Drospirenone

Although oral contraceptives (OCs) have been in use for more than 40 years, side effects continue to affect compliance. (1) Thus, 2 questions must be asked: Is there a need for changes in traditional OC regimens? Can new regimens and/or new progestins provide additional benefits to patients?

As evidenced by recent studies, (2-6) new regimens that shorten the hormone-free interval and/or extend the duration of active-pill administration offer the potential to ameliorate side effects and to reduce or eliminate monthly bleeding. The findings of these investigations challenge the accepted 21/7-day regimen for OC administration and document the incidence of hormone-withdrawal symptoms induced by the current 21/7 design.

New progestins are also of potential significance. Until recently, all progestins used in OCs available in the United States were derived from 19-nortestosterone. A new OC uses the progestin drospirenone (DRSP), an analogue of spironolactone, which has different pharmacologic properties that may result in improved side-effect profiles and additional noncontraceptive benefits, some of which will be discussed in the article Management Strategies for PMS/PMDD by Dr Yonkers.

Because OCs have beneficial effects on health conditions associated with menstruation, they are often used to decrease bleeding and cramps and to ensure a predictable bleeding pattern. New regimens and/or agents may increase these benefits further.

21/7 REGIMEN: A HIGH INCIDENCE OF SIDE EFFECTS

Our group investigated the side effects associated with the standard 21/7-day OC regimen in a prospective study. We reported that this schedule of administration leads to many common menstrual complaints that occur during the traditional 7-day hormone-free interval: bleeding, cramps, and premenstrual symptoms (PMS) such as mood swings, breast tenderness, bloating/swelling, headaches, and the increased use of pain medications (TABLE 1). (7) It should be noted that the 21/7 schedule originally was developed to mimic the normal menstrual cycle and reassure women that they were not pregnant.

Furthermore, although OCs frequently are prescribed to treat pelvic pain and dysmenorrhea, the traditional 21/7 regimen has been shown to worsen such symptoms in many patients.

Numerous studies have evaluated the effect of altering the traditional 21/7 regimen, noting that the standard regimen does not provide health benefits, is not necessary from a health perspective, and often induces hormone-withdrawal symptoms. (2,8-14)

21/7 regimen often changed in clinical practice

Discussions with practicing gynecologists and nurse practitioners reveal that most clinicians have recommended an extended active-pill administration for those patients who desire less frequent bleeding or who experience bothersome withdrawal side effects, such as heavy bleeding, headaches, pain, or PMS.

Alterations in the 21/7 regimen have been well accepted by patients, as reported in several studies by our group, which will be described subsequently in this article. (2,14)

21/7 regimen and follicular growth

Physiologically, the standard 7-day hormone-free interval has been shown to permit follicular growth: Follicle-stimulating hormone levels increase on day 3 or 4, which allows for follicular recruitment and estradiol production. The 7-day interval also provides less ovarian suppression than is seen with shorter hormone-free intervals. (8,9)

If active pills are initiated after the 7-day hormone-free interval, the estrogen levels that have begun to rise will decline slowly over the next 2 weeks, reaching their lowest levels during the last week of active-pill administration. This may explain why, for women on OCs, withdrawal symptoms often begin during the last week of active-pill administration. (7) The 21/7 regimen increases the potential for follicular cysts. (8,9,15)

NONCONTRACEPTIVE HEALTH BENEFITS OF OC USE

The potential benefits associated with OC use are particularly significant with respect to modern women's reproductive patterns. It is generally acknowledged that, compared with earlier generations, women today experience menarche at an earlier age and postpone childbearing. Women also tend to have fewer children, breastfeed for a shorter period of time, and enjoy a longer life span. Thus, compared with their ancestors, women experience many more menstrual cycles and, therefore, a higher risk for menorrhagia, irregular bleeding, dysmenorrhea, PMS, menstrual migraines, and perimenopausal bleeding and symptoms.

OC use increasing among perimenopausal women

Over a lifetime, the menstrual patterns of contemporary women may increase the risk for conditions associated with menstruation such as anemia, endometriosis (along with pain and infertility), ovarian cysts, and ovarian cancer.

In this light, it may be significant that according to a 1995-2000 survey, an increasing number of women are using OCs, with the most significant increase among perimenopausal women. (16) Many women may use OCs for the noncontraceptive benefits rather than for the purpose of contraception.

Importantly, tubal ligation, which is often used by women who do not wish to bear more children, does not offer protection from future gynecologic problems. A 2003 case-control study evaluated the effect of OCs versus that of tubal sterilization on functional ovarian cysts in 392 women, each of whom had a functional ovarian cyst, and 623 age-matched, randomly selected controls from a health-maintenance organization's enrollment files. Low-dose OC ([less than or equal to] 35 [micro]g ethinyl estradiol [EE] monophasic or multiphasic OCs) had little or no effect on the development of functional ovarian cysts while tubal sterilization increased the risk. (15)

NEW OC REGIMENS

Recent research has focused on reducing side effects, decreasing or eliminating monthly bleeding, and improving quality of life. Newer regimens are being developed to shorten the pill-free interval, extend the number of active-treatment days, or add estrogen during the hormone-free interval.

Patient acceptance of new regimens

A retrospective review of medical records for 292 women confirmed the acceptability of altering the 21/7-day regimen. (2) All of the women had been given the option of altering the traditional 21/7 regimen. Only 25 (9%) elected to continue the standard 21/7 regimen; others chose to extend the active-treatment days and/or reduce the duration of the pill-free interval, largely because of menstrual symptoms. Subsequently, 19% discontinued OC use altogether, primarily because they desired pregnancy.

More than half (59%) continued the use of the extended regimen, with a typical active-pill duration of 12 weeks and a hormone-free duration of 0-7 days, with a median of 5 days. A mere 13% returned to the 21/7 regimen; many of them cited the added cost of the extended regimen.

Benefits of a shorter hormone-free interval

The utility of a flexible regimen with respect to improvement in menstrual symptoms and breakthrough bleeding was confirmed in a retrospective study evaluating the incidence of breakthrough bleeding in 220 patients on extended regimens. (3) In this study, a shortened hormone-free interval was used to manage bothersome or persistent breakthrough bleeding.

Analysis of follow-up data was obtained on 181 patients who were between 14 and 52 years of age. TABLE 2 shows baseline symptoms associated with the hormone-free interval. Among patients who shortened the hormone-free interval and extended active-OC administration, symptoms were reduced significantly.

Sixty percent of those who shortened the hormone-free interval and extended the use of active pills maintained this schedule over 2 years without serious side effects or pregnancy. Among those who opted for an extended active-pill administration, 88% chose a hormone-free interval of 0 to 4 days. Approximately 50% adopted a pattern of OC administration of 13 weeks or more of active-pill use. Only 6% of patients returned to the traditional 21/7 regimen. A total of 43 patients extended and subsequently discontinued OC use. Most did so for reasons other than side effects (eg, a desire to become pregnant, onset of menopause, need to undergo a hysterectomy for fibroids).

Increasing the number of active pills reduces the frequency of hormone-withdrawal symptoms. Shortening the hormone-free interval provides greater ovarian suppression.

Recommendations for modifying the 21/7 regimen

Decisions regarding duration of active-pill administration and the hormone-free interval must be individualized to meet the needs of each specific patient. Those women who desire the reassurance of monthly withdrawal bleeding may prefer a regimen such as 24/4 that provides increased ovarian suppression and reduces side effects. Those who wish to have fewer periods may opt for an extended regimen, with or without reduction of the hormone-free interval based on the severity of menstrual-related symptoms and personal preferences.

NEW PROGESTINS

New progestins also provide an opportunity to decrease side effects and provide noncontraceptive benefits (FIGURE 1). One new progestin, DRSP, is an analogue of spironolactone. Both DRSP and spironolactone exhibit antiandrogenic and antimineralocorticoid activity; DRSP also has progestogenic properties.' Significantly, spironolactone has been shown to be effective in treating PMS, as Dr Yonkers' article, Management Strategies for PMSIPMDD, discusses in detail.

[FIGURE 1 OMITTED]

Other newer progestins derived from 19nortestosterone have been developed to improve side-effect profiles. Third-generation 19-nortestosterone derivatives, such as desogestrel and norgestimate, have lower levels of androgenicity than does levonorgestrel; however, they are not antiandrogenic. (17)

DRSP and acne

Although all OCs that contain estrogen are useful in treating mild-to-moderate acne, 2 OCs (1 containing norgestimate and the other containing norethindrone acetate) are approved by the US Food and Drug Administration for the treatment of mild-to-moderate acne. (18,19)

Still, only 2 progestins have antiandrogenic properties: DRSP and cyproterone acetate (CPA) (approved for treatment of acne in many countries, but not approved for use in the United States). The latter progestin has been shown to be effective in treating pronounced forms of ache and those accompanied by seborrhea or by inflammation or formation of nodes (acne papulopustulosa, acne nodulocystica), androgenetic alopecia, and mild forms of hirsutism.

The effects of DRSP and CPA were compared in a recent study. (5) Over 9 treatment cycles, 84 women received DRSP, 3 mg, plus EE, 30 [micro]g, and 43 women used CPA, 2 mg, with EE, 35 [micro]g. At the end of the study, the median total acne lesion count was reduced by 62.5% in the DRSP/EE group and 58.8% in the CPA/EE group (FIGURE 2).

[FIGURE 2 OMITTED]

Another study, by Thorneycroft and colleagues, compared DRSP/EE with norgestimate/EE. (20) The DRSP/EE regimen showed a greater effect in reducing total lesion count (-3.3% [95% confidence interval, -6.5 to-0.1; P = .02]) and an increased therapeutic effect on facial acne (+3.6% ]95% confidence interval, 0.8 to 6.3, P = .006]) by cycle 6.

DRSP and water excretion

Estrogen-related water retention can occur with OCs that contain progestins derived from 19-nortestosterone, and is thought to contribute to the perception of weight gain, resulting in noncompliance with OC use. However, DRSP exhibits antimineralocorticoid activity at the aldosterone receptor level, thereby increasing sodium and water excretion. (21)

One study examined water-related weight change associated with 20C formulations (FIGURE 3). Over 26 cycles, weight change was monitored in 887 women randomized to DRSP, 3 mg, plus EE, 30 [micro]g, or to desogestrel (DSG), 150 [micro]g, plus EE, 30 [micro]g. The women using DSG/EE experienced a small weight gain (mean range: +0.02 kg to +0.89 kg). (6) The mean weight change in the DRSP/EE group was slightly below the baseline weight for 24 of 26 cycles (range: -0.01 kg to -0.15 kg). There was a statistically significant difference between the 2 study groups with respect to change in mean body weight during cycles 1-13 (P = .0001) and in cycles 14-26 (P = .0009).

[FIGURE 3 OMITTED]

CONCLUSION

The traditional OC schedule of administration is being examined and challenged. For women who prefer the reassurance of monthly bleeding, the ideal regimen may be a shorter hormone-free period. The duration of active-pill administration can be extended with any OC. However; the effects of progestogenic agents used in OCs differ markedly. Differentiation among these effects provides clinicians with opportunities to improve side effects associated with menstruation and improve other health conditions. Progestogenic agents with antiandrogenic and antimineralocorticoid properties offer the potential to treat androgen-related health conditions and help reduce the water retention commonly experienced with OC use.

For women who prefer to extend the OC regimen, selection of the agent most appropriate for the individual patient may be guided by the potential either to avoid side effects commonly associated with OCs or to gain additional health benefits.

REFERENCES

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