with a lower estrogen dose. 3,8,18 Conversely, acne, hirsutism, and vaginal yeast infections have been associated with excess amounts of progestin, and these effects can be minimized by choosing an alternative product with a lower progestin content. 3,8,18 Common symptoms of estrogen and progesterone overload and deficiencies are found in table 4.




Side effects can also be associated with specific progestins, as each progestin has slight variations in its estrogenic, androgenic, or progestational activity (table 1). For example, levonorgestrel and norgestrel are progestins with high androgenic activity and are more prone to cause acne, hirsutism, weight gain, fatigue, and depression than progestins with less androgenic activity. By switching to a contraceptive with a less androgenic progestin, these side effects may subside. The side effects associated with high levels of estrogenic, progestational, and androgenic activity are found in Table 5.


Serious Adverse Effects: Despite the widespread use of hormonal contraceptive agents, there are some serious risks involved. Combination contraceptives have been associated with increased incidence of breast cancer, cervical cancer, myocardial infarction, stroke, and venous thromboembolism, including deep venous thrombosis (DVT) and pulmonary embolism.6,12,14,15 However, the overall risk for experiencing adverse events with hormonal contraceptive products is small and is closely associated with the woman's health status and presence of cardiovascular risk factors, as well as the agent's estrogen dose. Patients who smoke, are obese, have a family history of coronary artery disease, or are over 35 years of age, as well as women with concomitant disease states, including hypertension, diabetes, and hyperlipidemia, have been shown to be at significantly greater risk of adverse events when compared with healthy women. 6,12,14,15 Thus, a thorough patient history should be obtained when initially selecting a hormonal contraceptive agent, in order to evaluate the presence of contraindications (table 6) and risk factors.




A majority of the risks involved with hormonal contraceptives have been associated with combination products. As shown in table 6, many of the typical risk factors that are contraindications for combination products do not apply to progestin-only products. This is largely because progestins are not associated with the cardiovascular complications seen with estrogen use. Therefore, progestin-only products are good alternatives for women at high risk for adverse events or those with contraindications to estrogen.5,8,15

All patients started on hormonal contraceptives should be counseled on the signs and symptoms of ACHES: A bdominal pain, Chest pain, Headache, Eye pain, and Severe leg pain.3,8 The presence of these symptoms may be warning signs of stroke, hypertension, pulmonary embolism, DVT, or gallbladder disease and require further assessment to identify the cause.3,8

Noncontraceptive Benefits of Oral Contraceptive Use
In spite of perceived risks of contraceptive products, there are many benefits associated with their use. Oral contraceptives have been shown to decrease the risk of ectopic pregnancy, dysmenorrhea, anemia, endometrial cancer, ovarian cancer, ovarian cysts, colorectal cancer, benign breast disease, PID, osteopenia, and osteoporosis. Oral contraceptives may also improve cycle control, acne, and hirsutism. 3,6,8,15,24

Many clinicians believe that the noncontraceptive benefits outweigh the risks for a majority of patients. Regardless, the risks and benefits must be analyzed on an individual basis to identify high-risk patients and prevent adverse events.

Summary
Since the introduction of hormonal contraceptives to the market in 1960, there have been many changes that provide patients with a variety of contraceptive options. This variety allows a woman to choose a product that will be favorable to her lifestyle. It is therefore the job of the health care provider to help women find an agreeable contraceptive method and to ensure that each patient understands the requirements of perfect use in order to achieve the highest possible efficacy rates.

It is imperative that health care providers obtain a thorough patient history upon initial selection of a contraceptive agent in order to evaluate candidacy for hormonal contraceptives and narrow down available products. Patients should be monitored closely after initiation of contraceptives to identify any side effects or serious adverse events. Side effects should be addressed as they appear, and alternative agents should be chosen by correlating the dose and hormonal receptor affinity to the side effects present in order to prevent contraceptive discontinuation. By following these steps, the risks of unplanned pregnancies, side effects of contraceptives, and product discontinuation can be minimized.

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