Hormonal Contraception Update.

Despite considerable advances in contraceptive technologies in the 20th century, unintended pregnancies remain a substantial public health issue in the United States. Among industrialized nations, the United States has the largest proportion of unplanned pregnancies. Of 6 million pregnancies each year, half are unintended, and 60% of these unintended pregnancies occur in women using contraception. The unplanned pregnancies have a bimodal distribution, with 78% occurring in teenagers and 51% in perimenopausal women. Nearly 1 of every 2 unplanned pregnancies results in elective abortion. These statistics clearly highlight the need to improve contraceptive efficacy and compliance.

With the advent of the 21st century, women have gained access to a multitude of contraceptive options. The goal of this update is to review newer hormonal contraceptive methods to aid the clinician in selecting an appropriate contraceptive method, taking into account the patient's particular preferences.

NEWER ORAL AGENTS

Evolution of Estrogens

In 1960, the first oral contraceptive (OC) was approved by the US Food and Drug Administration (FDA). It contained 150-µg mestranol and 9.5-mg norethynodrel. Although it provided effective cycle control and contraception, women experienced many adverse effects, including weight gain, breast tenderness, bloating, and acne. By 1968, the high incidence of serious adverse health effects (eg, deep venous thrombosis, pulmonary embolism, and hypertension) led to a reduction in the estrogen dose to 50 µg.

By 1970, formulations with ethinyl estradiol (EE) doses as low as 20 µg were introduced. Although they reduced estrogen-related adverse effects, they also led to increased rates of breakthrough bleeding (BTB), as the dose of estrogen is directly related to the degree of endometrial support. The challenge is to balance the tendency toward BTB with the dose-dependent adverse effects of estrogen. In the past 2 decades, OCs with lower EE doses have been developed. Formulations can be found with EE doses as high as 50 µg and as low as 20 µg, but most are in the 30- to 35-µg dose range. Two newer OCs contain a unique dose of 25-µg EE using either triphasic norgestimate (NGM) or triphasic desogestrel (DSG). They provide both the reduced estrogenic effects of the 20-µg EE formulations and the better bleeding profiles of the 30- to 35-µg EE formulations. Both NGM and DSG have comparable safety and contraceptive efficacy, acceptable bleeding profiles, superior cycle control, and acceptable tolerability. The more potent and selective progestins used in these 2 formulations in a cyclic fashion allow further reductions in estrogen without sacrificing cycle control.

Evolution of Progestins

Unlike estrogens, progestins alone are sufficient for contraception. They suppress ovulation, thicken cervical mucus, and render the endometrium unsuitable for implantation of fertilized ovum. In conjunction with estrogen, they contribute to cycle control, changing proliferative endometrium to secretory endometrium. However, progestins are associated with androgenic sequelae, including acne, hirsutism, weight gain, and deleterious effects on lipid and carbohydrate metabolism. These adverse effects led to the development of newer, more selective, and less androgenic progestins that could be used in lower doses.

Initially, the progestins in OCs included norethindrone and its derivatives (eg, norethindrone acetate), levonorgestrel (LNG) and its derivatives, and medroxyprogesterone acetate. They have relatively low progesterone-receptor selectivity and therefore greater systemic androgenic activity. Dose reductions ameliorated unwanted androgenic adverse effects but also affected cycle control. This has led to the development of more selective, less androgenic progestins (eg, NGM, DSG, and drospirenone [DRSP]).

Norgestimate is a 19-nortestosterone derivative with relatively high progesterone-receptor selectivity that suppresses ovulation at doses lower than natural progesterone. It has minimal androgenicity, thus having little impact on carbohydrate metabolism. In addition, NGM does not reduce the favorable effects of estrogen on lipids; OCs containing NGM increase high-density lipoprotein cholesterol, reduce low-density lipoprotein cholesterol, and minimally increase triglycerides.7 The primary active metabolite of oral NGM is norelgestromin, which is currently used transdermally. It has clinical effects similar to those of NGM.

Desogestrel is a 19-nortestosterone derivative, and it has minimal androgenicity. Its active metabolite, etonogestrel, is contained in a contraceptive vaginal ring. Compared with NGM, DSG has slightly higher affinity for androgen receptors and slightly less affinity for progesterone receptors; overall, it is less androgenic than LNG. It provides good cycle control and has minimal effects on carbohydrate metabolism. Like NGM, DSG provides minimal attenuation of estrogen's beneficial effects on lipids. However, DSG increases triglycerides slightly more than NGM. There may be increased risk of venous thrombotic events in patients who use DSG-containing OCs. Data from epidemiological studies suggest an approximate 2-fold increased risk of venous thrombotic events in users of OCs that contain DSG vs other second- and third-generation progestins. However, it is not known whether the formulation of 25-µg EE with DSG is associated with an increased number of venous thrombotic events.

Drospirenone is a novel progestin that has been available for clinical use in the United States since June 2001. An analogue of 17-[alpha]-spironolactone, DRSP has antimineralocorticoid activity comparable with that of natural progesterone. Drospirenone is less androgenic than older progestins because it counteracts estrogen-induced stimulation of the renin-angiotensin-aldosterone system and blocks testosterone from binding to androgen receptors. Because DRSP is a spironolactone analogue, it may have natriuretic properties and may increase serum potassium levels. Thus, patients with concomitant medical problems who receive pharmacologic therapy may require additional monitoring.

Contraindications include renal insufficiency, hepatic dysfunction, and adrenal insufficiency. Women should avoid this progestin if they are taking medications that can increase serum potassium levels (eg, nonsteroidal anti-inflammatory agents, potassium-sparing diuretics, potassium, angiotensin-converting enzyme inhibitors, and angiotensin-II receptor antagonists). A 3-mg DRSP and 30-µg EE formulation has been in clinical use since 2001. A recently approved 3-mg DRSP and 20-µg EE has the unique feature of a 24/4-day format in contrast to the standard 21/7-day format. Rationale for this format stems from emerging evidence that using OCs containing 20-µg EE combined with the newer progestins results in a greater chance of ovulation and pregnancy if the active pills are not restarted within exactly 7 days after the last active pill was taken. Decreasing the duration of the hormone-free interval may also lessen the adverse symptoms some women experience during this time.

Triphasic OCs were developed to reduce the overall progestin dose while still providing effective cycle control and avoiding endometrial proliferation. The per-cycle dose of progestin for the triphasic formulation is generally 0.6 to 0.9 times that of the monophasic product. The 4 triphasic formulations available in the United States all contain EE and 1 of 4 progestins (norethindrone, NGM, LNG, or DSG). In the limited studies available, there appears to be no significant difference between monophasic and triphasic regimens with regard to BTB, side effects profile, and lipid and carbohydrate metabolism. One study identified increased libido and sexual arousal in women using triphasic OCs compared with women using monophasic OCs.

Extended-cycle Contraception

Oral contraceptives were originally designed to mimic the menstrual cycle by producing a monthly withdrawal bleed, and the traditional "Sunday start" allowed women to avoid menstruating on weekends. As early as the 1970s, researchers established that women wanted to control the timing of their menstrual cycles. More recent studies have echoed these findings. A Dutch telephone survey of 1279 women found that most women would choose to menstruate less than once a month. A Harris poll conducted in 2002 found that 1 in 4 respondents considered menstruation to have a negative impact on important aspects of their lives and that 44% preferred to never menstruate. Overall, many women expressed interest in having less frequent periods.

Women who use OCs also may experience unpleasant symptoms or exacerbation of underlying medical conditions during the hormone-free interval of the OC cycle. For this reason, investigators evaluated the safety and efficacy of extending the active pill cycle to decrease the number of withdrawal bleeds. A 2002 study demonstrated that extending the active-pill cycle to 6 to 12 weeks, followed by a 7-day pill-free interval, led to substantial alleviation of menstrual-related complaints and fewer reported adverse effects. Minor adverse effects included mastalgia, bloating, and headache.

In clinical practice, the most common way to provide extended-cycle contraception is to modify the standard use of monophasic OCs. Patients use active pills continuously for 84 days followed by 1 week of inactive pills, which induces a withdrawal bleed approximately 4 times a year. This strategy has been effective with monophasic OCs. Until recently, the use of extended-cycle contraception presented challenges related to packaging issues and insurance reimbursement constraints.

In 2003, the FDA approved a prepackaged extended-cycle monophasic OC regimen (84/7 days) containing 30-µg EE and 0.15-mg LNG. The largest trial of extended-cycle oral contraception was conducted with this product. That study showed that this product was as effective in pregnancy prevention as the conventional therapy (21/7 days), with no difference in duration of withdrawal bleeding. In some patients, unscheduled bleeding with extended-cycle use declined with successive cycles. Extended-cycle contraception now offers women fewer menstrual cycles, ease of administration, and convenient packaging.

NEWER DELIVERY METHODS

Injectable Hormonal Agents

The active ingredient in a new subcutaneous contraceptive is 104-mg medroxyprogesterone acetate (DMPA-104) available in an injectable suspension. It was approved by the FDA in 2004.

In contrast to the original intramuscular version, which contained 150-mg medroxyprogesterone acetate, DMPA-104 comes in prefilled syringes that can be clinician- or self-administered subcutaneously in the thigh or abdomen every 12 to 14 weeks. No dosage adjustment is needed for body weight. DMPA-104 prevents pituitary gonadotropin secretion to inhibit maturation of follicles, thereby inhibiting ovulation. Many women using DMPA-104 will experience altered menstrual bleeding, including heavy bleeding, irregular spotting, irregular menses, and amenorrhea. In contraception trials, 39% of women using DMPA-104 had amenorrhea in the sixth month, and 56.5% had amenorrhea at 1 year. By suppressing gonadotropins, DMPA-104 also suppresses estrogen concentration, making it an effective treatment of endometriosis.

A serious consequence of the estrogen suppression observed with DMPA-104 is loss of bone mineral density. For this reason, long-term use (more than 2 years) of DMPA-104 also requires calcium and vitamin D supplementation and may require monitoring of bone mineral density. Bone mineral density seems to improve in women 17 to 39 years of age after discontinuation of DMPA-104; however, bone loss may not be entirely reversible. The long-term effect of DMPA-104 on bone density in young adolescents (ages 14-16) is less clear and requires further study.

Additional factors to consider when prescribing DMPA-104 are mood disorders and fertility issues. Patients with a history of depression who take DMPA-104 should be monitored for recurrence. There is also a delay of fertility after injections are stopped: median time to ovulation is 10 months, earliest time to ovulation is 6 months, with 80% of women treated with DMPA-104 ovulating by 1 year. Long-term use of DMPA-104 should be considered only after a risk-benefit analysis and only when other methods are inadequate.

Hormonal Intrauterine Contraception

Worldwide, intrauterine contraception is a widely accepted contraceptive method, but it has never attained great popularity in the United States. Although intrauterine devices have been available for 50 years, fewer than 1% of US women use intrauterine contraception. In 2000, the FDA approved an LNG-releasing intrauterine system (LNG IUS), the only hormonal intrauterine device available. The LNG IUS releases 20-µg LNG per day, decreasing to approximately 10 µg by 5 years. The LNG IUS is inserted by a clinician and remains effective for 5 years. This contraceptive method has an efficacy rate of 99.7% and has the additional benefit of suppressing the endometrial lining, thus decreasing menstrual flow. Endometrial atrophy occurs as a consequence of the high endometrial levels of LNG and results in a high rate of amenorrhea. Twenty percent of women have cessation of menses after 1 year. The LNG IUS is an excellent contraceptive option for women experiencing menorrhagia, including those in the perimenopausal transition.

Transdermal Patch

The transdermal contraceptive patch, approved for use in the United States in 2001, delivers continuous daily doses of 150-µg norelgestromin and 20-µg EE. One patch is applied weekly for 3 weeks, followed by a patch-free week. Compliance with the patch is superior to that for OCs; however, the adverse effects profiles of both agents are similar. In November 2005, the FDA updated labeling of the patch with a boldfaced warning to alert clinicians and patients that this product exposes women to higher levels of estrogen than most OCs. Currently, the clinical implications of this increased estrogen exposure are unknown.

The transdermal patch is highly efficacious in women weighting less than 90 kg, whereas there is an increased risk of pregnancy in women exceeding that weight. The patch has been reported to have no effect on body weight or lipid profiles.

The adhesiveness of the patch is excellent; the need for early replacement is less than 3% and is usually related to environmental factors or exercise. Reactions at the site of application occur in as many as 20% of users, but only 2.6% subsequently discontinue use. Within the first few months, BTB is higher than that observed with OCs but decreases over time to a similar rate. The patch is an excellent option for women who find it difficult to comply with a daily pill-taking regimen.

Vaginal Ring

The vaginal ring, approved in 2001 by the FDA, is a novel technology designed to release daily doses of 120-µg etonogestrel, the active metabolite of DSG, and 15-µg EE through a flexible ring inserted vaginally. The hormones are absorbed through the vaginal epithelium, bypassing the first-pass effect on the liver. Serum concentrations of hormones are lower for women using a vaginal ring than those observed with OCs.

The ring is flexible and transparent, with an outer diameter of 54 mm. It can be easily inserted and removed by the patient and is well tolerated by patients and their partners. Efficacy does not depend on exact placement of the ring. It is inserted once per cycle and remains in place for 3 weeks. It is then removed for the last 7 days of the cycle, at which point menses occurs. After 7 days, a new ring is inserted to initiate the next cycle. The vaginal ring provides good cycle control, with BTB reported in less than 1.1% of cycles. Cost should be considered when prescribing this form of contraception because it may cost twice as much as an OC. The most common reasons for discontinuation are menstrual irregularities and device expulsion. Ongoing research is evaluating the ring in extended use for 6 weeks, 12 weeks, or 12 months of continuous use. The vaginal ring offers an excellent option for women who are concerned about compliance with a daily pill-taking regimen and want to avoid barrier contraception or a visible transdermal patch.

Implantable Hormonal Devices

A new implantable form of contraception containing 68-mg etonogestrel is currently available in most countries and is expected to be available in the United States soon. The implant, which lasts for 3 years, prevents pregnancy by inhibiting ovulation and altering cervical mucus, which impedes the passage of sperm.

Within 1 day of insertion, the implant produces a concentration of etonogestrel adequate enough to inhibit ovulation. In clinical trials, women had no ovulations during the first 2 years and only rarely in the third year. Lower concentrations of etonogestrel have been found in obese patients; therefore, heavier women may need a new implant every 2 years. The implant has no significant effect on bone mineral density or lipid metabolism. Since the etonogestrel implant is not biodegradable, it must be removed before insertion of a new one. It can be inserted subdermally on days 1 to 5 of the cycle but cannot be inserted after day 5. If the patient is currently taking OCs, the etonogestrel implant can be inserted on the first day of placebo pills but no later than the last day.

A 3-month follow-up is recommended to evaluate blood pressure and address any questions from the patient. Frequent or prolonged irregular bleeding is a common reason for discontinuation. However, in one study, 29% to 51% of women using the etonogestrel implant experienced infrequent bleeding or amenorrhea. Of those who initially experienced dysmenorrhea, 85% had improvement in symptoms after insertion of the implant. Of women who had acne at the beginning of the study, 59% reported that use of the etonogestrel implant improved or resolved the acne. Cycles usually return to normal within 3 months of removal. Contraindications are similar to those for any progestin-only form of contraception: pregnancy, severe hepatic disease, undiagnosed uterine bleeding, or hypersensitivity to the formulation. This form of contraception should be considered in women who have a contraindication to estrogen.

New Agents on the Horizon

Many of the new contraception technologies are highly accepted by patients and clinicians because of improved tolerability and adverse effects profiles, reversibility, ease of use, and the desire for less frequent dosing while maintaining high levels of efficacy. These factors have driven the trend for continued research in the field of contraception. Several products are either in phase 3 trials or in the new drug application stage with the FDA. An OC in the new drug application stage is a 91-day extended regimen of 84 days of 150-µg LNG and 30-µg EE followed by 7 days of 10-µg EE. Oral contraceptives in phase 3 trials include an 84/7 regimen of 100-µg LNG and 20-µg EE, a product with the progestin dienogest combined with estradiol targeted for perimenopausal women, and a continuous regimen for use up to 1 year with 100-µg LNG and 20-µg EE. A new weekly transdermal patch in phase 3 trials contains the progestin gestodene combined with EE.

CONCLUSION

Contraception is an important topic for women of reproductive age. An armamentarium of agents is available to provide a menu of contraceptive options. With effective counseling, women can make informed decisions and select contraception that is safe, effective, and convenient and that has a low adverse effects profile. Clinicians providing primary care to women must be well informed about the various hormonal contraceptive options and work with each patient to find her optimal regimen.