While there is a great increase in the number of hormonal contraceptive options, most of these methods are a "variation on a theme" and have similar mechanisms of action. Most of the contraceptive efficacy is derived from the effects of the progestin. The mechanism of action of hormonal contraception is primarily through the suppression of ovulation. Progestational effects include (7):

Estrogenic effects include (8):

There are inherent risks in our methodology to define efficacy of a contraceptive method. If 100 women used a contraceptive method for a year and five became pregnant, we cannot say that the method was 95% effective. We do not know who would have become pregnancy without using family planning. Thus, we rely on a failure rate to describe the effectiveness of a method. However, all failure rates are not calculated equally and have different implications.

Most estimates of a contraceptive's efficacy refer to the first year of its use. Overall, the longer a woman uses a contraceptive method the less likely it is to fail. Thus, the failure rate in the second year is lower than the first and the failure rate in the fifth year is lower than that of the second. There are two commonly used failure rates to compare contraceptive methods: typical use and perfect use. 'Perfect use' is a measure of efficacy if the method is used perfectly, consistently and according to specific guidelines. It compares to the efficacy of the method in the laboratory (method failure rate). 'Typical use' estimates the probability of pregnancy during the first year of typical use of the method. This measure of efficacy takes into account occasional non-use of the method, incorrect use of the method, as well as pure failure of the method. Generally speaking, methods that are coitally dependent such as condoms and diaphragms have a larger disparity between typical use and perfect use. The failure rate of perfect use for oral contraceptive pills is approximately 0.1-0.5% but the typical failure rate is about 5% (7). Methods that are long acting and require one visit to a clinician such as an injection or an implant have very little disparity between perfect use and typical use. The perfect use failure rate of Depo-Provera and Norplant are 0.03% and 0.05% respectively (7). The typical use is almost identical.

Today there is a range of non-oral, non-daily hormonal contraceptive available, and the face of contraceptive management has changed. However, oral contraceptives have been widely used for decades, and they represent the most extensively studied drug on the market. Research regarding oral contraceptives focused on possible health risks. Many of the concerns of these health risks have been allayed. There is now a large body of evidence demonstrating non-contraceptive health benefits of oral contraception. Table 3 is a list of potential non-contraceptive benefits. Specific clinical situations are described below.

Prevention of Ovarian Cancer: Reduction in ovarian cancer risk increases with greater oral contraceptive use although protection is provided after as little as 3 to 6 months (9). Compared to non-users, women who have used oral contraceptives for four years or less have a 30% decreased risk of ovarian cancer. If they used combined OC's for 5-11 years, they have a 50% reduction of risk; if they used combined OC's for more than 12 years, there is a 80% reduction in risk. This protective effect persists for at least 15 years after OC discontinuation (10, 11).

Prevention of Endometrial Cancer: There is a 50% reduction in endometrial cancer risk in OC users compared with never users (12). Reduced risk depends on duration of OC use. The risk is reduced by 20% with 1 year of use, 40% with 2 years of use, and 60% with 4 or more years of use (13). The actual duration of protection after discontinuation is unknown but is estimated to be at least 15 years (14).

Benign Breast Disease: OC use significantly reduces fibrocystic breast change and fibroadenoma development (15-17). The Oxford Family Planning Association Study found a decreased risk of benign breast disease with increasing duration of use; current users, however, were at lowest risk (18). Fibrocystic change is significantly decreased after 1 to 2 years of use (19), and lasts up to 1 year after OC discontinuation (18).

Bone Mineral Density: Studies of both premenopausal and postmenopausal women seem to favor bone-sparing effects of OC's. A past history of OC use provided protection against low bone mineral density in a cross-sectional, retrospective study (OR=0.4, 95%CI, 0.2-0.5) (20). The same study observed increasing protection with increasing duration of use. Few studies have shown a protective effect against fracture risk-a case-control study showed that use of any OC in women after the age of 40 years provided significant protection against hip fractures during their menopause (OR=0.7;95%CI, 0.5-0.9) (21). Many studies, however, have not found a favorable association between OC's and bone mass (22, 23). No study thus far has found a detrimental effect of OC's on bone mineral density (24).

Functional Ovarian Cysts: In general, studies of current monophasic or triphasic OC formulations demonstrate that OCs do not have a significant effect on the development of functional ovarian cysts (25, 26).

Colorectal Cancer: A meta-analysis of pooled relative risks of colorectal cancer for ever-use of OCs from case-control studies was 0.81 (95%CI, 0.69-0.94) and from four cohort studies was 0.84 (95%CI, 0.72-0.97) (27). Women using high-dose OCs (with 50mcg estrogen) for greater than 96 months had a relative risk of 0.6(95%CI, 0.4-0.9) (28). It is unclear if the results from this study apply to women using lower-dose oral contraceptives.

Relief from Menstrual Disorders: There are few studies that demonstrate the benefits of current low-dose OCs on dysmenorrhea and menstrual flow. A recent randomized clinical trial of patients with dysfunctional uterine bleeding showed an 81-87% improvement in bleeding within 3 months compared to a 36-45% improvement seen in placebo treated patients (29). The likelihood of iron-deficiency anemia appears to be decreased in both current and past combination OC users. Anecdotal reports of treating primary dysmenorrhea with OCs document their effectiveness (30).

Reduction of Acne: Recently, two randomized, placebo-controlled trials showed that nearly 50% of women treated with a triphasic OCs containing norgestimate had an improvement in acne compared to 30% of women on placebo (31, 32). Ortho Tri Cyclen and Estrostep are approved by the FDA for the treatment of acne. Another pill that contains ethinyl estradiol and drospirenone is also effective in treating this condition, and may lead to overall improvement in facial acne (33). Other OCs too are being evaluated for similar use (34, 35). All combination OCs likely reduce acne via an increase in sex hormone binding protein and a subsequent decrease in serum testosterone.

Reduced risk of adverse cardiovascular outcomes: In 2004, as study on the WHI database revealed that use of OCs is associated with better cardiovascular outcomes, including any cardiovascular disease, hypercholesterolemia, angina, myocardial infarction, transient ischemic attack, peripheral vascular disease, and need for cardiac catheterization. The data showed that increasing age, elevated body mass index and smoking greatly increased the risks, even in OC users (36, 37).

Many prescribing patterns of oral contraceptive and other hormonal contraceptive methods are based on perception rather than evidence-based medicine. Evidence-based medicine relies on the integration of clinical expertise with the best evidence from systematic review of research. As clinicians, we can use this methodology to refute misconceptions about oral contraceptives and promote many non-contraceptive benefits. In 2002, the finding of the Women's Health Initiative showed that there is an increased risk of breast cancer with use of menopausal combination hormone replacement therapy (38). The Women's CARE study, sponsored by the NIH and CDC indicate that regardless of period of use of OCs, age and family history, there is no relationship between breast cancer and OC use. Table 4 is a list of the disadvantages of combined oral contraceptives. Table 5 is a list of the contraindications of combined oral contraceptives.

The number of combined oral contraceptive pill preparations on the market has increased in recent years. There are new formulations of pills with a dosage of estrogen as low as 20 micrograms. Some preparations have changed the paradigm of 7 days of placebo (with 21 days of active pills) and now offer a 26 day active and two-day placebo period. Some physicians also use the 'Quick Start' approach to pill initiation, this allows for immediate ingestion of the first dose of the pill in the office after a negative pregnancy test. This approach disregards the status of the patient's menstrual cycle. A clinical trial has shown that is approach is safe, and results in higher ultimate rate of pill use than the conventional – after the onset of menses approach (61). In general, the efficacy, side effects and cycle control of these new preparations are similar to those with 35 micrograms of estrogen. The "lower" dose pills offer the theoretical advantage of less estrogen and therefore fewer estrogen side effects and medical complications. It remains to be determined if the new "lower" dose pills confer the same non-contraceptive benefits of the "higher" dose pills.

A new oral contraceptive containing 30mcg ethinyl estradiol and 3mg drospirenone, works in a manner similar to other oral contraceptives, effectively inhibiting ovulation and producing cervical mucus that is hostile to sperm motility. Unlike other progestins used in oral contraceptives, drospirenone is an analogue to spironolactone and has biochemical and pharmacologic profiles similar to endogenous progesterone (62). Drospirenone has both antimineralocorticoid and antiandrogenic activity. Its antiandrogenic activity may leads to suppression of undesired symptoms such as acne and hirsutism. Its antimineralocorticoid activity balances the aldosterone-stimulating effects of estrogen, thereby potentially reducing water-retention and weight gain.

Another preparation offers a hormone-free, placebo length of only 2 days. Twenty-one days of 20mcg ethinyl estradiol and 150mcg of desogestrel is followed by 2 days of placebo and 5 days of 10mcg ethinyl estradiol. Within 18 months of use, absence of withdrawal bleeding and intermenstrual bleeding have been reported to occur in 5.5% and 12% of total cycles, respectively. (63) Nearly three-quarters of participants in a large, open-label study reported one or more side effects, including headache, breast pain, dysmenorrheal, and menstrual irregularities.

Psychological/Behavioral effects of hormonal contraception:Few studies have investigated the effects of OCs on behavioral function. Some retrospective studies have shown that women discontinued the use of combined oral OCs due to negative mood changes (occurred in about 30% of women) (64). Women treated with lower doses of progestogen experience fewer symptoms than those treated with higher concentrations. The derivative compounds produced after metabolism of exogenous progestins contribute to the modulation of psycho physiological function. For example, oral micronized progesterone is metabolized to a product (3-alpha, 5-alpha-OH THP) that can cause sedation at high circulating concentrations (65). Furthermore, experimental studies have demonstrated anxiolytic effects of large doses of progesterone, which is mediated by 5-alpha reductase metabolites (66). This effect is observed in women affected by premenstrual dysphoric disorder; symptoms markedly improved during treatment with oral micronized progesterone. Interestingly, vaginal administration of progesterone is not associated with the above anxiolytic effects (67).

Combined non-parentral administrationRecent improvements in steroid hormone delivery have resulted in numerous new hormonal contraceptives methods. Effective, safe contraception is achieved with combination estrogen and progestin delivery via a monthly injection, contraceptive skin patch, and a vaginal ring. The general mechanism of action of these methods is similar to that of combined oral contraceptives. These methods offer the advantage of non-daily administration, relative ease of administration, potential greater compliance and thus potential greater efficacy.

Features of a monthly injectable contraceptive resemble those of the combined oral contraceptive. Monthly combined injectables provide predictable monthly cycle control in a rapidly reversible method upon discontinuation. The combination hormone monthly injectable contraceptive contains 5 mg of estradiol cypionate and 25 mg of medroxyprogesterone acetate (E2C/MPA). After injection, the cypionate ester is cleaved so that the circulating estrogen is similar to the ethinyl estradiol found in oral contraceptives. The monthly injectable is administered during the first five days of a woman's cycle and re-injected every 28 days with a margin of error of five days (23-33 days) (68).

Lunelle was voluntarily recalled from the American market in 2002, however, three clinical trials in the United States have shown that the efficacy of the monthly injectable contraceptive is very comparable to that of combined oral contraceptives (68, 69). More than 7 thousand women participated in clinical trials prior to its FDA approval. Eighty-four percent of patients who received the monthly combination injectable characterized their experience as favorable or very favorable (70). Approximately 90% of responders reported that they would recommend this method of contraception to a friend (71).

Reported side effects associated with this method are similar to that of the combined oral contraceptive pill. Side effects include breast tenderness, gastro-intestinal complaints, emotional liability, acne, and weight change. The number of women experiencing side effects approached 9% although the majority of these side-effects were considered mild. Weight change among those taking the injectable medication follow no predictable pattern compared to those taking the combined OCs. Some women lost weight while others gained weight. Bleeding patterns were well controlled with the combination hormone monthly injectable; breakthrough-bleeding pattern was also similar to that of combined oral contraceptive pills. Over time, bleeding control improved by the fourth cycle. Amenorrhea was uncommon.

Metabolic Effects:Hepatic function, glucose metabolism, and renal function are minimally changed in women using this method of contraception. The monthly injectable produces a median 2.5 mg/dl rise in LDL and a median 7mg/dl reduction in triglycerides. This is in contrast to a 13 mg/dl gain in LDL and a 22.5 mg/dl median gain in triglycerides for women that used oral contraceptive pills (68). There are no observed differences after one year of treatment in terms of clotting factors.

Return to ovulation and fertility is achieved two to three months after discontinuation of this method (72). Return of fertility does not appear to be related to duration of treatment. The predictable pharmokinetics explain its rapid reversibility and its predictable bleeding pattern. Serum estradiol levels reach peak concentration near mid cycle and decline after several days. Estradiol levels fall below the levels sufficient to maintain the endometrium, prompting a withdrawal bleeding, 2-3 weeks after administration (73).

The non-contraceptive benefits of this combined injectable contraceptive to date are unknown. Monthly injections of a combination of estrogen and progesterone regulate hormones in the same way as oral contraceptives. It is therefore likely that they have the same non-contraceptive benefits. Extended follow-up of women using this method will be necessary before long-term health benefits such as protection can be demonstrated.

The once-weekly contraceptive patch delivers 150mcg of norelgestromin, the active metabolite of norgestimate, and 20mcg of ethinyl estradiol daily to the systemic circulation (74), and is currently used by 2% of American women. Typical use includes placement of the patch on the same day of each week for 3 consecutive weeks followed by a patch-free week. Serum levels of the estrogen and progestin components are maintained for 2 days beyond the recommended 7 days of wear. Therefore, patients do not have to change the patch at the exact same time each week.

The patch is composed of 3 layers: an outer protective layer of polyester, a medicated, adhesive middle layer, and a clear, polyester liner that is removed before patch application. Patients can maintain normal activity, including bathing, swimming and heavy exercise while using the patch. It is recommended that wearers avoid use of oils, creams or cosmetics that may interfere with adhesion of the patch.

Compared to OCs with 250mcg norgestimate and 35mcg ethinyl estradiol, the patch suppresses ovulation to a similar degree (74). It is as effective as oral levonorgestrel/ethinyl estradiol in altering cervical mucus and in providing cycle control. The overall and method-failure probabilities of the transdermal patch (through 13 cycles) are 0.7% and 0.4%, respectively (75). Perfect compliance (21 days of consecutive dosing followed by 7 days of no medication) was achieved in 90% of patients in the above study. However, efficacy trials of the patch have shown that participants less than 20 years age were less likely to use the patch correctly than the pill (76). The noncontraceptive effects of trans-dermal administration have not yet been studied, but are expected to be similar to the combined oral contraceptive pill. A recent clinical trial did not demonstrate the same improved continuation rates with the "quick start" method in patch users as was seen in oral contraceptive users (77).

For numerous decades, the vagina has been identified as a potential organ for drug absorption (78, 79). The anatomy of the vagina allows for the easy placement of a ring to achieve this purpose.

A combination estrogen/progestin vagina ring was approved for use in 2001 and is used by 0.3% of US women of reproductive age group. It is a flexible transparent circular tube, 54 mm (2 inches) in diameter and 4 mm (1/4 inch) thick. The ring is made of ethylene vinyl acetate polymer and contains a hormone reservoir that releases 0.120 μg of etonogestrel and 0.015 μg of ethinyl estradiol each day over a three-week period (80). Hormone content in the ring is sufficient to provide a "grace period" of at least 14 additional days (81), so woman can leave it in place for a full month and then immediately replace it to avoid menstruation, if they so desire. Etonogestrel, also called 3-ketodesogestrel, is also a synthetic hormone. It is the active metabolite of desogestrel, the progestin component of commonly used oral contraceptives.

The mechanism of action of a vaginal ring is similar to other hormonal contraceptives. Initiating ring use during the first five days of a normal cycle ensures that ovulation in that cycle is suppressed. Similarly, allowing no more than seven ring-free days each month, and making sure that the ring is in place continuously, with no more than three hours out in one day are also important for efficacy (81). Overall pregnancy rates are reported to be 0.65 per 100 woman-years (all first-year users) (82). This level of effectiveness is similar to that found for women using combined oral contraceptives. Adherence to rules for ring use was very high, with consistent and correct use reported in 90.8% of all cycles. Women using the ring also reported good cycle control, with expected withdrawal bleeding in 98% of cycles, and bleeding at other times in only 6.4% of cycles (82).

The ring can be placed in any position in the vagina that is comfortable. A total of 8% of women note the sensation of the ring in the vagina. If the ring is removed for intercourse it can be cleaned with water and must be replaced within three hours. Risks and adverse reactions possible with use of combined hormonal oral contraceptives also are likely to apply to the vaginal contraceptive ring. The ring does not prevent against sexually transmitted disease. Some women using the ring experienced side effects related to the device itself including vaginal discomfort or problems during intercourse, vaginal discharge, or vaginitis. These device-related problems were reported by 2-5% of women (82). Overall acceptability and tolerability of the ring were very high in the clinical trials performed to date.